KRAS g12d mutation targeting compounds

Abstract

The present disclosure is directed towards a 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. The present disclosure also relates to pharmaceutical compositions comprising the compound of formula (I), or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, and methods of treatment of diseases, such as cancer, associated with KRAS G12D mutation.

Description

[0001] KRAS G12D Mutation Targeting Compounds

[0002] TECHNICAL FIELD

[0003] The present disclosure is directed towards 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 cancer associated with the KRAS G12D mutation using said targeting compounds.

[0004] BACKGROUND

[0005] The KRAS gene provides instructions for the production of the KRAS protein, which relays signals that promote cell division and growth (proliferation).

[0006] The KRAS protein is a GTPase, binding to guanosine triphosphate (GTP) and converting it to guanosine diphosphate (GDP) through hydrolysis. The gene oscillates between two forms, an ‘active’ form in which it is bound to GTP and able to transmit signals to promote proliferation, and an ‘inactive’ form in which it is bound to GDP, following GTP to GDP conversion, and unable to transmit signals. The KRAS protein typically maintains a balance between inactive and active states so that cell proliferation is appropriately regulated.

[0007] When this KRAS protein is damaged, a KRAS mutation may occur, causing the gene to mutate and change form. The most common KRAS mutations are known as KRAS G12C, G12D and G12V mutations. The ‘G12X’ nomenclature relates to the amino acid position (12) on the KRAS protein at which the mutation occurs, as well as the amino acid substitution involved in the mutation (X). Typically, these mutated (changed) forms of the KRAS protein (KRAS mutations) mean that the normal function of the gene is altered. The reversible nature (GTP to GDP activity) of the KRAS protein is impaired such that it remains predominantly in the active state and directs cells to proliferate in an uncontrolled manner.

[0008] KRAS mutations are associated with a number of cancers, including non-small cell lung cancer, colorectal cancer, and pancreatic cancer. It is one of the most frequently mutated gene families in human cancers. The conformational changes to the KRAS protein discussed above result in the protein directing cells to proliferate in an uncontrolled manner, leading to tumour formation and the spread of cancer.

[0009] KRAS mutated proteins were initially considered as ‘undruggable’ due to the failure to identify specific and potent molecules that could directly target the KRAS protein. However, in recent years, KRAS G12C inhibitors have been identified. These inhibitors typically work by covalently ‘tethering’ to a nucleophilic cysteine at position 12, i.e., G12C, of the active site of the KRAS protein whilst it is in the ‘inactive’ state, irreversibly stabilising this state and preventing the KRAS protein with the KRAS G12C mutation from instructing the excessive proliferation of cells.

[0010] However, a selective inhibitor has yet to be approved that can target the more prevalent and oncogenic mutation of the KRAS protein, KRAS G12D.

[0011] Identified KRAS G12C inhibitors cannot be utilised, as the point of mutation and thus target of the inhibitor differs greatly in terms of chemistry between KRAS G12C (cysteine) and KRAS G12D (aspartic acid). The configurations of other regions of the complex structure of the KRAS protein must also be considered. In addition, when compared to KRAS G12C mutations, selective inhibition of KRAS G12D mutations presents a significant challenge due to the requirement of the inhibitors to selectively bind with high enough affinity typically without the benefit of covalent interaction (aspartic acid binding is typically considered to require a non-covalent interaction).

[0012] There is therefore a need for new KRAS G12D mutation targeting compound capable of targeting the KRAS G12D mutation to enable treatment of diseases associated with the KRAS G12D mutation, such as cancer.

[0013] It is an object of the present disclosure to provide a solution to the above-mentioned or other problems.

[0014] BRIEF SUMMARY

[0015] According to a first aspect of the present disclosure there is provided a compound of formula (I):

[0016] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein R1 is selected from C CH or C1.4 alkyl;

[0017] R2 is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and monocyclic 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from C1-4 alkyl and halogen; n is from 1 to 6; m is 1 or 2; and

[0018] Li is selected from the following (Ila), (lib) and (lie): where R4and Re are each independently be selected from H or F; and R7is Ci.4alkyl. According to a second aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined above for the first aspect of the present disclosure, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, and a pharmaceutically acceptable carrier or excipient.

[0019] According to a third aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for use as a medicament.

[0020] According to a fourth aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for use in therapy or prophylaxis of a disease associated with the KRAS G12D mutation, such as cancer associated with the KRAS G12D mutation.

[0021] According to a fifth aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for the manufacture of a medicament for use in the treatment of a disease associated with the KRAS G12D mutation, such as cancer associated with the KRAS G12D mutation.

[0022] According to a sixth aspect of the present disclosure, there is provided a method of treating a disease associated with the KRAS G12D mutation, such as cancer associated with the KRAS G12D mutation, in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure.

[0023] According to a seventh aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for use in the treatment of a disease associated with the KRAS G12D mutation, such as cancer associated with the KRAS G12D mutation.

[0024] According to an eighth aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for use in the degradation of a KRAS protein having the KRAS G12D mutation.

[0025] According to a ninth aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for use in the degradation of a KRAS G12D mutation in a cell.

[0026] According to a tenth aspect of the present disclosure, there is provided a compound of formula (I) as defined above for the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above for the second aspect of the present disclosure, for use in the degradation of a KRAS G12D mutation in a KRAS protein.

[0027] The present disclosure finds application of the compounds of the present disclosure in the treatment of subjects with a disease, such as cancer, in which the KRAS G12D mutation has been diagnosed or detected.

[0028] DEFINITIONS

[0029] Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

[0030] As used herein, the term "KRAS G12D mutation" refers to mutation at the 12th amino acid glycine of the KRAS protein. The 12th amino acid glycine is changed to aspartic acid. Position of the mutation may be in reference to the wild-type KRAS protein, for example Uniprot accession number P01116 (SEQ ID NO: 1). The mutation is an altered form of the KRAS protein, and normal function is impaired. The mutated protein may be referred to as a "KRAS G12D mutated protein". As discussed above, the reversible nature (GTP to GDP activity) of the KRAS protein is impaired such that it remains predominantly in the active state and directs cells to proliferate in an uncontrollable manner. The term is well known in the art. As used herein, the term "disease associated with the KRAS G12D mutation" or "cancer associated with the KRAS G12D mutation" refers to a disease or cancer in which the KRAS G12D mutation has been diagnosed or detected, in any amount. This is typically done by PCR based KRAS sequencing of clinical samples.

[0031] As used herein, the term “wild-type” refers to the most common form, appearance or strain of a KRAS protein existing in nature. This is the normal, non-mutation version of the KRAS protein common in nature. This means that there is no mutation of the 12th amino acid of the KRAS protein. The sequence of the wild type KRAS protein can be found at Uniprot accession number P01116:

[0032] MTEYKLVWGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQWIDGETCLLDILDTAGQEE YSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRT VDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCII M (SEQ ID NO:1 ).

[0033] 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, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.

[0034] As used herein, the term "treatment" or "treating" includes an intervention (e.g. the administration of a compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, to a subject) which ameliorates or lessens the proliferation of cells and formation of tumours and the spread of a disease such as cancer through removal of (or lessening the impact of) its cause(s) (for example, through degradation of the KRAS G12D mutated protein of the KRAS protein). In this case, the term is used synonymously with the term “therapy”. Thus, the treatment of a disease, such as cancer, associated with the KRAS G12D mutation according to the disclosure may be characterized by the (direct or indirect) action of the compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. Thus, the compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, find application in methods of degrading the KRAS G12D mutation, preventing cell proliferation, decreasing tumour formation (or even shrinking tumour size), and preventing or reducing the spread of disease such as cancer.

[0035] Additionally, the term "treatment" or "treating" includes an intervention (e.g. the administration of a compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, to a subject) which prevents or delays the onset or progression of a disease associated with the KRAS G12D mutation such as cancer or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term “prophylaxis” or “prevention”.

[0036] The term "subject" (which is to be read to include "individual", "animal", "patient" or "mammal" where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on. Preferably, in the context of the present disclosure, the subject is a human.

[0037] The term ‘degrades’, ‘degrading’, or ‘degradation’, or like terms as used herein, in relation to the KRAS G12D mutation is meant the partial or complete physical breakdown of the unfavourable KRAS G12D protein. The KRAS G12D mutated protein is depleted and no longer directs cells to proliferate in an uncontrollable manner.

[0038] As used herein, an "effective amount" or a "therapeutically effective amount" of a compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure alone and can be used in combination with other agents.

[0039] The term "pharmaceutically acceptable salt" as applied to the compounds of formula (I) according to the first aspect of the disclosure defines any organic or inorganic acid addition salt of the free base which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit / risk ratio. Suitable pharmaceutically acceptable salts are well known in the art. Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4- aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxybenzoic, 2- acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p-toluenesulfonic acid).

[0040] The term “solvate” as applied to the compounds of formula (I) according to the first aspect of the disclosure means a physical association of the compound with one or more solvent molecules, whether organic or inorganic. This physical association can include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. “Solvate” encompasses both solutionphase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates and the like. Methods of solvation are generally known in the art.

[0041] The term “hydrate” as applied to a compound of formula (I) according to the first aspect of the disclosure refers to the compound when it is associated with water in the molecular form, i.e., in which the H — OH bond is not split, and may be represented, for example, by the formula R H2O, where R is a compound of formula (I) according to the first aspect of the disclosure. A given compound may form more than one hydrate including, for example, monohydrates (R H2O) or polyhydrates (R nH2O wherein n is an integer >1) including, for example, dihydrates (R 2H2O), trihydrates (R-3H2O), and the like, or hemihydrates, such as, for example, R n / 2H2O, R n / 3H2O, R n / 4H2O and the like wherein n is an integer. As used herein, the term "prodrug" as applied to a compound of formula (I) according to the first aspect of the present disclosure means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I) according to the first aspect of the present disclosure. The reference by Goodman and Gilman (The Pharmaco- logical Basis of Therapeutics, 8 ed, McGraw-HiM, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs of a compound of formula (I) according to the first aspect of the present disclosure are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs of the compounds of formula (I) according to the first aspect of the present disclosure include those compounds wherein the amino group(s) of the compound of formula (I) according to the first aspect of the present disclosure is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a free amino. The term includes all regioisomers thereof.

[0042] In its broadest aspect, the present disclosure contemplates all optical isomers of the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof.

