EP4676602A1

EP4676602A1 - Compounds targeting mutations in p53 and uses thereof

Info

Publication number: EP4676602A1
Application number: EP24717906.2A
Authority: EP
Inventors: Alexander Pasternak; Ping Liu; Anmol Gulati; Sarah DISHMAN; Indu Bharathan; Joey Methot; Steven Howard; Juan Antonio BUEREN-CALABUIG; Louise Marie Walsh; David Geoffrey TWIGG; Hugh Patrick Charles WALTON; Lynsey Helen Fazal; Steven Douglas Hiscock; James Edward Harvey DAY; Andrew James Woodhead
Original assignee: Otsuka Pharmaceutical Co Ltd; Merck Sharp and Dohme LLC
Current assignee: Otsuka Pharmaceutical Co Ltd; Merck Sharp and Dohme LLC
Priority date: 2023-03-08
Filing date: 2024-03-08
Publication date: 2026-01-14
Also published as: WO2024187153A1; JP2026509240A; GB202303419D0

Abstract

The present disclosure relates to compounds that target mutations in p53, to pharmaceutical compositions comprising said compounds, and to the use of said compounds and compositions as medicaments, such as in the treatment of cancer, and related aspects. Such compounds may bind, stabilise, and restore the level of correctly folded p53 by stabilising an active p53 conformation and restoring wild type-like transcriptional function of mutant p53.

Description

Agent Ref: 12617.0003-00304 COMPOUNDS TARGETING MUTATIONS IN P53 AND USES THEREOF FIELD OF INVENTION The invention relates to compounds, to pharmaceutical compositions comprising said compounds, and to the use of said compounds and compositions as medicaments, such as in the treatment of cancer, and related aspects. BACKGROUND The tumour suppressor p53 is a 393 amino acid protein which upon tetramer formation acts as a transcription factor that regulates cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. p53 has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis or ferroptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. A large number of cancers harbour cells in which TP53, the gene that encodes for p53, is mutated resulting in a loss of the protein’s tumour suppressor function and sometimes even in p53 protein versions that gain novel oncogenic functions. The loss of function results from the mutant p53 being unable to bind to DNA either by loss of residue contact to DNA or loss of the ability to fold into its active conformation required for binding to DNA. 50% of human cancers contain mutant p53 and almost all cancers exhibit malfunction along the p53 pathway. Homozygous loss of the p53 gene occurs in almost all types of cancer, including carcinomas of the breast, colon, and lung. The presence of certain p53 mutations in several types of human cancer can correlate with less favourable patient prognosis. In the absence of stress signals, p53 levels are maintained at low levels via the interaction of p53 with Mdm2, an E3 ubiquitin ligase. In an unstressed cell, Mdm2 can target p53 for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 is disrupted, and p53 accumulates. The critical event leading to the activation of p53 is phosphorylation of the N-terminal domain of p53 by protein kinases, thereby transducing upstream stress signals. The phosphorylation of p53 leads to a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair. p53 can activate proteins involved in the above pathways including, for example, Fas/Apo1, KILLER/DRS, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAFl). Additionally, p53 can repress the transcription of a variety of genes including, for example, c- MYC, Cyclin B, VEGF, RAD5 l, and hTERT. ‐ 1 ‐ Agent Ref: 12617.0003-00304 In its active conformation, the p53 protein is a homotetramer formed by four identical chains of 393 residues each. Each monomer is structurally and functionally divided into multiple domains. At the N-terminus, the transactivation domain (TAD) contains two subdomains (TAD1 and TAD2) that act as transactivation sites. TAD1 binds Mdm2, which sterically blocks p53 dependent transcription and leads to polyubiquitination and degradation of the p53 protein. The TAD domain is followed by a proline rich domain. At the core of the protein, there is a sequence-specific DNA binding domain (DBD). The carboxy terminal region (301-393) of p53 contains a tetramerisation domain and an intrinsically disordered C-terminal domain (CTD), which has a strong regulatory effect on p53 activity through lysine methylation (inactivation) or acetylation (activation). Deletion of the CTD enhances DNA binding and transcription. About 90% of oncogenic mutations found in TP53 from human cancers reside in the DBD. X-ray and NMR structures of the DBD show a compact immunoglobulin-like β-sandwich architecture. The DNA-binding surface is composed of two β-turn loops, L2 and L3, which are stabilised by a zinc ion, interacting with Cys176, Cys238, Cys242 and His179, and a loop- sheet-helix motif. Altogether, these structural elements form an extended DNA-binding surface that is rich in positively charged amino acids such as Arg248 and Arg273 and makes specific contact with various p53 response elements. Mutations in p53 located in the core of the DBD or periphery of the DNA-binding interface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. p53 mutations that can abrogate the activity of p53 include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H, and R282W. These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilise the folded protein at physiological temperature. The wild type p53 DBD has a low melting temperature, and there is a strong correlation between low melting temperature proteins that easily unfold and those that have short half lives in cells. The low melting temperature ensures efficient proteolysis and removal of unstructured proteins. Mutations that decrease the thermal stability of the p53 DBD even further increase its propensity to unfold and aggregate. Wild type function of p53 mutants can be recovered by binding of the p53 mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization and/or enhance the interaction between p53 and its DNA target. It is highly desirable to find small molecules which can bind, stabilise, and restore the level of correctly folded p53 by stabilising an active p53 conformation and restoring wild type-like transcriptional function of mutant p53. ‐ 2 ‐ Agent Ref: 12617.0003-00304 Y220C is a common mutation outside of the DNA-binding surface of p53. Although the Y220C mutation is located at the far end of the β-sandwich, remote from functional areas of the protein, the p53 protein is highly destabilised as a result of the mutation. P53 wild type function is compromised by a Y220C mutation. There remains a need to provide compounds that restore function of the Y220C mutant of p53 and that can be used as a medicament. More specifically, there remains a need to provide compounds that bind to the Y220C p53 mutant and can restore wild type activity of the p53 mutant including, for example, DNA binding function and activation of downstream targets involved in tumour suppression, and that can stabilise the Y220C mutant to reduce the likelihood of denaturation of the protein at body temperature. Furthermore, there remains a need to provide compounds that may demonstrate advantages over known compounds, such as one or more of the following aspects: (i) potency; (ii) in vivo efficacy (iii) pharmacokinetic properties; (iv) metabolic stability; (v) oral bioavailability; (vi) physiochemical properties; and (vii) safety profile or therapeutic index (TI). Novel compounds that demonstrate a desirable profile over a plurality of the above aspects may also be of benefit over known compounds. SUMMARY OF INVENTION The invention provides a compound of formula (I): (I) and ring A is a cyclohexyl, piperidinyl, oxanyl, or thianyl-1,1-dioxide, wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; ‐ 3 ‐ Agent Ref: 12617.0003-00304 X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; OCH₃, C₁haloalkyl, and OC₁haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached join to form a cyclopropyl ring or oxetanyl ring; R³ is chosen from H, S(O)_1-2CH₃, S(O)₂N(R⁵)(R⁶), C(=O)N(R⁵)(R⁶), P(=O)(C_1-3alkyl)₂, CN, and C(CH₃)₂CN; R⁴ is chosen from H, OC1-2alkyl, O-cyclopropyl, C1haloalkyl, halo, CN, and OC1- ₂haloalkyl; wherein when one of R³ or R⁴ is H, the other of R³ or R⁴ is not H; R⁵ is H or C_1-3alkyl; R⁶ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁵ and R⁶, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; R⁷ is chosen from C_1-4alkyl, C_3-6cycloalkyl, 4- to 7-membered heterocyclyl, and C(=O)CH₃, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH₃, and wherein the C_3-6cycloalkyl and 4- to 7-membered heterocyclyl are optionally substituted by one or two CH₃ groups; R⁸ is H or C_1-2alkyl; ‐ 4 ‐ Agent Ref: 12617.0003-00304 R⁹ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; and n is 0, 1, or 2. The invention also provides a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof for use as a medicament. The invention also provides use of a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof in the manufacture of a medicament. The invention also provides a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof for use in the prophylaxis or treatment of a disease or disorder associated with p53 mutation. The invention additionally provides use of a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder associated with p53 mutation. The invention further provides a method for the prophylaxis or treatment of a disease or disorder associated with p53 mutation, said method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. Also provided are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable excipient. Also provided are processes for preparing a compound of formula (I) and pharmaceutically acceptable salts and solvates thereof and novel intermediates of use in the preparation of compounds of formula (I) and pharmaceutically acceptable salts and/or solvates thereof. SEQUENCE LISTING SEQ ID NO: 1 MHHHHHHSGAFEFKLPDIGEGIHEGEIVKWFVKPGDEVNEDDVLCEVQNDKAVVEIPSPV Lipoyl domain fusion tag KGKVLEILVPEGTVATVGQTLITLDAPGYENMTTGSDTGENLYFQGGLNDIFEAQKIEWH Avi-Tag EGSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKLFCQLAKTCPVQLWVDSTP PPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRAEYLDDRNT ‐ 5 ‐ Agent