[0043] In its broadest aspect, the present disclosure contemplates all optical isomers, racemic forms, enantiomers and diastereoisomers of the compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, as described herein. Those skilled in the art will appreciate that the compounds may be produced in optically active and racemic forms. If a chiral centre or another form of isomeric centre, such as a stereocentre, is present in a compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, containing a chiral or stereocentre (or multiple chiral or stereo- centres) may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. Thus, references to particular compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, encompass a mixture of diastereoisomers, individual diastereoisomers, a mixture of enantiomers, as well as individual enantiomers.

[0044] Therefore, the present disclosure contemplates all optical isomers and racemic forms thereof of the compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, and unless indicated otherwise (e.g. by use of dash-wedge structural formulae) the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted. In cases where the stereochemical form of the compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, is important for pharmaceutical utility, the disclosure contemplates use of an isolated eutomer.

[0045] All references to particular chemical compounds herein are to be interpreted as covering the compounds per se, and also, where appropriate, or a pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof.

[0046] The term “Ci-4alkyl” denotes a straight or branched alkyl group having from 1 to 4 carbon atoms. For parts of the range Ci -4al kyl all subgroups thereof are contemplated such as Ci- salkyl, Ci-2alkyl, C2-4alkyl, C2-3alkyl and C3-4alkyl. Examples of said Ci-4alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and terf-butyl.

[0047] “Halogen” refers to fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine, most preferably fluorine.

[0048] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0049] The terms “heteroaryl” and “heteroaromatic ring” denote a monocyclic aromatic ring comprising 5 to 6 ring atoms in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen. The heteroaryl ring may contain up to 4 heteroatoms, such as up to 3 heteroatoms, or up to 2, for example a single heteroatom. The said heteroaromatic ring may be attached to the rest of the molecule through either a heteratom or a carbon atom of the ring system. Examples of heteroaryl groups include but are not limited to furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, oxatriazoly, thiazolyl, isothiazolyl, tetrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and thiadiazolyl. In some embodiments, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0050] It will be appreciated that a chemical group(s) or moiety is attached to the rest of the molecule by the atom or group listed first. In some instances, the feature also denotes the attachment of chemical groups or moieties to each other, or to the rest of the molecule. In formulas, the feature of a wave line, .also denotes the attachment of a chemical group(s) or moiety to each other, or to the rest of the molecule.

[0051] The term "one or more substituents” preferably refers to one or two substituents.

[0052] DETAILED DESCRIPTION

[0053] The present disclosure provides the solution to a previously unmet need for a KRAS G12D mutation targeting compound for the treatment of KRAS G12D mutation, including cancer associated with the KRAS G12D mutation.

[0054] The compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, function as a proteolysis targeting chimera (PROTAC) composed of two protein-binding molecules (left- and right-hand sides of the compound as depicted in formula (I)) joined by a linker. The linker includes Li shown in formula (I).

[0055] The compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, functions by inducing selective intracellular proteolysis. As depicted in formula (I), the left-hand side of the compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, binds to the unfavourable KRAS G12D mutation, and is connected to an E3 ubiquitin recognition unit (the right-hand side of the compound of formula (I)) via a central linker (including Li, shown in formula (I)).

[0056] The left-hand side of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, as shown below:

[0057] The right-hand side of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, as shown below:

[0058] The left-hand side of the compound of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, interacts with the protein of interest, in this case, the KRAS G12D protein when it is a KRAS G12D mutated protein. The right-hand side of the compound of formula (I), is an E3 ubiquitin recognition unit, which is able to interact with an E3 ubiquitin ligase protein. The left- and right-hand sides are joined by a central linker (including Li shown in formula (I)).

[0059] Ultimately, the structure and configuration of the compound of formula (I) according to the first aspect of the present disclosure means that the E3 ubiquitin recognition unit (right-hand side of the compound of formula (I) as depicted) can interact with an E3 ubiquitin ligase protein and facilitate the transfer of ubiquitin from a ubiquitin carrier to the target KRAS G12D mutation, advantageously resulting in selective degradation of the KRAS G12D mutation. The compound of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, brings the unfavourable KRAS G12D mutated protein into close proximity with the E3 ubiquitin ligase protein to catalyse the degradation thereof. This advantageously reduces the instance of the unfavourable KRAS G12D mutated protein and lessens the proliferation of cells and formation of tumours and the spread of cancer through removal of (or lessening the impact of) its cause(s).

[0060] Advantageously, the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, are selective for the degradation of the KRAS G12D mutation, in particular, and advantageously, over KRAS G12C mutations and KRAS wild type.

[0061] The compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, demonstrate potent effects on the degradation of the KRAS G12D mutated protein.

[0062] The advantageous effects of the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, with respect to potency and selectivity for the degradation of the KRAS G12D mutated protein are attributed by the present inventors to the structure and configuration of the compound of formula (I). The present inventors consider that the structure and configuration of the linker between the left- and right-hand sides of the compound of formula (I), or pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, as depicted, plays a significant role in this. In particular, the structure and configuration of the linker, including Li as described herein.

[0063] The linker of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, is shown below:

[0064] The linker of the compound of formula (I) according to the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, begins on the left-hand side of the compound, and includes, the cyclopropyl (m is 1 ) or cyclobutyl (m is 2) aliphatic group. The linker links the left-hand side of the compound to the right-hand side of the compound as discussed above. The linker ends at the right-hand side of the molecule and includes, the (CH2)nand CO moiety. The structure of this linker is important to achieving the advantages of the disclosure as set out above. As described in more detail below, it is the structural significance of an aliphatic group linked to a tertiary amine linkage (part of Li), preferably connected to an oxygen atom (part of Li), and to a carbon chain (CH2)n which means the linker is of sufficient length and forms a structural configuration optimal to interact with the E3 ubiquitin ligase protein and form a productive ternary complex.

[0065] The structure of the compound of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, ensures that the compound binds securely and strongly to the target KRAS G12D mutation and operable to bring an E3 ubiquitin ligase protein into connection therewith to selectively, and potently, degrade the KRAS G12D mutated protein.

[0066] For compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, Ri , R2, Li, m and n, may be as described below. Each of Ri , R2, Li , m and n, as described below, is applicable to all embodiments of the first aspect of the present disclosure.

[0067] Ri

[0068] Ri is selected from C=CH or Ci-4alkyl.

[0069] Preferably, Ri is C=CH, methyl or ethyl. More preferably, Ri is C=CH or ethyl. More preferably, Ri is C=CH.

[0070] R2

[0071] R2is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci-4alkyl and halogen. Preferably, R2is selected from a phenyl optionally substituted with one or more halogen substituents, such as fluorine, and a 5- or 6-membered heteroaryl optionally substituted with one or more Ci .4alkyl substituents.

[0072] Preferably, R2is selected from a phenyl or a monocyclic 5-membered heteroaryl, wherein the phenyl and 5-membered heteroaryl are optionally substituted with one or more substituents selected from Ci-4alky I and halogen. More preferably, R2is selected from a phenyl optionally substituted with one or more halogen substituents, such as fluorine, and a 5-membered heteroaryl optionally substituted with one or more Ci .4alkyl substituents.

[0073] More preferably, R2is selected from a phenyl or thiazole optionally substituted with one or more substituents selected from Ci4alkyl and halogen.

[0074] More preferably, R2is a phenyl optionally substituted with one or more halogen substituents, such as fluorine, or a thiazole optionally substituted with one or more Ci -4alkyl substituents.

[0075] For all descriptions of R2above, the phenyl or 5- or 6-membered heteroaryl is preferably substituted with the stated one or more substituents.

[0076] More preferably, R2is a phenyl substituted with one or more halogen substituents, such as fluorine, or a thiazole substituted with one or more Ci4al kyl substituents.

[0077] For all descriptions of R2above, the halogen is preferably fluorine.

[0078] More preferably, R2is selected from a compound of formula (Illa) or (II I b):

[0079] More preferably, R2is a compound of formula (Illa). n n is from 1 to 6.

[0080] Preferably, n is from 1 to 4. More preferably, n is 1 to 3. Most preferably, n is 2.

[0081] Hl m is 1 or 2. Preferably, m is 1 . Li

[0082] Li is selected from the following (Ila), (lib) and (lie): where R4and R6are each independently selected from H or F; and

[0083] R7is Ci-4alkyl.

[0084] It will be appreciated that the carbon atom to which R4or Re is attached in (Ila) and (lib) also has a H attached thereto.

[0085] Preferably, R7is methyl or ethyl. More preferably, R7is methyl.

[0086] (Ila), (lib) and (lie) are advantageous as they contain a tertiary amine. It is this tertiary amine that is protonated at physiological pH (the pH typically prevailing in the human body, around 7.4) and interacts with E62 of KRAS more strongly.

[0087] Preferably, Li is of formula (Ila) or (lib), more preferably formula (lib).

[0088] Preferably, when Li is of formula (Ila), R4is F.

[0089] Preferably, when Li is formula (lib), either or both of R4and R6are F. More preferably, both of R4and Re are F. Most preferably, Re is H, and R4is F. It will be appreciated that when R4and Re are not selected to be F, they are H.

[0090] Li is thus preferably of formula (lid):

[0091] The presence of an electron withdrawing group (F) on the piperidine ring of formula (Ila) or (lib) advantageously reduces the pKa of the tertiary amine (piperidine nitrogen). Preferably, the electron withdrawing group (F) reduces the pKa of the tertiary amine (piperidine nitrogen) to less than 10, such as less than 8. However, this does not reduce potency of the compound of formula (I), or pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, according to the first aspect of the present disclosure. Cellular activity and KRAS G12D selectivity of the compound of formula (I) according to the first aspect of the present disclosure is improved through one or both of R4and R6being independently selected to be F.

[0092] When one or both of R4and Re being independently selected to be F, such as, for example, when Li is of formula (lid) shown below, the compound of formula (I), according to the first aspect of the present disclosure , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, may be a mixture of diastereomers - cis and trans, or may be a mixture of enantiomers, e.g. a mixture of cis enantiomers or mixture of trans enantiomers, or may be a cis or trans enantiomer. Preferably, the compound of formula (I), according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, may be a mixture of cis enantiomers or a cis enantiomer. The presence of the substituent F introduces chirality into the compound of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. The present disclosure thus encompasses this mixture of diasteroeisomers, or mixture of enantiomers as detailed above, for all compounds of formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, one or both of R4and Re being independently selected to be F.

[0093] Accordingly, the following embodiments of the first aspect of the present disclosure are contemplated.

[0094] According to an embodiment, the first aspect of the present disclosure comprises a compound of formula (la):

[0095] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein R1 is selected from C=CH or Ci -4alkyl;

[0096] R2is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci .4alky I and halogen; n is from 1 to 6; and

[0097] Li is selected from the following (Ila), (lib) and (lie): where R4and R6are each independently selected from H or F; and R? is Ci-4alkyl.

[0098] For this embodiment, preferred Ri , R2, R4, Rs and R7, Li, and n groups or values may be as described above. According to a further embodiment, the first aspect of the present disclosure comprises a compound of formula (lb) or (Ic): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Ri is selected from C CH or Ci-4alkyl;

[0099] R2 is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci _4alky I and halogen; n is from 1 to 6; and

[0100] R4 and Re are each independently selected from H or F. For this embodiment, preferred Ri, R2, R4, and R6, and n groups or values may be as described above.

[0101] According to a further embodiment, the first aspect of the present disclosure comprising a compound of formula (Ic): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein R1 is selected from C CH or Ci-4alkyl;

[0102] R2 is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci .4alkyl and halogen; n is from 1 to 6; and

[0103] R4and R6are each independently selected from H or F.

[0104] For this embodiment, preferred R1, R2, R4, and Re, and n groups or values may be as described above.

[0105] According to a further embodiment, the first aspect of the present disclosure comprising a compound of formula (Id):

[0106] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Ri is selected from C=CH or Ci _4alkyl; R2is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci _4alkyl and halogen; and

[0107] R4and Re are each independently selected from H or F. For this embodiment, preferred Ri, R2, R4, and R6groups may be as described above.

[0108] According to a further embodiment, the first aspect of the present disclosure comprising a compound of formula (le): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein R2is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci-4alkyl and halogen; and R4 and Re are each independently selected from H or F.

[0109] For this embodiment, preferred R2, R4, and Re groups may be as described above.

[0110] According to a further embodiment, the first aspect of the present disclosure comprising a compound of formula (If): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein R4 and Re are each independently selected from H or F.

[0111] For this embodiment, preferred R4 and Re groups may be as described above.

[0112] Preferably, the compound of formula (I), or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, according to the first aspect of the present disclosure is selected from the following compounds:

[0113]

[0114]

[0115] More preferably, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, according to the first aspect of the present disclosure is selected from:

[0116] A compound of formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or a pharmaceutical composition according to the second aspect of the present disclosure may be used in the treatment of disease associated with the KRAS G12D mutation, such as cancers associated with the KRAS G12D mutation. Thus, the present disclosure contemplates the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, as described herein, for use in medicine (e.g. for use in treatment or prophylaxis / prevention), methods of medical treatment or prophylaxis involving the administration of the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, as described herein. The present disclosure also contemplates the administration of pharmaceutical compositions comprising the compounds of formula (I) according to the first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0117] It will be appreciated by a skilled person that the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, are KRAS G12D mutation targeting compounds. They selectively degrade the KRAS G12D mutated protein. They provide treatment for diseases associated with the KRAS G12D mutation, such as cancer associated with the KRAS G12D mutation, by binding to and degrading the KRAS proteins displaying this KRAS G12D mutation (the KRAS G12D mutated proteins). Degradation of the KRAS G12D mutations means that proliferation of cells is prevented or significantly reduced, such that, for example, the growth of a tumour decreases (or even shrinks in size), and the spread of disease such as cancer is reduced. The compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, can therefore be considered to be anti-tumour agents.

[0118] The compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical composition according to the second aspect of the present disclosure, may target any disease associated with the KRAS G12D mutation, including any cancer associated with the KRAS G12D mutation.

[0119] Preferably, the KRAS G12D mutation may be diagnosed or identified prior to administration of the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or prior to administration of the pharmaceutical composition according to the second aspect of the present disclosure.

[0120] Various types of malignancies may display the KRAS G12D mutation. Cancers typically associated with the KRAS G12D mutation 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 leukaemia and breast cancer, ovarian cancer, and other gastrointestinal cancers such as oesophageal, and gastroesophageal junction adenocarcinoma. Accordingly, the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical compositions according to the second aspect of the present disclosure are particularly effective at treating cancer associated with the KRAS G12D mutation, in particular 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 leukaemia and breast cancer, ovarian cancer, and other gastrointestinal cancers such as oesophageal, and gastroesophageal junction adenocarcinoma, associated with the KRAS G12D mutation.

[0121] Preferably, the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical compositions according to the second aspect of the present disclosure, are used to treat any disease associated with the KRAS G12D mutation, such as any cancer associated with the 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 leukaemia and breast cancer, ovarian cancer, and other gastrointestinal cancers such as oesophageal, and gastroesophageal junction adenocarcinoma, associated with the KRAS G12D mutation.

[0122] Preferably, the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical compositions according to the second aspect of the present disclosure, are used in the treatment of disease associated with KRAS G12D mutation, such as cancer associated with KRAS G12D mutations, in the human body. However, they may also be used in the treatment of disease associated with the KRAS G12D mutations, such as cancer having KRAS G12D mutations, in the animal body. In particular, the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical compositions according to the second aspect of the present disclosure, can be used to treat commercial animals such as livestock. Alternatively, the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical composition according to the second aspect of the present disclosure can be used to treat companion animals such as cats, dogs, etc. For the compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, or the pharmaceutical compositions according to the second aspect of the present disclosure, the dosage of the compound of formula (I) administered will vary with, for example, the mode of administration, the treatment desired, the type of disease such as cancer, and the combinational regimen (such as in combination with chemotherapy or radiation.

[0123] The size of the dose for therapeutic purposes of compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, will naturally vary according to the nature and severity of the cancer, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0124] Compounds of formula (I) according to the first aspect of the present disclosure may be obtained, stored and / or administered in the form of a pharmaceutically acceptable salt.

[0125] Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, p-hydroxybutyric, galactaric and galacturonic acids. Suitable pharmaceutically acceptable salts include pharmaceutically acceptable base salts such as metallic ion salts and organic ion salts. Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts and other physiologically acceptable metal ions. Such salts can be made from the ions of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc. Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, / V- A / '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0126] Compounds of formula (I) according to the first aspect of the present disclosure may be obtained, stored and / or administered in the form of conjugates, for example to biological molecules, or encapsulated in particles. The compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, may be provided to the subject in a pharmaceutical composition.

[0127] Accordingly, the present disclosure encompasses the pharmaceutical composition according to the second aspect of the present disclosure as described herein. All of the preferred or optional features of the first aspect of the present disclosure are applicable to the second aspect of the present disclosure, and vice versa.

[0128] Pharmaceutical compositions according to the second aspect of the present disclosure may include stabilizers, antioxidants, colorants and diluents, as well as pharmaceutically acceptable additives. The components of the pharmaceutical compositions are chosen such that side effects are minimized and the performance of the compound of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, is not compromised to such an extent that treatment is ineffective.

[0129] The compounds of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, may be formulated into pharmaceutical compositions, such as the pharmaceutical composition according to the second aspect of the present disclosure, for various modes of administration. It will be appreciated that the compounds of formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof maybe administered together with a pharmaceutically acceptable carrier(s) or excipient(s).

[0130] Pharmaceutical compositions according to the second aspect of the present disclosure may be administered to the subject in need by any suitable route, including but not limited to: enteral administration such as oral, rectal, gastric or duodenal administration; nasal administration; transdermal administration; intrathecal administration; transmucosal administration; parenteral administration including subcutaneous, intramuscular, intravenous, intraperitoneal administration and intradermal; buccal or sub-lingual administration; topical administration; or inhalation.

[0131] Pharmaceutically acceptable excipients and carriers are known in the art. Considerations concerning 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, N. Y. (1980) and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).

[0132] Pharmaceutically acceptable excipients and carriers will vary depending upon the mode of administration. Suitable pharmaceutically acceptable carrier(s) or excipient(s) include isotonic solutions such as water, saline, phosphate buffered saline, lactated Ringer’s solution, ~ 5% dextrose in water (D5W), aqueous dextrose, Ringer’s solution, hydroxypropyl p cyclodextrin, phosphate buffer, an alcohol (such as ethanol, isopropanol, or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2-dimethyl-1 ,3-dioxolane-4-methanol), ethers (such as poly(ethylene-glycol) 400), an oil, a fatty acid, a fatty acid ester or glyceride, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.

[0133] Pharmaceutical compositions according to the second aspect of the present disclosure may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. Pharmaceutical formulations according to the second aspect of the present disclosure are usually prepared by mixing the active substance (compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof) with conventional pharmaceutically acceptable carriers or excipient. Pharmaceutical compositions according to second aspect of the present disclosure may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like. The pharmaceutical compositions according to the second aspect of the present disclosure can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The pharmaceutical compositions according to the second aspect of the present disclosure may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles (carriers or excipients). Tablets and granules may be coated in a conventional manner. To maintain therapeutically effective plasma concentrations for extended periods of time, compounds of formula (I) disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, may be incorporated into slow-release formulations.

[0134] Accordingly, the present disclosure encompasses the use of the compound of formula (I) according to the first aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, or the pharmaceutical composition comprising the compound of formula (I) according to the second aspect of the present disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, in the uses and methods of treatment according to the third to tenth aspects of the present disclosure as defined herein. It will be appreciated that all of the preferred or optional features of the first aspect of the present disclosure are applicable to all other aspects of the present disclosure, and vice versa.

[0135] All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full.

[0136] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

[0137] EXAMPLES

[0138] The present disclosure will now be described with reference to specific examples. These are merely exemplary and for illustrative purposes only; they are not intended to be limiting in any way to the scope of the monopoly claimed or to the disclosure described. These examples constitute the best mode currently contemplated for practising the disclosure.