Ref: 12617.0003-00304 FRHSVVVP*C*EPPEVGSDCTTIHYNYMCYSSCMGGMNRRPILTIITLEDSSGNLLGRDSFE *Y220C mutation* ring A is a cyclohexyl, piperidinyl, oxanyl, or thianyl-1,1-dioxide, wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; ‐ 6 ‐ Agent Ref: 12617.0003-00304 X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; OCH₃, C₁haloalkyl, and OC₁haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached join to form a cyclopropyl ring or oxetanyl ring; R³ is chosen from H, S(O)_1-2CH₃, S(O)₂N(R⁵)(R⁶), C(=O)N(R⁵)(R⁶), P(=O)(C_1-3alkyl)₂, CN, and C(CH₃)₂CN; R⁴ is chosen from H, OC_1-2alkyl, O-cyclopropyl, C₁haloalkyl, halo, CN, and OC_1- 2haloalkyl; wherein when one of R³ or R⁴ is H, the other of R³ or R⁴ is not H; R⁵ is H or C_1-3alkyl; R⁶ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; Or R⁵ and R⁶, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; R⁷ is chosen from C1-4alkyl, C3-6cycloalkyl, 4- to 7-membered heterocyclyl, and C(=O)CH₃, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH₃, and wherein the C_3-6cycloalkyl and 4- to 7-membered heterocyclyl are optionally substituted by one or two CH₃ groups; R⁸ is H or C_1-2alkyl; R⁹ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; ‐ 7 ‐ Agent Ref: 12617.0003-00304 Or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; and n is 0, 1, or 2. The invention further provides pharmaceutically acceptable salts of a compound of formula (I). The invention also provides pharmaceutically acceptable solvates of a compound of formula (I). The invention further provides pharmaceutically acceptable salts and solvates of a compound of formula (I) (i.e., a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). The compounds of formula (I), and salts and/or solvates thereof, may be referred to herein as compounds of the invention. Unless the context indicates otherwise, references to formula (I) in all sections of this document (including the uses, methods, and other aspects of the invention) include references to all other sub-formula, sub-groups, and examples as defined herein. Aspects set out below relating to relative stereochemistry and the nature of groups, including A, B, X¹, X², Y, Z, V¹, V², V³, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and n, are envisaged as being independently and fully combinable with one another to form further combinations of the invention. Such aspects apply equally to intermediates that may be of use in the synthesis of a compound of formula (I) (e.g., compounds of formulae (II), (III), (IV), (V), and (VI), and pharmaceutically acceptable salts of any thereof. It will be appreciated that the selection of combinations of functional groups for compounds of formula (I) should result in chemically sensible structures. For example, the positioning of heteroatoms in inappropriate proximity may cause instability. The term ‘halo’ or ‘halogen’ as used herein refers to fluorine, chlorine, bromine, or iodine. Particular examples of halo are fluorine and chlorine, for example fluorine. The term ‘alkyl’ as used herein, such as in C_1-2alkyl, C_1-3alkyl, or C_1-4alkyl, whether alone or forming part of a larger group such as an Oalkyl group (e.g., OC_1-2alkyl), is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. C1alkyl is used interchangeably with methyl. Reference to “propyl” includes n-propyl and iso-propyl, and reference to “butyl” includes n-butyl, iso-butyl, sec-butyl, and tert-butyl. The term ‘haloalkyl’ as used herein, such as in C_1-2haloalkyl or C₁haloalkyl, whether alone or forming part of a larger group such as an Ohaloalkyl group, such as in OC₁haloalkyl, is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, for example fluoro. ‐ 8 ‐ Agent Ref: 12617.0003-00304 An example of haloalkyl is CF₃. Further examples of haloalkyl are CH₂F, CH₂CF₂Cl, CHF₂, CHFCH₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, CF₂CH₃, and CF₂CF₃. The term ‘cycloalkyl’ as used herein, such as in or C_3-6cycloalkyl, whether alone or forming part of a larger group such as OC_3-6cycloalkyl is a fully saturated mono or polycyclic hydrocarbon ring system containing the specified number of ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group is suitably monocyclic. The term ‘heterocyclyl’ as used herein, such as in 6-membered heterocyclyl and 4- to 7-membered heterocyclyl, is a fully saturated or partially unsaturated ring system containing the specified number of carbon and non-carbon ring atoms (i.e., not including any aromatic rings), wherein at least one of the ring atoms is a heteroatom chosen from a N, S, O, and B. Suitable heteroatoms are chosen from N, S, and O. As required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. A heterocyclyl group may be monocyclic. In some examples, the heterocyclyl group is spirocyclic, wherein the two rings are connected through just one atom and at least one of the rings contain a heteroatom chosen from N, S, O, and B. The rings can be different or identical. A suitable example is 2- oxa-6-azaspiro[3.3]heptane. In some examples, a heterocyclyl group may contain one heteroatom chosen from N, S, and O. In some examples, a heterocyclyl group may contain one nitrogen heteroatom. In some examples, a heterocyclyl group may contain one oxygen heteroatom. In some examples, a heterocyclyl group may contain one sulfur heteroatom. In other examples, a heterocycle may contain two heteroatoms independently chosen from N, S, and O. In some examples, a heterocyclyl group may contain two nitrogen heteroatoms. In some examples, a heterocyclyl group may contain one nitrogen heteroatom and one oxygen heteroatom. In some examples, a heterocyclyl group may contain one nitrogen heteroatom and one sulfur heteroatom. In some examples, a heterocyclyl group may contain one oxygen heteroatom and one sulfur heteroatom. Wherein a ring heteroatom is S, the term heterocycle includes wherein the S atom(s) is substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e., S(O) or S(O)₂) to form a sulfone or sulfoxide. Alternatively, any sulfur atom(s) in the heterocycle ring are not substituted. Particular examples include morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidine-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, oxanyl (also known as tetrahydropyranyl) (e.g., oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, and piperazinyl. Heterocyclyl groups may include fully saturated rings such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl. ‐ 9 ‐ Agent Ref: 12617.0003-00304 In some examples, a 6-membered heterocyclyl containing up to two heteroatoms is a fully saturated or partially unsaturated ring system containing six ring atoms, wherein one or two of the ring atoms is a heteroatom chosen from N, O, and S. Particular examples include morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, pyranyl (2H-pyran or 4H-pyran), dihydropyranyl, dioxanyl, oxanyl (also known as tetrahydropyranyl) (e.g., oxan-4-yl), piperazinonyl, and piperazinyl. The term ‘oxo’ as used herein refers to the group =O. The term ‘optionally substituted’ as used herein refers to a group which may be unsubstituted or substituted by a substituent as herein defined. In some compounds of formula (I), ring A is cyclohexyl. When ring A is cyclohexyl, n is 0. Alternatively, n is 1. Alternatively, n is 2. Alternatively, ring A is piperidinyl, such as 4-piperidinyl i.e., indicates the point of attachment and the numbers represent ring atom Ring A may also be 2-piperidinyl. Alternatively, ring A may be 3-piperidinyl. When ring A is piperidinyl, n is 0. Alternatively, n is 1. Alternatively, n is 2. In some compounds of formula (I), the N atom of the piperidinyl ring is not substituted. Alternatively, the N atom of the piperidinyl ring is substituted by R⁷. Alternatively, ring A is oxanyl such as 4-oxanyl i.e., indicates the point of attachment and the numbers represent ring atom When ring A is oxanyl, n is 0. Alternatively, n is 1. Alternatively, n is 2. Alternatively, ring A is thianyl-1,1-dioxide such as 4-thianyl-1,1-dioxide i.e., ‐ 10 ‐ Agent Ref: 12617.0003-00304 indicates the point of the numbers represent ring atom A is thianyl-1,1-dioxide, n is 0. Alternatively, n is 1. Alternatively, n is 2. In some compounds of formula (I), X¹ is C and X² is N. In such compounds, the compounds of formula (I) have the following structure: . Alternatively, of formula (I) have the following . In some ‐ 11 ‐ Agent Ref: 12617.0003-00304 . is CH. Alternatively, V¹ is N. is CH. Alternatively, V² is N. In some compounds of formula (I), V³ is CH. Alternatively, V³ is CF. Alternatively, V³ is N. In the compounds of formula (I), at least one of V¹, V², and V³ is not N, i.e., at least one of V¹, V², and V³ is CH or CF. Thus, in some compounds of formula (I), V¹, V², and V³ are each CH. Alternatively, V¹ and V² are each CH and V³ is N. Alternatively, V¹ and V³ are each CH and V² is N. Alternatively, V² and V³ are each CH and V¹ is N. Alternatively, V¹ and V² are each N and V³ is CH. Alternatively, V¹ and V³ are each N and V² is CH. Alternatively, V² and V³ are each N and V¹ is CH. Alternatively, V¹ is CH, V³ is CF, and V² is N. Alternatively, V² is CH, V³ is CF, and V¹ is N. Alternatively, V¹ and V² are each N and V³ is CF. In some compounds of formula (I), R¹ is H. Alternatively, R¹ is fluoro. Alternatively, R¹ is chloro. Alternatively, R¹ is CH₃. Alternatively, R¹ is OCH₃. Alternatively, R¹ is C₁haloalkyl, such as C₁fluoroalkyl, e.g., CF₃. Alternatively, R¹ is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. In the compounds of formula (I), each R² is replaces one (or two when R² is oxo) hydrogen atom(s) attached to a carbon atom in ring A, such that R² is attached to a carbon atom in ring A. In some compounds of formula (I), R² is attached at the 3-position of ring A, as defined above. In some compounds of formula (I), n is 0. Alternatively, n is 1. Alternatively, n is 2. In some compounds of formula (I), at least one R² is fluoro. Alternatively, at least one R² is chloro. Alternatively, at least one R² is CH₃. Alternatively, at least one R² is C₁haloalkyl, such as C₁fluoroalkyl, e.g., CF₃. Alternatively, at least one R₂ is CH₂OH. Alternatively, at least one R² is oxo. Alternatively, at least one R² is OH. Alternatively, at least one