[0139] The following abbreviations have been used:

[0140] Ac acetyl

[0141] ACN acetonitrile

[0142] AcOH acetic acid

[0143] AcOK potassium acetate aq aqueous

[0144] DABCO 1 ,4-diazabicyclo[2.2.2]octane

[0145] DCM dichloromethane

[0146] DIPEA diisopropylethylamine

[0147] DMA dimethylacetamide

[0148] DMF dimethylformamide

[0149] DMSO dimethyl sulfoxide

[0150] EDCI.HCI 1-ethyl-3-(3-dimethylamiinopropyl)carbodiimide

[0151] EtOAc ethyl acetate h hour(s)

[0152] HOBt 1 -hydroxybenzotriazole

[0153] HPLC High Performance Liquid Chromatography

[0154] LCMS Liquid Chromatography Mass Spectrometry m-CPBA meta-chloroperoxybenzoic acid min minute(s) MOMCI chloromethyl methyl ether MsCI methanesulfonyl chloride MS mass spectrometry NIS N-iodosuccinimide Pd(dppf)CI2(1 , 1’-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride

[0155] PTSA p-toluenesulfonic acid rac- racemic mixture of enantiomers rt room temperature

[0156] SPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll) methanesulfonate

[0157] TFA trifluoroacetic acid

[0158] Tf2O trifluoromethanesulfonic anhydride

[0159] THF tetra hydrofuran

[0160] &1 in a compound structure, two stereocentres have the &1 designation because of their fixed relative configuration. Both enantiomers are present.

[0161] Experimental Method

[0162] Reactions were conducted at room temperature unless otherwise specified. Preparative flash chromatography was performed using silica gel (100-200 mesh).

[0163] Prep HPLC was performed using one of the following methods: Instrument - Agilent-1260 infinity; Column: Sunfire C8 (19x250) mm, 5p or Sunfire C18 (19x250) mm, 5p; Solvents: solvent A = 5mM Ammonium acetate in water; solvent B = acetonitrile / sol vent A = 0.1 % TFA; solvent B = acetonitrile / ; Detection wavelength 214 nm. Instrument - Waters 2767 autoprep with 2998 detector; Column: X TERRA C18 (19x250)mm, 10p or Sunfire C18 (19x250) mm, 10p ; Solvents: solvent A = 5mM Ammonium acetate in water; solvent B = acetonitrile / solvent A = acetonitrile; solvent B = 0.1% TFA in Water; Detection wavelength 214 nm. The purest fractions were collected, concentrated and dried under vacuum. Compounds were typically dried in a vacuum oven at 40 °C prior to purity analysis. Compound analysis was performed by Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 100 mm; Gradient [time (min)Zsolvent B in 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; Solvents: solvent A = 5 mM ammonium acetate in water; solvent B = acetonitrile; Injection volume 1 pL; 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 HSS-T3, 1.8 micron, 2.1 x 100 mm; Gradient [time (min)Zsolvent B in 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; Solvents: solvent A = 0.1% trifluoroacetic acid in water; solvent B = acetonitrile; Injection volume 1 pL; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL / min.

[0164] 400MHz 1 H nuclear magnetic resonance spectra (NMR) were recorded on an Avance Bruker AV400 spectrometer. In the NMR spectra the chemical shifts (6) are expressed in ppm relative to the residual solvent peak. Abbreviations have the following significances: b = broad signal, s = singlet, d = doublet, t = triplet, dd = doublet of doublets, ddd = doublet of double doublets. Abbreviations may be compounded and other patterns are unabbreviated.

[0165] The compounds prepared were named using ChemBioDraw Ultra 13.0 by CambridgeSoft.

[0166] In the absence of intermediate synthesis, the compounds are commercially available.

[0167] Examples and Intermediate Compounds

[0168] Synthetic 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound (1))

[0169]

[0170] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0171] To a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1 H,3H)-dione (5.0 g, 23.2 mmol) in toluene (90 mL, 847 mmol) were added DIPEA (20.3 mL 116 mmol) and POCI3 (8.67 mL, 92.8 mmol) at 0 °C. The reaction was allowed to warm to rt and further stirred at 120 °C for 3h. 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 afford 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 next step without further purification. tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0172] 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) was added DI PEA (26.9 ml_, 154 mmol) at rt under N2atmosphere drop-wise. The reaction mixture was stirred at rt for 15 min, 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 to it in dropwise manner. The resulting reaction mass was further stirred at -40 °C for 0.5 h. The crude reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 X 50 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography using 40 g silica gel column, eluting with 50% EtOAc in hexane to afford tertbutyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate as a light yellow solid. Yield: 4.5 g, 46%. MS (ESI+) for CHNOS m / z 428.21 [M+H]+.;1H NMR (400 MHz, DMSO-cfe): <59.06 (s, 1 H), 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). tert-Butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0173] To a solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3.0 g, 7.0 mmol) in DMSO (15 mL) were added KF (3.26 g, 56 mmol) and cyclopropane-1 , 1-diyldimethanol (1.43, 14 mmol) at rt. The reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was allowed to cool to rt, quenched with the ice-cold water (50 mL) and resulted suspension was filtered. The solid obtained was dissolved in EtOAc (30 mL), washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum to afford crude residue. The crude residue was purified by combi- flash chromatography using 12 g silica column, eluting with 40% EtOAc in hexane to afford tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-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+) for CHNOS m / z 494.30 [M+H]+. tert-Butyl 3-(7-chloro-8-fluoro-2-((1 - (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0174] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 2.43 mmol) in EtOAc (15 mL) were added Et3N (3.38 mL, 24.3 mmol) and MsCI (0.94 mL, 12.1 mmol) at 0 °C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with the water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford crude tert-butyl 3-(7-chloro-8-fluoro-2-((1-

[0175] (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a brown waxy solid. Yield: 980 mg (crude). The crude was used in next step without further purification. tert-Butyl 3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidin-1- yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-

[0176] (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.4 mmol) and K2CO3 (1.16 g, 8.39 mmol) in DMA (20 mL) was added methyl 3-(4-piperidyloxy)propionate.HCI (626 mg, 2.8 mmol) at rt. The resulted reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was allowed to cool to rt, quenched with the ice-cold water (20 mL). The precipitated solid was filtered and washed with the water (20 mL). The solid product was dissolved in EtOAc (20 mL), washed with the water (20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford a crude product. The crude product was purified by combiflash chromatography using 40 g silica gel column, eluting with 40% EtOAc in hexane to afford tert-butyl 3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidin-1- yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate as a yellow solid. Yield: 660 mg, crude, 78% by LCMS). CHNOS m / z 663.63 [M+H]+. tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-(3-methoxy-3- oxopropoxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0177] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidin-1- yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-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 -y l)ethy ny l)tri i sopropy I si lane (464 mg,

[0178] 0.905 mmol) in n-BuOH (2.0 mL) was added 1 ,5M aq. solution of K3PO4 (800 mg, 3.77 mmol) at rt. The reaction mixture was purged with N2(g) for 15 min and SPhos Pd G3 (58.8 mg, 0.075 mmol)_was added at rt. The resulted reaction mixture was again purged with N2 (g) for 5 min. Reaction vessel was sealed and the reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was allowed to cool to rt, diluted with H2O (20 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified by combiflash chromatography using 12g silica gel column, eluting with 40% EtOAc in hexane to afford tertbutyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid. Yield: 230 mg (26% by LCMS). MS (ESI+) for CHNOS m / z 1013.66 [M+H]+. It was used in the next step without further purification. 3-((1-(('l-(((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]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid

[0179] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((tri isopropy Isily l)ethy nyl)naphthalen-1 -y l)-2-(( 1 -((4-(3-methoxy-3-oxopropoxy)piperidin-1 - yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-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 a solution of UOH.H2O (166 mg, 3.95 mmol) in H2O (0.5 mL) at rt. The resulted reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, acidified to 3-4 pH with 1 .0 M aq. solution of HCI and extracted with DCM (3 X 20 mL). The combined organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 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]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid as a light brown solid. Yield: 410 mg (crude, 46% by LCMS). MS (ESI+) for CHNOS m / z 999.59 [M+H]+. The crude material was used in the next step without further purification.

[0180] 3-((1-((1-(((4-(8-(tert-Butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid

[0181] 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]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid (400 mg, 0.4 mmol) in DMF (4.0 mL) was added CsF (608 mg, 4 mmol) at rt. The resulted reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with water (2 X 20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 3-((1 -((1 -(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid. Yield: 280 mg (crude, 45% by LCMS). MS (ESI+) for CHNOS m / z 843.91 [M+H]+. The crude material was used in the next step without further purification. 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

[0182] To a solution of 3-((1 -((1 -(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid (280 mg, 0.3332 mmol) in DMF (4.0 mL) were added EDCI.HCI (191 mg, 0.997 mmol), HOBt (153 mg, 0.997 mmol) and DIPEA (0.29 mL, 1.66 mmol) at rt. The resulted reaction mixture was stirred at rt for 10 min 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.HCI (192 mg, 0.399 mmol) was added at rt. The resulted reaction mixture was stirred at rt for 6 h. The reaction mixture was poured into ice-cold water (20 mL) and extracted with EtOAc (3 X 25 mL). The combined organic layer was washed with water (2 X 30 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford tert-butyl 3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l -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 -y l)-3 , 3-di methyl- 1 -oxobutan-

[0183] 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 as a light brown solid. Yield: 310 mg (crude, 62% by LCMS). MS (ESI+) for CHNOS m / z 1269.60 [M+H]+. The crude material was used in next step without further purification.

[0184] (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-

[0185] 3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (J31-237)

[0186] To a stirred solution of 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 (260 mg, 0.205 mmol) in 1 ,4-dioxane (2.0 mL) was added 4.0 N HCI in 1 ,4 dioxane (2.0 mL) at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with Et2O (5.0 mL) and dried under reduced pressure to afford the desired product as a HCI salt, which was further purified by prep HPLC using TFA buffer to afford (2S,4R)-1-((2S)-2- (3-((1 -((1 -(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)oxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1 -(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide. TFA salt as an off white solid. Yield: 22 mg, 9% (based on free base). MS (ESI+) for CHNOS m / z 1125.47 [M+H]+; LC purity 96.10 % (Ret. Time- 4.89 min);1H NMR (400 MHz, DMSO-cfe + Cf-TFA): 5 9.35 (s, 1 H), 9.24 (s, 1 H), 7.96- 8.02 (m, 1 H), 7.42-7.50 (m, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.25 (s, 1 H), 4.87-4.95 (m, 1 H), 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).

[0187] Intermediate synthesis 1

[0188] Methyl 3-(piperidin-4-yloxy)propanoate.HCI tert-Butyl (E)-4-((3-methoxy-3-oxoprop-1-en-1-yl)oxy)piperidine-1 -carboxylate

[0189] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 49.7 mmol) in DCM (50 mL) were added methyl prop-2 -ynoate (5.01 g, 59.6 mmol) and N-methylmorpholine (8.19 mL, 74.5 mmol) at rt under N2atmosphere. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 X 50 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude was purified by combiflash chromatography using 40 g silica column, eluting with 10% EtOAc in hexane to afford tert-butyl (E)-4-((3-methoxy-3-oxoprop- 1-en-1 -yl)oxy)piperidine-1 -carboxylate as a colourless liquid. Yield: 11 g, 77%.1H NMR (400 MHz, DMSO-cfe): 5 7.61 (d, J = 12.4 Hz, 1 H), 5.30 (d, J = 12.4 Hz, 1 H), 4.30-4.40 (m, 1 H), 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). tert-Butyl 4-(3-methoxy-3-oxopropoxy)piperidine-1 -carboxylate

[0190] A solution of tert-butyl (E)-4-((3-methoxy-3-oxoprop-1-en-1-yl)oxy)piperidine-1 -carboxylate (10.9 g, 38.2 mmol) in MeOH (100 mL) was purged with N2(g) for 10 min and 10% Pd / C (5.5 g) was added at rt. The reaction mixture stirred at rt under H2pressure (1 atm) for 16 h. The crude reaction mixture was filtered through celite bed. The celite bed was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-(3- methoxy-3-oxopropoxy)piperidine-1-carboxylateas a colourless liquid. Yield: 10.1 g, 92%.1H NMR (400 MHz, DMSO-cte): <53.53-3.68 (m, 7H), 3.40-3.49 (m, 1 H), 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).

[0191] Methyl 3-(piperidin-4-yloxy)propanoate.HCI

[0192] To a solution of tert-butyl 4-(3-methoxy-3-oxopropoxy)piperidine-1 -carboxylate (10 g, 34.8 mml) in 1 ,4-dioxane (50 mL) was added 4.0 N HCI in dioxane (35 mL, 1.01 mol) dropwise at 0°C. The resulted reaction mixture was stirred at rt for 2 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. The crude residue was triturated with Et2O (20 mL) and dried under reduced pressure to afford methyl 3-(4- piperidyloxy)propionate.HCI as an off white solid product. Yield: 6.4 g, 98%.1H NMR (400 MHz, DMSO-de): <5 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).

[0193] The following intermediate was prepared in a similar manner to tert-butyl (E)-4-((3-methoxy- 3-oxoprop-1 -en-1 -yl)oxy)piperidine-1 -carboxylate following intermediate synthesis 1 (Step'l -

[0194] The following intermediate was prepared in a similar manner to tert-butyl 4-(3-methoxy-3- oxopropoxy)piperidine-1 -carboxylate following intermediate synthesis 1 (Step-2). The following intermediate was prepared in a similar manner to methyl 3-(piperidin-4- yloxy)propanoate.HCI_following intermediate synthesis 1 (Step-3).

[0195] Intermediate synthesis 2

[0196] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0197] 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0198] To a stirred solution of 7-fluoronaphthalene-1 ,3-diol (10 g, 56.1 mmol) and (bromoethynyl)triisopropylsilane (15.4g, 58.9 mmol) in 1 ,4-dioxane (100 mL) was added AcOK (11 g, 112 mmol) at rt under N2atmosphere. The reaction mixture was purged with N2(g) for 10 min and [Ru(p-cymene)CI2]2(3.44 g, 5.61 mmol) was added. The reaction mixture was again purged with N2(g) for 5 min and stirred at 110 °C for 2 h. The reaction mixture was allowed to cool to rt and filtered through celite bed. The celite bed was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel silica (100-200 mesh) eluting with 10% EtOAc in hexane to afford 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol as a black solid. Yield: 16.8 g, 79%. MS (ESI+) for CHNOS m / z 359.25 [M+H]+.;1H NMR (400 MHz, DMSO-cfe): 10.04 (s, 1 H), 9.57 (s, 1 H), 7.61-7.65 (m, 1 H), 7.23-7.27 (m, 1 H), 6.62 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 1.12-1.16 (m, 21 H).

[0199] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0200] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol (16.5 g, 43.7 mmol) and DIPEA (22.8 mL, 131 mmol) in DCM (50 ml_) was added MOMCI (4.32 mL 56.8 mmol) at 0 °C dropwise. The reaction mixture was further stirred at 0 °C for 0.5 h. The crude reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 X 50 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SC>4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel silica (100-200 mesh) eluting with 5% EtOAc in hexane to afford 7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol as a yellow solid. Yield: 11.8 g, 43%. MS (ESI+) for CHNOS m / z 403.24 [M+H]+.;1H NMR (400 MHz, DMSO-cfe): 10.29 (s, 1 H), 7.75-7.78 (m, 1 H), 7.32-7.37 (m, 1 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.69 (d, J = 2.4 Hz, 1 H), 5.23 (s, 2H), 3.39 (s, 3H), 1.12-1.16 (m, 21 H).

[0201] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0202] 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) was added Tf2O (7.62 mL, 43.2 mmol) at -40°C dropwise. The reaction mixture was further stirred at -40°C for 1 h. The crude reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 X 50 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel silica (100-200 mesh) eluting with 2% EtOAc in hexane to afford 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate as a yellow oil. Yield: 8.3 g, 53%.1H NMR (400 MHz, DMSO-cfe): 8.09-8.13 (m, 1 H), 7.77 (d, J = 2.6 Hz, 1 H), 7.62-7.67 (m, 1 H), 7.50 (d, J = 2.6 Hz, 1 H), 5.37 (s, 2H), 3.42 (s, 3H), 1.10-1.14 (m, 21 H).

[0203] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0204] To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1 -yl trifluoromethanesulfonate (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) in toluene (415 ml_, 3.9 mol) was added AcOK (4.57 g, 46.6 mmol) at rt. The reaction mixture was purged with N2(g) for 15 min and Pd(dppf)CI2(2.27 g, 3.1 mmol) was added. The resulted reaction mixture was again purged with N2(g) for 5 min and stirred at 130°C for 5 h. The reaction mixture was allowed to cool to rt and filtered on the celite bed. The celite bed was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel silica (100-200 mesh) eluting with 2% EtOAc in hexane to afford desired compound as a yellow solid. The solid was further triturated with CH3CN (5.0 mL) to afford ((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+) for CHNOS m / z 513.29 [M+H]+.;1H NMR (400 MHz, CDCI3): 7.63-7.67 (m, 1 H), 7.49 (d, J = 2.6 Hz, 1 H), 7.37 (d, J = 2.6 Hz, 1 H), 7.16-7.21 (m, 1 H), 5.26 (s, 2H), 3.49 (s, 3H), 1.41 (s, 12H), 1.14-1.19 (m, 21 H). The following intermediate was prepared in a similar manner to tert-butyl 3-(7-chloro-8-fluoro- 2-((1-((4-(3-methoxy-3-oxopropoxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate following synthetic route 1 (step-5).

[0205] The following intermediates were prepared in a similar manner to tert-butyl 3-(8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-(3- methoxy-3-oxopropoxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate following synthetic route 1 (Step-6).

[0206] Intermediate synthesis 3 tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-

[0207] ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(((3-methoxy-3- oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0208] 2-Chloro-3-fluoro-5-iodopyridin-4-amine

[0209] To a solution of 2-chloro-3-fluoro-4-pyridylamine (10 g, 68.2 mmol) in ACN (120 mL) were added NIS (18.4 g, 81.9 mmol) and PTSA (588 mg, 3.41 mmol) at rt. The resulting reaction mixture was allowed to stir at 70 °C for 16 h. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The crude residue was diluted with water (200 mL). The solid precipitated was filtered, washed with saturated aq. Na2SOs solution (100 mL), water (100 mL) and dried under reduced pressure to afford 2-chloro-3-fluoro-5-iodo-4- pyridylamine as a brown solid. Yield: 17.1 g, 92%. MS (ESI+) for CHNOS m / z 272.91 [M+H]+.;1H NMR (400 MHz, CDCI3): 58.17 (s, 1 H), 4.84 (bs, 2H).

[0210] Ethyl 4-amino-6-chloro-5-fluoronicotinate

[0211] 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 min and Pd(PPh3)2Cl2 (4.37 g, 6.24 mmol) was added to it at rt. The resulted reaction mixture was stirred at 90 °C under CO atmosphere (70 PSI) for 16 h. The reaction mixture was allowed to cool to rt and filtered on celite bed. The celite bed was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The solid residue was diluted with cold EtOH (50 mL), stirred for 15 min and filtered. The solid was washed with cold EtOH (20 mL) and dried under reduced pressure to afford ethyl 4-amino-6-chloro-5-fluoronicotinate as an off white solid. Yield: 7.4 g, 54%. MS (ESI-) for CHNOS m / z 217.19 [M-H]+.

[0212] 4-Amino-6-chloro-5-fluoronicotinic acid

[0213] To a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (11.7 g, 53.5 mmol) in THE (110 mL) was added a solution of NaOH (8.56 g, 214 mmol) in water (55 mL) at rt. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH 2 with 2.0 M HCI. The solid precipitated was filtered, washed with water (100 mL) and dried under vacuum to afford 4-amino-6-chloro-5-fluoronicotinic acid as an off white solid. Yield: 8.4 g, 82%. MS (ESI-) for CHNOS m / z 189.01 [M-H]+.;1H NMR (400 MHz, DMSO- cfe): 6 13.43 (bs, 1 H), 8.35 (s, 1 H), 7.63 (bs, 2H).

[0214] 7-Chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1 H)-one

[0215] To a solution of 4-amino-6-chloro-5-fluoronicotinic acid (5.0 g, 26.2 mmol) was added POCI3 (50 mL, 532 mmol) slowly at rt. The reaction mixture was stirred at 90 °C for 3 h. The reaction progress was monitored with TLC. The reaction mixture was allowed to cool to rt and concentrated under vacuum to afford 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 rt. The resulted reaction mixture was further stirred at rt for 16h. The reaction mixture was diluted with the water (100 mL) and extracted with the EtOAc (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under vacuum to afford the residue. The residue was triturated with the EtOAc (30 mL) and dried under reduced pressure to afford 7-chloro-8-fluoro-2-thioxo-2,3- dihydropyrido[4,3-d]pyrimidin-4(1 H)-one as a yellow solid. Yield: 4.1 g, 68%. MS (ESI-) for CHNOS m / z 230.0 [M-H]+.;1H NMR (400 MHz, DMSO-cfe): <5 13.35 (bs, 1 H), 12.93 (bs, 1 H), 8.64 (s, 1 H).