R² is OCH₃. Alternatively, at least one R² is OC₁haloalkyl such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, at least one R² is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is fluoro and the second R² group is fluoro. Alternatively, the second R² group is chloro. Alternatively, the second R₂ group is CH₃. Alternatively, the second R² group is C₁haloalkyl, such as C₁fluoroalkyl, e.g., CF₃. Alternatively, the second R² group is CH₂OH. Alternatively, the second R² group is oxo. Alternatively, the second R² group is OH. Alternatively, the second R² group is OCH₃. ‐ 12 ‐ Agent Ref: 12617.0003-00304 Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is chloro and the second R² group is chloro. Alternatively, the second R₂ group is CH₃. Alternatively, the second R² group is C₁haloalkyl, such as C₁fluoroalkyl, e.g., CF₃. Alternatively, the second R² group is CH₂OH. Alternatively, the second R² group is oxo. Alternatively, the second R² group is OH. Alternatively, the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is CH3 and the second R² group is CH₃. Alternatively, the second R² group is C₁haloalkyl, such as C₁fluoroalkyl, e.g., CF₃. Alternatively, the second R² group is CH₂OH. Alternatively, the second R² group is oxo. Alternatively, the second R² group is OH. Alternatively, the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is C₁haloalkyl and the second R² group is C1haloalkyl, such as C1fluoroalkyl, e.g., CF3. Alternatively, the second R² group is CH₂OH. Alternatively, the second R² group is oxo. Alternatively, the second R² group is OH. Alternatively, the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is CH₂OH and the second R² group is CH₂OH. Alternatively, the second R² group is oxo. Alternatively, the second R² group is OH. Alternatively, the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is oxo and the second R² group is oxo. Alternatively, the second R² group is OH. Alternatively, the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is OH and the second R² group is OH. Alternatively, the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is OCH₃ and the second R² group is OCH₃. Alternatively, the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). ‐ 13 ‐ Agent Ref: 12617.0003-00304 When n is 2, in some compounds of formula (I), one R² is OC₁haloalkyl and the second R² group is OC₁haloalkyl, such as OC₁fluoroalkyl, e.g., OCF₃. Alternatively, the second R² group is N(R⁸)(R⁹). When n is 2, in some compounds of formula (I), one R² is N(R⁸)(R⁹) and the second R² group is N(R⁸)(R⁹). Alternatively, two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached join to form a cyclopropyl ring, i.e., Alternatively, two R² groups to the same carbon and together with 2 the carbon to which the two R groups join to form an oxetanyl ring, i.e., indicates the point of attachment. is 2, two R² are attached to different carbon atoms in ring A, e.g., two fluoro or methyl groups are attached to different carbon atoms in ring A. Alternatively, when n is 2, two R² are attached to the same carbon atom in ring A, e.g., two fluoro or methyl groups are attached to the same carbon atom in ring A. In some compounds of formula (I), R³ is H. Alternatively, R³ is S(O)CH₃. Alternatively, R³ is S(O)₂CH₃. Alternatively, R³ is S(O)₂N(R⁵)(R⁶). Alternatively, R³ is C(=O)N(R⁵)(R⁶). Alternatively, R³ is P(=O)(C_1-3alkyl)₂ such as P(=O)(CH₃)₂. Alternatively, R³ is CN. Alternatively, R³ is C(CH₃)₂CN. In some compounds of formula (I), R⁴ is H. Alternatively, R⁴ is OC_1-2alkyl, such as OCH₃ or OCD₃, e.g., OCH₃. Alternatively, R⁴ is O-cyclopropyl. Alternatively, R⁴ is C₁haloalkyl such as C₁fluoroalkyl, e.g. CF₃. Alternatively, R⁴ is halo, such as fluoro. Alternatively, R⁴ is CN. Alternatively, R⁴ is OC_1-2haloalkyl such as OC₁fluoroalkyl, e.g., OCF₃. ‐ 14 ‐ Agent Ref: 12617.0003-00304 In some compounds of formula (I), R⁵ is H. Alternatively, R⁵ is C_1-3alkyl. Alternatively, R⁵ is methyl. Alternatively, R₅ is ethyl. Alternatively, R⁵ is propyl. In some compounds of formula (I), R⁶ is H. Alternatively, R⁶ is C_1-2alkyl that is optionally substituted by one OCH₃. In some compounds of formula (I), R⁶ is unsubstituted C_1-2alkyl. In some compounds of formula (I), R⁶ is unsubstituted methyl. Alternatively, R₆ is unsubstituted ethyl. In some compounds of formula (I), R₆ is C_1-2alkyl that is substituted by one OCH₃. In some compounds of formula (I), R⁶ is methyl that is substituted by one OCH₃. Alternatively, R⁶ is ethyl that is substituted by one OCH₃. In other compounds of formula (I), R⁵ and R⁶, together with the nitrogen to which they are attached, join to form a 6-membered heterocyclyl containing two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S. In some compounds of formula (I), R⁵ and R⁶ join to form a 6-membered heterocyclyl containing one heteroatom, wherein the one heteroatom is the N atom of the S(O)₂N(R⁵)(R⁶) or C(=O)N(R⁵)(R⁶) group. In some compounds of formula (I), the 6-membered heterocyclyl contains two nitrogen heteroatoms. Alternatively, the 6-membered heterocyclyl contains one nitrogen heteroatom and one oxygen heteroatom. Alternatively, the 6-membered heterocyclyl contains one nitrogen heteroatom and one sulfur heteroatom. In some compounds of formula (I), R⁵ and R⁶ join to form morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, piperazinonyl, or piperazinyl, such as morpholinyl. In some compounds of formula (I), R⁷ is C_1-4alkyl such as methyl, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH₃. In some compounds of formula (I), the C_1-4alkyl group is not substituted. Alternatively, the C_1-4alkyl group is substituted by one or more OH and/or one or more OCH₃. In some compounds of formula (I), the C_1-4alkyl group is substituted by one or more (such as one) OH. Alternatively, the C_1-4alkyl group is substituted by one or more (such as one) OCH₃. Alternatively, the C_1- ₄alkyl group is substituted by one or more (such as one) OH and one or more (such as one) OCH₃, e.g., the C_1-4alkyl group is substituted by one OH and one OCH₃. Alternatively, R⁷ is C_3-6cycloalkyl. In some compounds of formula (I), R⁷ is C₃cycloalkyl. Alternatively, R⁷ is C4cycloalkyl. Alternatively, R⁷ is C5cycloalkyl. Alternatively, R⁷ is C₆cycloalkyl. Alternatively, R⁷ is 4- to 7-membered heterocyclyl. In some compounds of formula (I), R⁷ is 4-membered heterocyclyl. Alternatively, R⁷ is 5-membered heterocyclyl. Alternatively, R⁷ is 6-membered heterocyclyl. Alternatively, R⁷ is 7-membered heterocyclyl. When R⁷ is 7- membered heterocyclyl, the 7-membered heterocyclyl is a 7-membered heterospirocyclyl, such as a 7-membered heterospirocyclyl containing one nitrogen atom and one oxygen atom, e.g., 2-oxa-6-azaspiro[3.3]heptane. ‐ 15 ‐ Agent Ref: 12617.0003-00304 In some examples, the 4- to 7-membered heterocyclyl group contains one heteroatom chosen from N, S, and O. In some examples, the 4- to 7-membered heterocyclyl group contains one nitrogen heteroatom. Alternatively, the 4- to 7-membered heterocyclyl group contains one oxygen heteroatom. Alternatively, the 4- to 7-membered heterocyclyl group contains one sulfur heteroatom. In other examples the 4- to 7-membered heterocyclyl group may contain two heteroatoms chosen from N, S, and O. In some examples, the 4- to 7- membered heterocyclyl group contains two nitrogen heteroatoms. Alternatively, the 4- to 7- membered heterocyclyl group contains one nitrogen heteroatom and one oxygen heteroatom. Alternatively, the 4- to 7-membered heterocyclyl group contains one nitrogen heteroatom and one sulfur heteroatom. Alternatively, the 4- to 7-membered heterocyclyl group contains one oxygen heteroatom and one sulfur heteroatom. In some compounds of formula (I), the R⁷ C_3-6cycloalkyl group is not substituted. In some compounds of formula (I), the R⁷ C₃cycloalkyl group is not substituted. In some compounds of formula (I), the R⁷ C₄cycloalkyl group is not substituted. In some compounds of formula (I), the R⁷ C₅cycloalkyl group is not substituted. In some compounds of formula (I), the R⁷ C6cycloalkyl group is not substituted. In some compounds of formula (I), the R⁷ C_3-6cycloalkyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷ C₃cycloalkyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷ C₄cycloalkyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷ C₅cycloalkyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷ C₆cycloalkyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷4- to 7-membered heterocyclyl group is not substituted. In some compounds of formula (I), the R⁷4-membered heterocyclyl group is not substituted. In some compounds of formula (I), the R⁷5-membered heterocyclyl group is not substituted. In some compounds of formula (I), the R⁷6-membered heterocyclyl group is not substituted. In some compounds of formula (I), the R⁷7-membered heterocyclyl group is not substituted. Alternatively, the R⁷4- to 7-membered heterocyclyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷4-membered heterocyclyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷5-membered heterocyclyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷ 6-membered heterocyclyl group is substituted by one or two (such as one) CH₃ groups. In some compounds of formula (I), the R⁷7-membered heterocyclyl group is substituted by one or two (such as one) CH3 groups. ‐ 16 ‐ Agent Ref: 12617.0003-00304 Alternatively, R⁷ is C(=O)CH₃. In some compounds of formula (I), R⁸ is H. Alternatively, R⁸ is C_1-2alkyl. In some compounds of formula (I), R⁸ is methyl. Alternatively, R⁸ is ethyl. In some compounds of formula (I), R⁹ is H. Alternatively, R⁹ is C_1-2alkyl that is optionally substituted by one OCH₃. In some compounds of formula (I), the C_1-2alkyl group is not substituted. In some compounds of formula (I), R⁹ is methyl and is not substituted. Alternatively, R⁹ is ethyl and is not substituted. Alternatively, the C_1-2alkyl group is substituted by OCH₃. In some compounds of formula (I), R⁹ is methyl and is substituted by one OCH₃. Alternatively, R⁹ is ethyl and is substituted by one OCH3. In some compounds of formula (I), R⁸ and R⁹ join to form a 6-membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S. In some compounds of formula (I), R⁸ and R⁹ join to form a 6-membered