[0216] 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0217] To a solution of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1 H)-one (4.0 g, 17.3 mmol) in DMF (40 mL) was added MeONa (933 mg, 17.3 mmol) at rt. The reaction mixture was allowed to stir for at rt for 10 min and CH3I (1.08 mL, 17.3 mmol) was added to it dropwise. The resulted suspension was stirred at rt for 4 h. The reaction mixture was poured into ice-cold water (100 mL). The precipitated solid was filtered, washed with the cold water (50 mL) and dried under vacuum to afford the 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one as a yellow solid. Yield: 3.8 g, 89%. MS (ESI-) for CHNOS m / z 243.99 [M-H]+.;1H NMR (400 MHz, DMSO-cfe): 6 13.26 (bs, 1 H), 8.79 (s, 1 H), 2.60 (s, 3H).

[0218] 4,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0219] To a solution of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (3.8 g, 15.5 mmol) in POCI3 (46 mL) was added DI PEA (5.39 mL, 30.9 mmol) dropwise at rt. The reaction mixture was stirred at 100 °C for 16 h. The solvent was concentrated under reduced pressure. The crude residue was purified by combiflash chromatography using 12 g silica gel column, eluting with 20% EtOAc in hexane to afford 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidine as an off white solid. Yield: 2.8 g, 68%. MS (ESI+) for CHNOS m / z 264.0 [M+H]+.;1H NMR (400 MHz, CDCI3): 59.10 (s, 1 H), 2.71 (s, 3H). tert-Butyl 3-(7-chloro-8-fluoro-2-(rnethylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0220] To a solution tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.93 g, 13.8 mmol) in DCM (100 mL) was added DI PEA (12.4 mL, 71 mmol) drop-wise at rt under N2 atmosphere. The reaction mixture was cooled to -40 °C, stirred for 5 min and a solution of 4,7-dichloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.8 g, 10.6 mmol) in DCM (15 mL) was added to it at -40 °C. The resulted reaction mixture was stirred at -40 °C for 0.5 h. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 X 100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography using 40 g silica gel column, eluting with 50% EtOAc in hexane to afford tert-butyl 3-(7-chloro-8-fluoro- 2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light yellow solid. Yield: 4.5 g, 96%. MS (ESI+) for CHNOS m / z 440.24 [M+H]+.;1H NMR (400 MHz, CDCb): 58.70 (s, 1 H), 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). tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0221] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (810 mg, 1.82 mmol), ((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) was added K3PO4 (6.06 mL, 1.5 M aq. solution, 9.09 mmol) at rt under N2atmosphere. The reaction mixture was degassed for 15 min under N2(g) atmosphere and S PhosPdG3 (142 mg, 0.182 mmol) was added. The reaction mixture again degassed for 10 min and the reaction vial was sealed. The reaction mixture was stirred at 75 °C for 2 h.. The reaction mixture was allowed to cool to rt and quenched with the ice-cold water (100 mL). The resulting suspension was filtered on the sintered funnel and washed with the ice-cold water (20 mL). The solid product was dissolved in the EtOAc (20 mL) and washed with the water (30 mL) and brine (30 mL). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to afford crude. The crude was purified through combi-flash chromatography using 12 g silica column and eluting with 40% EtOAc in hexane to afford tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1 -yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid. Yield: 810 mg, 56%. MS (ESI+) for CHNOS m / z 790.76 [M+H]+.;1H NMR (400 MHz, DMSO-cfe): <59.16 (s, 1 H), 8.08-8.12 (m, 1 H), 7.75 (d, J = 2.4 Hz, 1 H), 7.56 (t, J = 8.8 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 5.36 (s, 2H), 4.79- 4.82 (m, 1 H), 4.05-4.34 (m, 3H), 3.78-3.82 (m, 1 H), 3.42 (s, 3H), 3.32-3.35 (m, 1 H), 2.54 (s, 3H), 1.80-1.87 (m, 3H), 1.59-1.63 (m, 1 H), 1.45 (s, 9H), 0.80-0.82 (m, 18H), 0.41-0.51 (m, 3H). tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0222] 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]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.01 mmol) in EtOAc (32 ml_, 325 mmol) was added m-CPBA (524 mg, 3.04 mmol) at 0 °C portion wise . The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with the saturated aq. solution of sodium sulphite (50 mL) and extracted with the EtOAc (3 X 30 mL). The combined organic layerwas washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum to afford crude. The crude was purified through combi-flash chromatography using 12 g silica column and eluting with 60% ethyl acetate in hexane to afford tert-butyl 3-(8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. Yield: 680 mg, 82%. MS (ESI+) for CHNOS m / z 822.45 [M+H]+.;1H NMR (400 MHz, DMSO-cfe): 0 9.43 (s, 1 H), 8.11 -8.15 (m, 1 H), 7.79 (d, J = 2.4 Hz, 1 H), 7.59 (t, J = 8.8 Hz, 1 H), 7.38 (d, J = 2.4 Hz, 1 H), 5.37 (s, 2H), 4.91 -4.93 (m, 1 H), 4.23-4.42 (m, 3H), 3.90- 4.10 (m, 1 H), 3.41 (s, 3H), 3.40 (s, 3H), 3.38-3.39 (m, 1 H), 1.61 -1.92 (m, 4H), 1.43 (s, 9H), 0.76-0.82 (m, 18H), 0.39-0.51 (m, 3H). 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]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0223] 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]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (580 mg, 0.706 mmol) in CH3CN (5.0 mL) were added Cs2CO3(690 mg, 2.12 mmol) and DABCO (7.91 mg, 0.071 mmol) at rt. The vial was sealed and reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was allowed to cool to rt, quenched with the water (10 ml_) and extracted with the EtOAc (3 x 20 ml_). The combined organic layer was washed with brine (20 mL), dried (Na2SC>4), filtered and concentrated under vacuum to afford crude. The crude was purified through combi-flash chromatography using 12 g silica column, eluting with 90% EtOAc in hexane to afford tertbutyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as an off white solid. Yield: 420 mg, 72%. MS (ESI+) for CHNOS m / z 844.66 [M+H]+.;1H NMR (400 MHz, DMSO-cfe): 6 9.16 (s, 1 H), 8.08-8.12 (m, 1 H), 7.74 (d, J = 2.4 Hz, 1 H), 7.56 (t, J = 8.8 Hz, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 5.36 (s, 2H), 4.73-4.76 (m, 1 H), 4.61-4.64 (m, 1 H), 4.19-4.34 (m, 5H), 3.72-3.75 (m, 1 H), 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). tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1- formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0224] To a stirred solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((tri isopropy Isily l)ethy nyl)naphthalen-1 -y l)-2-(( 1 - (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (380 mg, 0.450 mmol) in DCM (15.0 mL, 237 mmol) was added Dess Martin periodinane (764 mg, 1.8 mmol) at rt in portion wise manner. The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated aq. solution of Na2S2O3(30 mL) and extracted with DCM (2 x 30 mL). The combined organic layerwas washed with brine (40 mL), dried (Na2SO4), filtered and concentrated under vacuum to afford crude. The crude was purified by combi-flash chromatography using 12 g silica column and eluting with 90% EtOAc in hexane to afford tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1 - formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-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+) for CHNOS m / z 842.48 [M+H]+. 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]pyrimidin-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]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.416 mmol) in DCM (5.0 mL) were added methyl 3-(methylamino)propionate (146 mg, 3 eq., 1.25 mmol) and AcOH (4.99 mg, 0.083 mmol) at rt. The reaction mixture was stirred at rt for 5 h under N2atmosphere and Na(OAc)sBH (80.9 mg, 1.25 mmol) was added to it. The resulted reaction mixture was further stirred at rt for 16 h. The reaction mixture was quenched with the water (10 mL) and extracted with the DCM (3 x 10 mL). The combined organic layer was washed with saturated aq. solution of NaHCOs (20 mL), brine (30 mL), dried (Na2SC>4) filtered and concentrated under vacuum to afford 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]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid. Yield: 290 mg (crude, 47% by LCMS). MS (ESI+) for CHNOS m / z 943.98 [M+H]+. The crude was used in next step without further purification.

[0225] The following intermediates were prepared in a similar manner to 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]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanoic acid following synthetic route 1 (Step-7).

[0226] Intermediate synthesis 4

[0227] (2S.4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(2',6'-difluoro-[1,T-biphenyl]-4- yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide.HCI tert-Butyl ((S)-1 -((2S,4R)-2-(((S)-1 -(4-bromophenyl)ethyl)carbamoyl)-4- hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0228] To a solution of (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid (2.0 g, 5.81 mmol) in dry DMF (30 mL) were added HOBt (2.35 g, 17.4 mmol), EDCI. HCI (3.34 g, 17.4 mmol) and DIPEA (5.0 mL, 29 mmol) at rt under N2 atmosphere. The reaction mixture was stirred at rt for 15 min and (S)-1-(4- bromophenyl)ethan-1 -amine (1.39 g, 6.97 mmol) was added to it. The reaction mixture was further stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with EtOAc (3 X 30 mL). The combined organic layer was washed with brine (50 mL) dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography using 12 g silica column, eluting with 50% EtOAc in hexane to afford tert-butyl ((S)-1 -((2S,4R)-2-(((S)-1-(4- bromophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1 -yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamate as a white solid. Yield: 2.0 g, 65%. MS (ESI+) for CHNOS m / z 526.24 [M+H]+. tert-Butyl ((S)-1-((2S,4R)-2-(((S)-1-(2',6'-difluoro-[1,T-biphenyl]-4-yl)ethyl)carbamoyl)- 4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0229] To a solution of tert-butyl ((S)-1-((2S,4R)-2-(((S)-1 -(4-bromophenyl)ethyl)carbamoyl)-4- hydroxypyrrolidin-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) was added Na2CO3 (604 mg, 5.7 mmol) at rt. The reaction mixture was purged with N2(g) for 10 min, (2,6-difluorophenyl)boronic acid (1.5 g, 9.5 mmol) and Pd(dppf)Cl2 (139 mg, 0.190 mmol) were added to it at rt. The reaction mixture was again purged with N2(g) for 5 min. The reaction vessel was sealed and reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was allowed to cool to rt, diluted with water (20 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine (30 mL) dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography using 40 g silica gel column, eluting with 50% EtOAc in hexane to afford tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(2',6'-difluoro- [1 , 1 '-biphenyl]-4-yl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1 -y l)-3, 3-di methyl - 1 -oxobutan-2- yl)carbamate as an off white solid. Yield: 700 mg, 66%. MS (ESI +) for CHNOS m / z 560.30 [M+H]+.

[0230] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(2',6'-difluoro-[1,T-biphenyl]-4- yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide.HCI

[0231] 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-d i methyl -1 -oxobutan-2-yl)carbamate (690 mg, 1.23 mmol) in DCM (5 mL) was added 4.0 N HCI in 1 ,4 dioxane (0.7 mL) at 0 °C . The reaction mixture was stirred at rt for 3h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was triturated with Et2O (5.0 mL) and dried under vacuum to afford N-[(S)-1-(2',6'-difluoro-4-biphenylyl)ethyl]-(2S,4R)-1 -[(S)-2- amino-3,3-dimethylbutyryl]-4-hydroxy-2-pyrrolidinecarboxamide.HCI as an off white solid. Yield: 570 mg. MS (ESI+) for CHNOS m / z 460.31 [M+H]+.The crude was used in next step without further purification.

[0232] 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 following synthetic route 1 (Step-9).

[0233]

[0234] Intermediate synthesis 5 tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (((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- oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0235] To the stirred solution tert-butyl 3-(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)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 0.248 mmol) in DMF (3.0 mL) was added CsF (377 mg, 2.48 mmol) at rt. The reaction mixture was stirred at rt for 2h. The reaction mixture was quenched with the ice-cold water (5 mL) and stirred for 10 min. The resulting suspension were filtered on the sintered funnel and solid cake was washed with the water (20 mL). The solid product was dried under vacuum to afford tert-butyl 3-(7-(8-ethynyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1 -yl)-8-fluoro-2-((1 -(((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-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light brown solid. Yield: 315 mg (crude, 44% by LCMS). MS (ESI+) for CHNOS m / z 1199.96 [M+H]+. The crude was used in the next step without further purification.

[0236] 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-( ((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-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate following intermediate synthesis 5.

[0237] The following compounds were prepared in a similar manner to (2S,4R)-1-((2S)-2-(3-((1-((1- (((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)oxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide following synthetic route 1 (Step-10).

[0238] ((2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1 -(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound (4))

[0239] A solution of (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)propanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2 -carboxamide. TFA (25 mg, 0.022 mmol) in MeOH (4.0 mL) was degassed for 5 min and 10% Pd / C (50 mg) was added to it at rt under N2atmosphere. The reaction mixture was further stirred under H2(g) pressure (1 atm) at rt for 4 h. The reaction progress was monitored with LCMS. The reaction mixture was filtered through a small celite bed. The celite bed was thoroughly washed with the MeOH (10 mL). The filtrate was concentrated under vacuum to obtain the crude. The crude was purified by prep HPLC using TFA buffer to afford ((2S,4R)-1 -((2S)-2-(3-((1 -((1- (((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)oxy)propanamido)-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+) for CHNOS m / z 1129.53 [M+H]+.;1H NMR (400 MHz, DMSO-cfe + d- TFA): 6 9.79 (s, 1 H), 9.28 (s, 1 H), 7.67-7.73 (m, 1 H), 7.35-7.58 (m, 4H), 7.23-7.30 (m, 1 H), 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, 11 H), 1.29-1.38 (m, 3H), 0.68-0.94 (m, 16H).

[0240] Biological assays

[0241] Results of biological assays for Compounds (1) to (6) are shown in Table 1 below.

[0242] KRAS G12D Nucleotide Exchange Assay

[0243] Biochemical compound potencies were assessed by evaluating inhibition of SOS1 mediated nucleotide exchange in KRAS G12D. Evaluation of inhibition was evaluated using the KRAS G12D Nucleotide exchange assay kit from Aurora Biolabs (Catalogue number: 5727- 4123NK). The SCSI mediated exchange of fluorescently labelled GTP was monitored by TR-FRET. Compounds solubilized in DMSO (100X final concentration) were dispensed as dilution series into 384-well white assay plates. GST-tagged KRAS G12D was diluted from stock 440 fold in 1 x assay buffer. 4 pL diluted KRAS G12D was preincubated with 2 pL of compound for 30 minutes at room temperature. SOS1 stock was diluted 800 fold 1 x assay buffer and 4 pL added to a master mix containing 10 pL dye solution made with terbium labelled anti-GST antibody (1 :200 in 1 x assay buffer) and fluorescence labelled GTP (1 :40 in 1 x assay buffer). 14 pL of master mix (SOS1 ; antibody; GTP) was added to the preincubated KRAS G12D and compound mix and incubated for a further 2 hours at room temperature in sealed plates. For negative controls, SOS1 and GTP were replaced with 1 x assay buffer. GTP binding to KRAS was quantitated on a Clariostar plus measuring the fluorescent ratio of 665 nm / 620 nm.

[0244] Results are shown in Table 1 below.

[0245] KRAS G12C Nucleotide Exchange Assay

[0246] Biochemical compound potencies were assessed by evaluating inhibition of SOS1 mediated nucleotide exchange in KRAS G12C. Evaluation of inhibition was evaluated using the KRAS (G12C Nucleotide exchange assay kit from Aurora Biolabs (Catalogue number: 5727- 4122NK). The S0S1 mediated exchange of fluorescently labelled GTP was monitored by TR-FRET. Compounds solubilized in DMSO (100X final concentration) were dispensed as dilution series into 384-well white assay plates. GST-tagged KRAS G12C was diluted from stock 380 fold in 1 x assay buffer. 4 pL diluted KRAS G12C was preincubated with 2 pL of compound for 30 minutes at room temperature. SOS1 stock was diluted 2000 fold 1 x assay buffer and 4 pL added to a master mix containing 10 pL dye solution made with terbium labelled anti-GST antibody (1 :200 in 1 x assay buffer) and fluorescence labelled GTP (1 :40 in 1 x assay buffer). 14 pL of master mix (SOS1 ; antibody; GTP) was added to the preincubated KRas G12C and compound mix and incubated for a further 2 hours at room temperature in sealed plates. For negative controls, SOS1 and GTP were replaced with 1 x assay buffer. GTP binding to KRAS was quantitated on a Clariostar plus measuring the fluorescent ratio of 665 nm / 620 nm.

[0247] Results are shown in Table 1 below.

[0248] KRAS wt Nucleotide Exchange Assay

[0249] Biochemical compound potencies were assessed by evaluating inhibition of SOS1 mediated nucleotide exchange in KRAS wt. Evaluation of inhibition was evaluated using the KRAS wt nucleotide exchange assay kit from Aurora Biolabs (Catalogue number: 5727-4121 NK). The SOS1 mediated exchange of fluorescently labelled GTP was monitored by TR-FRET. Compounds solubilized in DMSO (100X final concentration) were dispensed as dilution series into 384-well white assay plates. GST-tagged KRAS wt was diluted from stock 210 fold in 1 x assay buffer. 4 pL diluted KRAS wt was preincubated with 2 pL of compound for 30 minutes at room temperature. SOS1 stock was diluted 800 fold 1 x assay buffer and 4 pL added to a master mix containing 10 pL dye solution made with terbium labelled anti-GST antibody (1 :200 in 1 x assay buffer) and fluorescence labelled GTP (1 :40 in 1 x assay buffer). 14 pL of master mix (SOS1 ; antibody; GTP) was added to the preincubated KRAS wt and compound mix and incubated for a further 2 hours at room temperature in sealed plates. For negative controls, SCSI and GTP were replaced with 1 x assay buffer. GTP binding to KRAS was quantitated on a Clariostar plus measuring the fluorescent ratio of 665 nm / 620 nm.

[0250] Results are shown in Table 1 below.

[0251] Phospho-ERK assay (pERK)

[0252] HTRF advanced phospho-ERK1 / 2 (THR202 / TYR204) detection kit (Cisbio, catalogue number: 64AERPET) was used to determine the levels of phosphorylated-ERK1 / 2 in AsPC- 1 cells (ATCC CRL-1682). Advanced 70hosphor-ERK1 / 2 (Thr202 / Tyr204) is detected in a sandwich assay format using 2 different specific antibodies, one labelled with Eu3+-Cryptate (donor) and the second with d2 (acceptor). AsPC-1 cells expressing KRAS G12D were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, and Penicillin / Streptomycin. 50 pL cells were seeded into 96 well plates at 2 x 106cells / mL (100,000 cells per well). Plates were incubated overnight at 37C, 5% CO2. Compounds were solubilized in DMSO and titrated in DMSO. Compound dilutions were diluted in RPMI medium (10% FBS, Pen / Strep) 1 in 500 and 50 pL added to the preincubated cells (final DMSO concentration was 0.1%). Plates were incubated for a further 24 hours at 37C, 5% CO2. Media was removed and 50 pL supplemented lysis buffer (blocking reagent in lysis buffer at 1 :100) added to wells and incubated shaking (300 rpm) for 50 minutes at room temperature. 16 pL lysate added to a 96-well small volume HTRF plate. 4 pL premixed antibody solution (d2 and Eu cryptate antibodies diluted 1 :20 in detection buffer) was added to wells containing lysates. Plates were sealed and incubated at 20C for 4 hours and read on a Clariostar plus using 665 nm / 620 nm ratio. For negative controls supplemented lysis buffer was swapped in for lysate.

[0253] Results are shown in Table 1 below.

[0254] KRAS degradation assay (DC5o)

[0255] The levels of KRAS protein, normalised to the house keeping protein a-tubulin, were determined using protein simples 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 x pen / strep). 1 mL of cells were seeded into 12 well plates at 300,000 cells / mL and incubated at 37C, 5% CO2 overnight. Compounds were solubilised in DMSO and also titrated in DMSO. 1 pL of compound was added to each well of the preincubated cells and incubated for a further 24 hours. Media was removed and cells washed with 1 mL of PBS. Cells were lysed for 10 minutes at 4C with 200 pL cold RIPA buffer, containing 1 x HALT protease and phosphatase inhibitor. Lysates were protein quantified using a Bradford assay to ensure lysate protein concentrations were similar across concentrations. Lysates were probed on the Jess system using mouse-a-tubulin (Novus catalogue number: NB100-690) for both AsPC-1 and MiaPaCa-2 cell lysates. Rabbit-Ras (G12D Mutant specific) (D8H7) (Cell signalling, catalogue number: 14429) for AsPC-1 lysates. Rabbit-K-Ras (E2M9G) (Cell signalling, catalogue number: 71835). Secondary antibodies used were, 20x Anti-Rabbit NIR (Protein simple, catalogue number: 043-819) and 20x anti-Mouse IR (Protein simple, catalogue number: 043-822). Area under Curve (AUC) for probe signal was generated by protein simples’ compass software and KRAS was normalised against a-tubulin for each sample. DC50 (concentration resulting in 50% reduction in KRAS protein level) was generated using GraphPad prism.

[0256] Results are shown in Table 1 below.

[0257] 3D cell proliferation assay

[0258] Compounds were tested for their anti-proliferative 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 were cultured in DMEM (10% FBS, 2.5% horse serum, 1 x pen / strep). The specific cell lines used contain the specific driver mutations: ASPC-1 expresses KRASG12D, and MiaPaCa expresses KRASG12C. 100 pL cells were seeded in Low adhesion 96-well plates (S-Bio, catalogue number MS-9096WZ) at 5000 cells / well, using appropriate media. Plates were incubated at 37C, 5% CO2 overnight. Compounds were solubilised in DMSO and also diluted in DMSO. Compounds were diluted 1 :90.9 in RPMI- 1640 (10% FBS, 1 x Pen / Strep) before adding 10 pL to the cells (Final DMSO concentration is 0.1 %). Staurosporine was used as a baseline control at a final concentration of 1 pM (0.1 % DMSO). Plates were incubated for a further 72 hours. 50 pL 3D cell titer GLO reagent (Promega) was added to each well and plates were shaken at 250 rpm for 5 minutes at room temperature. Plates were incubated for a further 25 minutes at room temperature, static. Plates were read using a luminescence filter on Perkin Elmer Envision plate reader. All data was baseline subtracted (Staurosporine control wells) before IC50s were generated in GraphPad prism, using a sigmoidal 4-parameter fit (Data constrained).

[0259] Results are shown in Table 1 below.

[0260] Cytotoxicity assay

[0261] HepG2 (ATCC HB-8065) is KRAS wt hepatocellular carcinoma cell line which is commonly used for cytotoxicity assays. HepG2 cells were cultured in EMEM, 10% FBS and Pen / Strep at 37C, 5% CO2. 100 pL HepG2 cells were seeded in to 96-well white plates at 2000 cells per well. Plates were incubated overnight at 37C, 5% CO2. Compounds were solubilised in DMSO and also titrated in DMSO. Compound titrations were diluted 1 in 10 in EMEM 10% FBS, No Pen / Strep. Media was removed from wells’ and 90 pL prewarmed EMEM, 10% FBS, No Pen / Strep was added to each well. 10 pL of diluted compound was added to each well (Final DMSO 1 %). 20% DMSO was used as 100% cell death control. 100 pL media (1 % DMSO) was added to separate wells as blank correction wells. Plates were incubated for a further 24 hours at 37C, 5% CO2. 100 pL Cell titer GLO (Promega) was added to each well. Plates were shaken for 5 minutes at 350 rpm before measuring luminescence on Perkin Elmer Envision plate reader. Data was blank corrected and IC50s generated using Dotmatics (4-parameter fit).

[0262] Results are shown in Table 1 below.

[0263] Table 1 n / d: not detected, n / a: not measured, wt: wild-type KRAS protein, G12D: KRAS G12D mutation, G12C: KRAS G12C mutation

[0264] EMBODIMENTS

[0265] 1. A compound of formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Ri is selected from C=CH or Ci-4alkyl ;

[0266] R2 is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the monocyclic phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci .^alkyl and halogen; n is from 1 to 6; m is 1 or 2;

[0267] Li is selected from the following (Ila), (lib) and (lie): where R4and R6are each independently be selected from H or F; and R7is Ci-4alkyl.

[0268] 2. The compound of formula (I) according to embodiment 1 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Ri is C=CH, methyl or ethyl, preferably wherein Ri is C CH or ethyl, and more preferably wherein Ri is C=CH.

[0269] 3. The compound of formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is selected from a phenyl optionally substituted with one or more halogen substituents and a 5- or 6-membered heteroaryl optionally substituted with one or more Ci-4alkyl substituents.

[0270] 4. The compound of formula (I) according to embodiment 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is selected from a phenyl or a monocyclic 5-membered heteroaryl, wherein the phenyl and monocyclic 5-membered heteroaryl are optionally substituted with one or more substituents selected from Ci-4alkyl and halogen, preferably wherein R2is selected from a phenyl optionally substituted with one or more halogen substituents and a 5- membered heteroaryl optionally substituted with one or more Ci -4alky I substituents.

[0271] 5. The compound of formula (I) according to embodiment 3 or 4, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is selected from a phenyl or thiazole optionally substituted with one or more substituents selected from Ci-4alkyl and halogen, preferably wherein R2is a phenyl optionally substituted with one or more halogen substituents or a thiazole optionally substituted with one or more Ci-4alkyl substituents.

[0272] 6. The compound of formula (I) according to any of embodiments 3 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is a phenyl substituted with one or more halogen substituents or a thiazole substituted with one or more Ci -4alkyl substituents. 7. The compound of formula (I) according to any of embodiments 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein, for R2, the halogen is fluorine.

[0273] 8. The compound of formula (I) according to any of embodiments 3 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the phenyl, 5- or 6-membered heteroaryl or thiazole is substituted with the one or more substituents.

[0274] 9. The compound of formula (I) according to any of embodiments 3 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is selected from a compound of formula (Illa) or (lllb): (lllb); and preferably R2is a compound of formula (Illa).

[0275] 10. The 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 from 1 to 4, preferably wherein n is from 1 to 3, and more preferably wherein n is 2.

[0276] 11. The 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.

[0277] 12. The compound of formula (I) according to any of embodiments 1 to 11 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R7is methyl or ethyl, preferably methyl. 13. The compound of formula (I) according to any of embodiments 1 to 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein Li is of formula (Ila) or (lib), preferably formula (lib).

[0278] 14. The compound of formula (I) according to any of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Li is of formula (Ila), and R4is F.

[0279] 15. The compound of formula (I) according to any of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Li is of formula (lib), and one or both of R4and R6are F.

[0280] 16. The compound of formula (I) according to any of embodiments 1 to 13 or 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein Li is of formula (lib), and both R4and Re are F.

[0281] 17. The compound of formula (I) according to any of embodiments 1 to 13 or 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein Li is of formula (lib), and R6is H and R4is F.

[0282] 18. The compound of formula (I) according to any of embodiments 1 to 17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is of formula (la): The compound of formula (I) according to any of embodiments 1 to 18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is of formula (lb):

[0283] The compound of formula (I) according to any of embodiments 1 to 18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is of formula (Ic): The 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, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is of formula (Id):

[0284]

[0285] The 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, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is of formula (le): The 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, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof of formula (If):

[0286] The compound of formula (I) according to any of embodiments 1 to 23 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is selected from the following:

[0287] and

[0288] The compound of formula (I) according to any of embodiments 1 to 24, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is selected from:

[0289] 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. 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 medicament. 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 therapy or prophylaxis of a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation. 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 the manufacture of a medicament for use in the treatment of a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation. A method of treating a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation, in a subject in need thereof, the method comprising administering to said 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. 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 a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation. 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 a KRAS protein having the KRAS G12D mutation. 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 a KRAS G12D mutation in a cell. 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 a KRAS G12D mutation in a KRAS protein.

[0290] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed 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 to the extent not inconsistent with the present description. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

Claims

CLAIMS1. A compound of formula (I):or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Ri is selected from C=CH or Ci-4alkyl;R2is selected from a phenyl or a monocyclic 5- or 6-membered heteroaryl, wherein the monocyclic phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from Ci _4alkyl and halogen; n is from 1 to 6; m is 1 or 2;Li is selected from the following (Ila), (lib) and (lie):where R4and R6are each independently be selected from H or F; and R7is Ci-4alkyl.

2. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Ri is C=CH, methyl or ethyl, preferably wherein Ri is C CH or ethyl, and more preferably wherein Ri is C CH.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is selected from a phenyl optionally substituted with one or more halogen substituents and a 5- or 6-membered heteroaryl optionally substituted with one or more Ci-4alkyl substituents, preferably wherein R2is selected from a phenyl or a monocyclic 5- membered heteroaryl, wherein the phenyl and monocyclic 5-membered heteroaryl are optionally substituted with one or more substituents selected from Ci-4alkyl and halogen, more preferably wherein R2is selected from a phenyl optionally substituted with one or more halogen substituents and a 5-membered heteroaryl optionally substituted with one or more Ci-4alkyl substituents, more preferably wherein R2is selected from a phenyl or thiazole optionally substituted with one or more substituents selected from Ci^alkyl and halogen, more preferably wherein R2is a phenyl optionally substituted with one or more halogen substituents or a thiazole optionally substituted with one or more Ci^alkyl substituents, and more preferably wherein R2is a phenyl substituted with one or more halogen substituents or a thiazole substituted with one or more Ci^alkyl substituents.

4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R2is selected from a compound of formula (Illa) or (lllb):(lllb); and preferably wherein R2 is a compound of formula (Illa).

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

6. The compound of formula (I) according to any of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein R7is methyl or ethyl, preferably methyl.

7. The compound of formula (I) according to any of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein Li is of formula (Ila) or (lib), preferably formula (lib).

8. The compound of formula (I) according to any of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Li is of formula (Ila), and R4is F.

9. The compound of formula (I) according to any of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein Li is of formula (lib), and one or both of R4and Re are F, and preferably Re is H and R4is F.

10. The compound of formula (I) according to any of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is of formula (la):preferably of formula (Id):and preferably of formula (If):

1. The compound of formula (I) according to any of claims 1 to 10 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof is selected from the following:šnd12. A pharmaceutical composition comprising a compound of formula (I) according to any 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 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 medicament.

14. A compound of formula (I) according to any 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 therapy or prophylaxis of a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation.

15. A compound of formula (I) according to any 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 medicament for use in the treatment of a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation.

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

17. A compound of formula (I) according to any 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 a disease associated with the KRAS G12D mutation, preferably cancer associated with the KRAS G12D mutation.

18. A compound of formula (I) according to any 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 the KRAS G12D mutation.

19. A compound of formula (I) according to any 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 G12D mutation in a cell.

20. A compound of formula (I) according to any 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 G12D mutation in a KRAS protein.

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