heterocyclyl containing one heteroatom, wherein the one heteroatom is the N atom of the N(R⁸)(R⁹) group. Alternatively, R⁸ and R⁹ join to form a 6-membered heterocyclyl containing two heteroatoms wherein one heteroatom is the N atom of the N(R⁸)(R⁹) group and the second heteroatom is independently chosen from N, O, and S. In some compounds of formula (I), the 6-membered heterocyclyl contains two nitrogen heteroatoms. Alternatively, the 6-membered heterocyclyl contains one nitrogen heteroatom and one oxygen heteroatom. Alternatively, the 6-membered heterocyclyl contains one nitrogen heteroatom and one sulfur heteroatom. In some compounds of formula (I), R⁸ and R⁹ join to form morpholinyl, piperidinyl (e.g., piperidin- 1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, piperazinonyl, or piperazinyl, such as morpholinyl. In some embodiments, the compound of formula (I) is a compound of formula (Ic): wherein: X¹ is C and X² is N such that or ‐ 17 ‐ Agent Ref: 12617.0003-00304 X¹ is N and X² is C such that ring B ; Y is chosen from NH, NCH3 and SO2; ; NHCH₃, and P(=O)(CH₃)₂; and n is 0 or 1. In some embodiments, the compound of formula (I) is a compound of formula (Id): wherein R¹, R², X¹, Alternatively, the compound of formula (I) is a compound of formula (Ie): wherein R¹, R², X¹, In some embodiments, the compound of formula (I) is chosen from: ‐ 18 ‐ Agent Ref: 12617.0003-00304 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; 4-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine; 3-methoxy-N-methyl-4-[(3-{7-[(oxan-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; 4-[(3-{7-[(1,1-dioxo-1λ⁶-thian-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)-1-methylpiperidin-4-amine; N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)-1-methylpiperidin-4-amine; (3S,4R)-N-[2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl]-3-fluoro-1-methylpiperidin-4-amine; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine; 4-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; N-(3-{7-[(piperidin-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2- yn-1-yl)acetamide; N-(3-{7-[(oxan-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1- yl)acetamide; N-[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl]acetamide; ‐ 19 ‐ Agent Ref: 12617.0003-00304 3-methoxy-N-methyl-4-[(3-{7-[(1-methylpiperidin-4-yl)amino]-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; 5-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylpyridine-2-carboxamide; 3-methoxy-N-methyl-4-((3-(8-((1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)acetamide; 3-methoxy-N-methyl-4-((3-(8-(piperidin-4-ylamino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1- yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine; N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzonitrile; 3-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylpicolinamide; (3-cyclopropoxy-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (3-(difluoromethoxy)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; 3-chloro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; ‐ 20 ‐ Agent Ref: 12617.0003-00304 2-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylbenzamide; (3-(difluoromethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; 3-cyano-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxypyridin-2-yl)dimethylphosphine oxide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxypyrimidin-2-yl)dimethylphosphine oxide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)dimethylphosphine oxide; 4-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-methoxy-4-((3-(8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 4-((3-(8-((1-(2-hydroxyethyl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((2-(3-((4-methoxypyridin-3-yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-8-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide; (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; 4-((3-(8-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide; 4-((3-(8-(((3S,4R)-1,3-dimethylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-methoxy-N-methyl-4-((3-(8-((5-methyl-5-azaspiro[2.5]octan-8-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; ‐ 21 ‐ Agent Ref: 12617.0003-00304 (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyridin-2- yl)dimethylphosphine oxide; (4-((3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((Trans)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(morpholino)methanone; N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; N-(3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-6-(methylsulfonyl)pyridin-3- yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine; (4-((3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((3R,4R)-3-(hydroxymethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; 1-cyclopropyl-3-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-2-one; 4-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-1-methylpiperidin-2-one; (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2- yl)dimethylphosphine oxide; (3-fluoro-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; ‐ 22 ‐ Agent Ref: 12617.0003-00304 (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; N-((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine; 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 5-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; 4-((3-(8-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; and (4-((3-(7-(((1r,4r)-4-aminocyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. Such compounds may be in the form of a pharmaceutically acceptable salt. Such compounds may be in the form of a pharmaceutically acceptable solvate. Such compounds may be in the form of pharmaceutically acceptable salt and solvate (i.e., a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). The compounds of formula (I) may be synthesised according to the methods set out below and as disclosed in the Examples section. The general synthetic protocol for the compounds is shown in Schemes 1 and 2 and described in detail below. Variations of this protocol to synthesise other compounds described herein are known to the skilled person. Thus, according to a further aspect of the invention there is provided a process for preparing a compound of formula (I) or a salt and/or solvate thereof, which comprises the scheme shown in Scheme 1. ‐ 23 ‐ Agent Ref: 12617.0003-00304 Scheme 1: Synthesis of compounds of formula (I) group as e.g., or a group as halo, e.g., chloro or bromo. Step 1: Compounds of formula (V) are coupled with compounds of formula (IV) in the presence of an organic base such as diisopropylamine, a catalyst such as Pd(PPh₃)₄ and a Cu⁺ catalyst (e.g., CuI) to give compounds of formula (II). Step 2: Compounds of formula (II) undergo nucleophilic aromatic substitution with compounds of formula (III) in the presence of a base (e.g., Cs₂CO₃) and a catalyst such as a Pd²⁺ catalyst (e.g., Pd(OAc)₂) to give compounds of formula (I). The synthetic route set out in Scheme 1 is particularly suitable when Z is: , wherein V¹, V², V³, R³, and R⁴ are as defined elsewhere herein. to a further aspect of the invention, there is provided a process for preparing a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof, which comprises the scheme shown in Scheme 2. ‐ 24 ‐ Agent Ref: 12617.0003-00304 Scheme 2: Alternative synthesis of compounds of formula (I) herein, Q¹ is a leaving group such as halogen, e.g., iodo, or trifluoromethanesulfonate, and is a leaving group such as halo, e.g., chloro or bromo. Step 1: Compounds of formula (V) undergo nucleophilic aromatic substitution with compounds of formula (III) in the presence of an organic base such as triethylamine to give compounds of formula (VI). Heteroatoms such as N atoms in ring A may be optionally protected using a standard nitrogen protecting group known to the skilled person such as Boc. The Boc may be removed after step 1 or step 2. Step 2: Compounds of formula (VI) are coupled with compounds of formula (IV) in the presence of an organic base such as triethylamine, a catalyst such as Pd(PPh3)4 and Cu⁺ (e.g., CuI) to give compounds of formula (I). The synthetic route set out in Scheme 2 is particularly suitable when Z is -C(=O)CH₃. Compounds of formulae (III) and (IV) are commercially available or may be synthesised as set out in the examples section or as described in literature. Compounds of formula (V) may be synthesised as set out in the examples section or as described in literature. In some embodiments, the invention provides a compound of formula (II): ‐ 25 ‐ Agent Ref: 12617.0003-00304 or a salt and/or solvate wherein Q², X¹, X², B, and Z In some embodiments, the invention also provides a compound of formula (V): or a salt and/or solvate thereof; ein Q², X¹, X² wher , B, and Q¹ are as herein. In some embodiments, the invention provides a compound of formula (VI): or a salt and/or solvate wherein A, B, R¹, R², n, X¹, X², and Q¹ are as defined elsewhere herein. The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, dosage forms, and the like which are within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals (e.g., human beings) without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio. It will be appreciated that for use in medicine, the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharmaceutically acceptable salts include acid addition salts ‐ 26 ‐ Agent Ref: 12617.0003-00304 formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, and organic acids (e.g., succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p- toluenesulfonic, methanesulfonic, or naphthalenesulfonic acid). Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines (e.g., ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine). Salts which are not considered to be pharmaceutically acceptable may still be of use, for example, in the preparation of compounds of formula (I) and pharmaceutically acceptable salts and/or solvates thereof, and as such are included within the scope of this invention. In some embodiments, compounds of formula (I) may form pharmaceutically acceptable salts with one or more equivalents of acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In some embodiments, the compound of formula (I) is the free base form. Alternatively, there is provided a compound of formula (I) in the form of a free acid. When a compound contains a basic group as well as the free acid it may be zwitterionic. The compounds of formula (I) may be prepared in crystalline or non-crystalline (amorphous) form and, if crystalline, may optionally be solvated, e.g., as the hydrate. This invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water, MeOH, and EtOH). Also encompassed by formula (I) are any pro-drugs of the compounds of the formula (I). The term “prodrug” as used herein may mean any compound that is converted in vivo into a biologically active compound of the formula (I). It is to be understood that the present invention encompasses all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures) of the compounds of the invention. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where compounds exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in some embodiments, it may be desirable to use only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound of the invention having one or more chiral centres, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the compound of the invention is present as a single optical isomer (e.g., enantiomer or diastereoisomer). In some embodiments, 99% or more of the total amount of the compound ‐ 27 ‐ Agent Ref: 12617.0003-00304 of the invention may be present as a single optical isomer (e.g., enantiomer or diastereoisomer). In some embodiments, compounds of the invention are stereochemically pure. When a compound of the invention is, for example, specified as R, this means that the compound is substantially free of the S isomer. The terms R and S are well known to a person skilled in the art. Compounds containing amine function may also form N-oxides. Consequently, references herein to a compound that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. Additionally, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane. The invention includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring (e.g. to the level of >20%, >50%, >75%, >90%, >95%, or >99%) by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e., they incorporate radioisotopes) and non-radioactive forms. Radioactive forms may be isotopically enriched variant forms. An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (²H or D), carbon-11 (¹¹C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-15 (¹⁵N), oxygen-15 (¹⁵O), oxygen-17 (¹⁷O), ‐ 28 ‐ Agent Ref: 12617.0003-00304 oxygen-18 (¹⁸O), phosphorus-32 (³²P), sulfur-35 (³⁵S), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), fluorine-18 (¹⁸F), iodine-123 (¹²³I), or iodine-125 (¹²⁵I) in one or more atoms or may contain an increased proportion of said isotopes as compared to the proportion that predominates in nature in one or more atoms. Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium, i.e., ²H or D, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, or ¹³N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. In some compounds of formula (I), the compounds are provided in a natural isotopic form. Alternatively, compounds of formula (I) are provided in natural isotopic form unless otherwise indicated. Alternatively, compounds of formula (I) are provided in natural isotopic form other than deuterium (i.e., ²H or D) replacement of a hydrogen atom. The invention therefore also provides a composition, such as a pharmaceutical composition, comprising a compound of the invention, wherein the atoms at each position of the compound have a mass number (or mixture of mass numbers) which is in the normal range of proportions found in nature. In some embodiments, the compounds of the invention are provided in an unnatural variant isotopic form. For example, the unnatural variant isotopic form is a form in which deuterium (i.e., ²H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In some embodiments, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In some embodiments, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. In some embodiments, radioactive isotopes are stable isotopes. In some embodiments, the unnatural variant isotopic form is a pharmaceutically acceptable form. In some embodiments, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. Alternatively, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form. Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein e.g., processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate ‐ 29 ‐ Agent Ref: 12617.0003-00304 isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. THERAPEUTIC METHODS It is envisaged that the compounds of formula (I) will be useful in therapy, including both prophylaxis and treatment. The compounds of formula (I) have been shown to bind to mutant p53 and restore or increase the ability of the p53 mutant to bind DNA, see Biological Example 1. Such activity of the p53 mutant can lead, for example, to inhibition of cancer progression as described in the “Background of the Invention”. In particular, compounds for formula (I) can bind to the p53 Y220C mutant, see Biological Example 3. As a result, compounds of formula (I) may stabilise the Y220C mutant to reduce the likelihood of denaturation in the body. Compounds of formula (I) may therefore induce a conformational change in the p53 mutant and reactivate p53 function. The compounds can, for example, slow the proliferation of cancer cell lines or kill cancer cells, see Biological Example 3. Thus, the invention provides a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof for use as a medicament. The invention also provides use of a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof in the manufacture of a medicament. The invention also provides a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof for use in the prophylaxis or treatment of a disease or disorder affected by p53 mutation. The invention also provides use of a compound of formula (I) and pharmaceutically acceptable salts and/or solvates thereof in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder affected by p53 mutation. The invention also provides a method for the prophylaxis or treatment of a disease or disorder affected by p53 mutation, said method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. Suitably, the disease or disorder affected by p53 mutation is a proliferative disease or disorder. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof increases the ability of the p53 mutant to bind to DNA. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound ‐ 30 ‐ Agent Ref: 12617.0003-00304 of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of increasing the ability of the p53 mutant to bind to DNA. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof reactivates p53 function. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of reactivating p53 function. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof induces a conformational change in the p53 mutant. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of inducing a conformational change in the p53 mutant. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof alters (e.g., increases) the stability of a p53 mutant. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of altering (e.g. increasing) the stability of a p53 mutant. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof restores wild type-function to mutant p53. Restoration may be partial or suitably complete function. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of restoring wild type-function to mutant p53. Restoration may be partial or suitably complete function. ‐ 31 ‐ Agent Ref: 12617.0003-00304 The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is a Y220C reactivator. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of reactivating Y220C. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof reactivates wild type p53 function in cancerous cells. Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is capable of reactivating wild type p53 function in cancerous cells. In some embodiments, the p53 mutant includes a Y220C mutation. In some embodiments, the p53 mutant carries a Y220C mutation. In some embodiments, the p53 mutant carries only a Y220C mutation. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a haematological cancer. Alternatively, the cancer is a non-haematological cancer. The cancer may be a solid cancer such as a cancer comprising lesions or a tumour. In some embodiments, the cancer is chosen from: tumours of epithelial origin (e.g., adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas, and other carcinomas), carcinomas of the bladder and urinary tract (including urothelial carcinoma), breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, bowel, colorectal, rectum, and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney (e.g., renal cell carcinoma), lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas, and mesotheliomas), head and neck (e.g., cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity, and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testes, cervix, myometrium, endometrium, thyroid (e.g., thyroid follicular carcinoma), brain, adrenal, prostate, skin, and adnexae (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, and dysplastic naevus); ‐ 32 ‐ Agent Ref: 12617.0003-00304 haematological malignancies (i.e., leukaemias and lymphomas), premalignant haematological disorders, and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (e.g., acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, T-cell lymphomas and leukaemias, natural killer (NK) cell lymphomas, Hodgkin’s lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (e.g., acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML), chronic myelomonocytic leukaemia (CMML), hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukaemia); tumours of mesenchymal origin (e.g., sarcomas of soft tissue, bone, or cartilage, such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi’s sarcoma, Ewing’s sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans); tumours of the central or peripheral nervous system (e.g., astrocytomas (e.g., gliomas), neuromas and glioblastomas, meningiomas, ependymomas, pineal tumours, and schwannomas); endocrine tumours (e.g., pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours, and medullary carcinoma of the thyroid); ocular and adnexal tumours (e.g., retinoblastoma); germ cell and trophoblastic tumours (e.g., teratomas, seminomas, dysgerminomas, hydatidiform moles, and choriocarcinomas); paediatric and embryonal tumours (e.g., medulloblastoma, neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); and syndromes, congenital or otherwise, which leave the subject susceptible to malignancy (e.g., Xeroderma Pigmentosum or Li-Fraumeni Syndrome). In some embodiments, the cancer is a tumour of the brain, for example glioma, or neuroblastoma. Alternatively, the cancer is a cancer of the skin, for example melanoma. Alternatively, the cancer is a cancer of the lung, for example mesothelioma. Suitably the mesothelioma is malignant peritoneal mesothelioma or malignant pleural mesothelioma. Alternatively, the cancer is a cancer of the gastrointestinal tract, for example gastrointestinal stromal tumour, gastric, colorectal, or bowel. Alternatively, the cancer is osteosarcoma. ‐ 33 ‐ Agent Ref: 12617.0003-00304 Alternatively, the cancer is liposarcoma. Alternatively, the cancer is Ewing’s sarcoma. Alternatively, the cancer is liposarcoma, soft tissue sarcoma, osteosarcoma, oesophageal cancer, and certain paediatric malignancies including B-cell malignancies. Alternatively, the cancer is colorectal, breast, lung, or brain cancer. Alternatively, the cancer is a paediatric cancer. Alternatively, the cancer is of the bladder, urothelial carcinoma, or gastric cancer. Alternatively, the cancer is ovarian, fallopian, endometrial, cervical, or peritoneal. Alternatively, the cancer is a solid tumour, malignant neoplasm, metastatic cancer, or a metastatic solid tumour. Alternatively, the cancer is head and neck cancer (e.g., head and neck squamous cell carcinomas), or pancreatic cancer. Alternatively, the cancer is myelodysplastic syndrome, Acute myeloid leukaemia, myeloproliferative neoplasm, or hematologic neoplasms. Alternatively, the cancer is prostatic neoplasms. A haematological cancer may be a leukaemia. A haematological malignancy may be a lymphoma. Thus, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be used in the prophylaxis or treatment of leukaemia, such as acute or chronic leukaemia, in particular acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), or chronic myeloid leukaemia (CML). Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be used in the prophylaxis or treatment of lymphoma, such as acute or chronic lymphoma, in particular Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, or AIDS related lymphoma. In some embodiments, the cancer is acute myelogenous leukaemia (AML). Alternatively, the cancer is acute lymphocytic leukaemia (ALL). In some embodiments, the cancer is a cancer which is characterised by a p53 mutation such as a Y220C mutation. The compounds of the invention may be useful in the treatment of metastasis and metastatic cancers. Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. The cancers which can be treated by the compounds of formula (I) include primary tumours (e.g., cancer cells at the originating site), local invasion (e.g., cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumours (e.g., tumours that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body). In particular, the compounds of formula (I) may be useful in the treatment of metastasis and metastatic cancers. ‐ 34 ‐ Agent Ref: 12617.0003-00304 The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in the treatment of a lesion or tumour in which p53 carries a Y220C mutation. The invention also provides use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for the treatment of a lesion or tumour in which p53 carries a Y220C mutation. The invention also provides a method for the treatment of a lesion or tumour in which p53 carries a Y220C mutation, said method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in the treatment of a haematological cancer in which p53 carries a Y220C mutation. The invention also provides a use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for the treatment of a haematological cancer in which p53 carries a Y220C mutation. The invention also provides a method for the treatment of a haematological cancer in which p53 carries a Y220C mutation, said method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in the treatment of cell in which p53 carries a Y220C mutation. The invention also provides a use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for the treatment of a cell in which p53 carries a Y220C mutation. Also provided by the invention is a method for treating a cell in which p53 carries a Y220C mutation, said method comprising administering to the cell a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. The invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in the prophylaxis or treatment of cancer in a subject chosen from a sub-population possessing cancers which are p53 mutant. The invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for the prophylaxis or treatment of cancer in a subject chosen from a sub-population possessing cancers which are p53 mutant. The invention provides a method for the prophylaxis or treatment cancer in a subject chosen from a sub-population possessing cancers which are p53 mutant, said method ‐ 35 ‐ Agent Ref: 12617.0003-00304 comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. In any one of the above uses or methods, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is for use in vivo or in vitro. Whether a particular cancer is sensitive to p53 may be determined by methods described herein. Certain cancers are resistant to treatment with particular drugs. This can be due to the type of the tumour or resistance can arise spontaneously as the disease progresses or as a result of treatment. Most common epithelial malignancies are inherently chemoresistant and prostate is relatively resistant to currently available regimens of chemotherapy or radiation therapy. In this regard, reference to prostate includes prostate with resistance towards anti- androgen therapy, in particular abiraterone or enzalutamide, or castrate-resistant prostate. Similarly, reference to multiple myeloma includes bortezomib-insensitive multiple myeloma or refractory multiple myeloma and reference to chronic myelogenous leukaemia includes imitanib-insensitive chronic myelogenous leukaemia and refractory chronic myelogenous leukaemia. In this regard, reference to mesothelioma includes mesothelioma with resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds, and radiation therapy, in particular cisplatin-resistant mesothelioma. The compounds of formula (I) and pharmaceutically acceptable salts and/or solvates thereof may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitizing cells to chemotherapy, and as an anti-metastatic agent. Therapeutic anticancer interventions of all types necessarily increase the stresses imposed on the target tumour cells. p53 reactivators represent a class of chemotherapeutics with the potential for: (i) sensitizing malignant cells to anticancer drugs and/or treatments; (ii) alleviating or reducing the incidence of resistance to anticancer drugs and/or treatments; (iii) reversing resistance to anticancer drugs and/or treatments; (iv) potentiating the activity of anticancer drugs and/or treatments; and (v) delaying or preventing the onset of resistance to anticancer drugs and/or treatments. The compounds of formula (I) or pharmaceutically acceptable salts and/or solvates thereof may be administered in conjunction with radiotherapy, surgery, hyperthermia therapy, or cryotherapy. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts and/or solvates thereof may be administered prior to, after, or in conjunction with the radiotherapy, surgery, hyperthermia therapy, or cryotherapy. The term "prophylaxis" is used herein to mean the provision in advance, and as such may involve preventing symptoms of a disease or disorder in a subject or preventing ‐ 36 ‐ Agent Ref: 12617.0003-00304 recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction. The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms. “Potency” is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations. Potency is proportional to affinity and efficacy. Affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue, or system level. A subject will typically be a subject in need of treatment or prophylaxis according to the invention. Uses according to the present invention may facilitate an improvement of quality of life of a subject and/or prolonged survival or the like. In some instances, proliferation of cancer cells may be reduced, for example tumour growth may be slowed, or tumour size may be reduced. A subject is typically a mammal. Suitably, the subject is a human. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is used in treatment. Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is used in prophylaxis. METHODS OF DIAGNOSIS Prior to administration of a compound of the formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, a subject may be screened to determine whether a disease or condition from which the subject is or may be suffering is one which would be susceptible to treatment with a compound which increases the DNA binding activity of a p53 mutant, such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. The term ‘subject’ includes human and veterinary subjects such as primates, in particular human patients. For example, a biological sample taken from a subject may be analysed to determine whether a cell, such as from a cancer that the subject is or may be suffering from, is one which is characterised by a p53 Y220C mutation. For example, the sequence of the p53 Y220C mutant used for testing compound efficiency can be SEQ ID NO.2 or SEQ ID NO.3. The diagnostic tests and screens are typically conducted on a biological sample (e.g., body tissue or body fluids) chosen from tumour biopsy samples, blood samples (isolation and enrichment of shed tumour cells), cerebrospinal fluid, plasma, serum, saliva, stool biopsies, ‐ 37 ‐ Agent Ref: 12617.0003-00304 sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal smears, skin biopsy, and urine. Methods of identification and analysis of cytogenetic aberration, genetic amplification, mutations, and up-regulation of proteins are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods such as DNA sequence analysis by conventional Sanger or next-generation sequencing methods, reverse- transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), nanostring hybridisation proximity RNA nCounter assays, or in-situ hybridization such as fluorescence in situ hybridization (FISH), or allele-specific polymerase chain reaction (PCR). The skilled person will recognise that all such well-known techniques can be used for detection of p53 variants or mutants. In some embodiments, the subject is one who has been identified as having cells characterised by a p53 Y220C mutation. In some embodiments, the subject is one who has been identified as being susceptible to treatment with a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. Susceptibility to treatment may be determined by screening of cells, such as from a cancer that the subject is or may be suffering from, to identify if the cells are responsive to a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the subject is one who has been identified as having a cancer of a type which is likely to have a p53 mutation that is susceptible to treatment with a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in the prophylaxis or treatment of a disease or disorder affected by p53 mutation in a subject who has been screened and has been determined as suffering from a cancer susceptible to treatment with a compound that can restore wild type function to mutant p53. In some embodiments, the invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder affected by p53 mutation in a subject who has been screened and has been determined as suffering from a cancer susceptible to treatment with a compound that can restore wild type function to mutant p53. In some embodiments, the invention provides a method for the prophylaxis or treatment of a disease or disorder affected by p53 mutation comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein the subject has been screened and has been determined as suffering from a cancer susceptible to treatment with a compound that can restore wild type function to mutant p53. ‐ 38 ‐ Agent Ref: 12617.0003-00304 PHARMACEUTICAL COMPOSITIONS While it is possible for an active compound to be administered alone, it is generally presented as a pharmaceutical composition (e.g., a formulation). Thus, the invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable excipient. The compounds of formula (I) or pharmaceutically acceptable salts and/or solvates thereof may be provided in substantially pure form, for example at least 60% pure, at least 75% pure, and at least 85%, for example at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions. Thus, the present invention further provides methods of making a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt and/or solvate, together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents as described herein. The pharmaceutically acceptable excipient(s) can be chosen from, for example, carriers (e.g., a solid, liquid, or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers, or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below. Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof can be formulated in accordance with known techniques. See for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or for direct delivery into a target organ or tissue by injection, infusion, or other means of delivery. The delivery can be by bolus injection, short-term infusion ‐ 39 ‐ Agent Ref: 12617.0003-00304 or long-term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilizing the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, p 201-230). The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials, and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. In some embodiments, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution using an appropriate diluent. The pharmaceutical formulation can be prepared by lyophilising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate, or sub-groups thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil, or olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of thickening materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. ‐ 40 ‐ Agent Ref: 12617.0003-00304 The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminium monostearate and gelatin. In some embodiments, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration. The pharmaceutical composition may be in a form suitable for sub-cutaneous (s.c.) administration. Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, wafers, or patches such as buccal patches. Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g. lactose, sucrose, sorbitol or mannitol, and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., butylated hydroxytoluene or BHT), buffering agents (e.g., phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract. Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof. ‐ 41 ‐ Agent Ref: 12617.0003-00304 The solid dosage forms (e.g., tablets, capsules, etc.) can be coated or un-coated. Coatings may act either as a protective film (e.g., a polymer, wax, or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes. The coating (e.g., a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum, or colon. Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be presented in a polymer coating (e.g., a polymethacrylate polymer coating), which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g., a maleic anhydride polymer), which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (e.g., formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art. The compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may be formulated with a carrier and administered in the form of nanoparticles. The increased surface area of the nanoparticles may assist in increasing absorption of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof. In addition, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13th March 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909. The pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95% active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient or combination of excipients. Typically, the compositions comprise from approximately 20% (w/w) to approximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, ‐ 42 ‐ Agent Ref: 12617.0003-00304 typically from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragées, tablets, or capsules. The pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be chosen from diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g., release retarding or delaying polymers, or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents, and coating agents. The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example, tablets and capsules typically contain 0- 20% disintegrants, 0-5% lubricants, 0-5% flow aids, and/or 0-99% (w/w) fillers or bulking agents (depending on drug dose). Tablets and capsules may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, and 0-5% (w/w) pigments. Slow-release tablets may additionally contain 0-99% (w/w) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w/w) release-controlling (e.g., delaying) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers. Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w/w) oils. Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts. The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids. Solid solutions (molecularly disperse systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs. This invention also provides solid dosage forms comprising the solid solution described herein. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution blended with (a) ‐ 43 ‐ Agent Ref: 12617.0003-00304 a disintegrant and a lubricant, or (b) a disintegrant, a lubricant, and a surfactant. In addition, a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent, and a glidant. A chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours. Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘non- pareils’). These beads can subsequently be filled into capsules or compressed into tablets. The pharmaceutical formulations may be presented to a subject in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a subject’s supply of a pharmaceutical from a bulk supply, in that the subject always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve subject compliance with the physician’s instructions. Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops, and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods. Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration. Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose. A compound of the formula (I) or a pharmaceutically acceptable salt and/or solvate may be presented in unit dosage form and, as such, contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g., from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g., 0.1 milligrams to 2 milligrams of active ingredient). ‐ 44 ‐ Agent Ref: 12617.0003-00304 For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g., 100 miligrams to 1 gram, of active compound. The active compound may be administered to a subject in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect. ADMINISTRATION The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, typically a human patient. The compounds may be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations (for example in the case of life-threatening diseases), the benefits of administering a compound of the formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity. The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g., a pulsatile manner). A typical daily dose of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate can be in the range from 100 picograms to 100 milligrams per kilogram of body weight. The compounds of the invention can also be administered by bolus or continuous infusion. The quantity of compound administered, and the type of composition used, may be commensurate with the nature of the disease or physiological condition being treated and may be at the discretion of the physician. It may be beneficial to use a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as a single agent or to combine the compound of the invention with another agent which acts via a different mechanism to regulate cell growth thus treating two of the characteristic features of cancer development. Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose- effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27–55. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof can be administered as the sole therapeutic agent or can be administered in combination ‐ 45 ‐ Agent Ref: 12617.0003-00304 therapy with one of more other compounds (or therapies) also suitable for the treatment or prophylaxis of the diseases and disorders listed herein. In some embodiments, the combination therapy comprises a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and one or more other anticancer compounds (or therapies) for treatment of cancer. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants (supporting agents in the therapy) in cancer therapy. Examples of other therapeutic agents or treatments that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) or pharmaceutically acceptable salts and/or solvates thereof are chosen from: topoisomerase I inhibitors, antimetabolites and nucleoside derivatives, tubulin targeting agents including the vinca alkaloids, epothilones, tubulin-binding agents and taxanes, DNA binders such as platinum agents and anthracyclines, and topoisomerase II inhibitors, alkylating agents, monoclonal antibodies, anti-hormones such as GnRAs, estrogen receptor antagonists, selective estrogen receptor modulators (SERMs), aromatase inhibitors, antiandrogens, signal transduction inhibitors, proteasome inhibitors, DNA methyl transferase inhibitors, recombinant interferons, retinoids, chromatin targeted therapies, radiotherapy, and other therapeutic or prophylactic agents. Examples of other therapeutic agents or treatments that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) or pharmaceutically acceptable salts and/or solvates thereof are chosen from: platinum compounds, taxane compounds, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, nucleoside derivatives, antimetabolites, alkylating agents, cytotoxics, anthracyclines, anthracenediones and related drugs, epothilones; DNA methyl transferase inhibitors, histone methyl transferase inhibitors, antifolates, cytotoxic antibiotics, tubulin- binding agents, signal transduction inhibitors, mitotic kinase inhibitors, CDK inhibitors, PI3K/AKT pathway inhibitors, ERK inhibitors, Hsp90 inhibitors, monoclonal antibodies, antibody derivatives, bispecific antibodies and "antibody-like" therapeutic proteins or other therapeutic proteins and related agents, estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, aromatase inhibitors and related drugs, antiandrogens (i.e., androgen receptor antagonists) and related agents, hormones and analogues thereof, steroids, steroidal cytochrome P45017-alpha-hydroxylase- 17,20-lyase inhibitor (CYP17), gonadotropin releasing hormone agonists or antagonists (GnRAs), glucocorticoids, differentiating agents, hedgehog pathway inhibitors, dehydrogenase inhibitors, exportin 1 inhibitors, polymerase inhibitors, farnesyltransferase ‐ 46 ‐ Agent Ref: 12617.0003-00304 inhibitors, chromatin targeted therapies, drugs targeting the ubiquitin-proteasome pathway including proteasome inhibitors, photodynamic drugs, marine organism-derived anticancer agents, radiolabelled drugs for radioimmunotherapy, telomerase inhibitors, matrix metalloproteinase inhibitors, recombinant interferons and interleukins, selective immunoresponse modulators, therapeutic vaccines, cytokine-activating agents, cytokine- conjugates, arsenic trioxide, inhibitors of G-protein coupled receptors (GPCR), enzymes, DNA repair inhibitors, agonists of death receptor, other immunotherapies, regulators of cell death (apoptosis), gene modifiers or editors, inhibitors of bromodomains, radiotherapy for radical, palliative, or prophylactic purposes (or, for adjuvant or neoadjuvant purposes), and prophylactic agents (adjuncts) i.e., agents that reduce or alleviate some of the side effects associated with chemotherapy agents. In some embodiments, the combination therapy comprises a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and one or more other anticancer compounds (or therapies) for treatment of cancer optionally in combination with radiotherapy and/or prophylactic agents. In some embodiments, the combination therapy comprises a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in combination with radiotherapy and/or prophylactic agents. Particular examples of anti-cancer agents or adjuvants (or salts thereof) are chosen from: platinum compounds (e.g., cisplatin, cisplatin optionally combined with amifostine, carboplatin, oxaliplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, satraplatin or triplatin tetranitrate, in particular cisplatin, carboplatin, or oxaliplatin); taxane compounds (e.g., paclitaxel, paclitaxel protein bound particles (Abraxane^TM), docetaxel, cabazitaxel, larotaxel; ortataxel, tesetaxel, or simotaxel, in particular paclitaxel, paclitaxel protein bound particles (Abraxane^TM), or docetaxel); topoisomerase I inhibitors (e.g., camptothecin compounds such as camptothecin, irinotecan (CPT11), SN-38, topotecan, bryostatin, callystatin, nogitecan, belotecan, exatecan, rubitecan or lurtotecan, in particular camptothecin, irinotecan or topotecan); topoisomerase II inhibitors (e.g., anti-tumour epipodophyllotoxins or podophyllotoxin derivatives such as etoposide, teniposide, sobuzoxane, edotecarin, amonafide, amrubicin or pixantrone, in particular etoposide or teniposide); vinca alkaloids (e.g., vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine, vinvesir, eribulin, or thaliblastine; in particular vinblastine, vincristine or vinorelbine); nucleoside derivatives (e.g., 5-fluorouracil (5-FU, optionally in combination with leucovorin, e.g., LV5FU2), gemcitabine, capecitabine, tegafur (optionally in combination with uracil known as UFT, or in combination with gimeracil and oteracil potassium known as TS-1 or S1), cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, nelarabine; forodesine, doxifluridine, galocitabine, sapacitabine, emitefur, or troxacitabine); ‐ 47 ‐ Agent Ref: 12617.0003-00304 antimetabolites (e.g., clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, hydroxyurea (hydroxycarbamide) or trifluridine (optionally in combination with tipiracil)); alkylating agents, such as nitrogen mustards or nitrosourea (e.g., cyclophosphamide, chlorambucil, carmustine (BCNU), ambamustine, bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, mechlorethamine oxide hydrochloride, methylcyclohexylchloroethylnitrosurea, nimustine (ACNU), prednimustine, meclorethamine, etoglucid; streptozotocin, irofulven, mitolactol, glufosfamide, evofosfamide, ethylenimines or methylamelamines including altretamine, triethylenemelamine, trimethylolomelamine, triethylenephosphoramide, triethylenethiophosphoramide, or trimemylolomelamine); other cytotoxics, (e.g., dolastatin, eleutherobin, pancratistatin, sarcodictyin A, or spongistatin); anthracyclines, anthracenediones and related drugs (e.g., daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g., Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin); epothilones (e.g., ixabepilone, patupilone, BMS-310705, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS-862), aza-epothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin); DNA methyl transferase inhibitors (e.g., temozolomide, azacytidine, decitabine (alone or in combination with a cytidine deaminase inhibitor, such as cedazurdine) or guadecitabine (SGI-110)); histone methyl transferase inhibitors (e.g., EZH2 inhibitors such as tazemetostat, PF-06821497, CPI-1205 or CPI-0209); antifolates (e.g., methotrexate, pemetrexed disodium, raltitrexed, pralatrexate, edatrexate or trimetrexate); cytotoxic antibiotics (e.g., antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin, aclarubicin, pirarubicin, anthramycin, azaserine, cactinomycin, calicheamicin, carabicin, carzinophilin, chromomycins, detorubicin, esorubicin, esperamicins, geldanamycin, marcellomycin, olivomycins, peplomycin, puromycin, quelamycin, rebeccamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, dynemicin including dynemicin A, centanamycin (CC-1065), including its adozelesin, carzelesin, and bizelesin synthetic analogue, duocarmycin, including the synthetic analogue pibrozelesin (KW-2189), or zinostatin); tubulin-binding agents (e.g., combrestatin, colchicines, demecolcine, noscapine, or nocodazole); signal transduction inhibitors such as kinase inhibitors (e.g., receptor tyrosine kinase inhibitors including EGFR (epidermal growth factor receptor (Erbb1) inhibitors), VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, FGFR (fibroblast growth factor receptor) inhibitors, Axl inhibitors, MTKI (multi target kinase ‐ 48 ‐ Agent Ref: 12617.0003-00304 inhibitors), c-Kit inhibitors, other Erbb inhibitors such as Errb2 (HER2), Errb3 (HER3) or Errb4 (HER4), Trk inhibitors, Flt3 inhibitors, JAK inhibitors, RET inhibitors, MET inhibitors, Btk inhibitors, ALK inhibitors, ROS1 inhibitors, FYN inhibitors, Src inhibitors, Bcr-Abl inhibitors, hexokinase inhibitors, Raf inhibitors, ROCK inhibitors, MEK inhibitors or PI3K Inhibitors such as imatinib, erlotinib, gefitinib, afatinib (dual EGFR/HER2), brigatinib (ALK/EGFR), osimertinib (EGFR), almonertinib (EGFR), olmutinib (EGFR), icotinib (EGFR), alflutinib (EGFR), lazertinib (EGFR), zorifertinib (EGFR), mefatinib (EGFR), sutetinib (EGFR), dasatinib, lapatinib, dovitinib (CHIR 258), axitinib (AG-13736), nilotinib, vandetanib, vatalinib, saracatinib (AZD- 0530), bosutinib, bafetinib (NS-187), abivertinib (EGFR, Btk), mobocertinib (EGFR, Erbb2), anlotinib (multi-kinase), avapritinib (KIT, PDGF), lenvatinib (E-7080)(multi-kinase), pyrotinib (multi kinase), lonidamine (hexokinase), BMS- 690514, nintedanib (tyrosine kinase), ponatinib (multi-kinase), tivozanib (KRN-951)(multi kinase), R-1530 (multi kinase), vatalanib (PDGF, VEGF), PF-337210 (VEGF), AEE-788 (multi kinase), tesevatinib (XL-647)(multi kinase), K- 0706, ripretinib (KIT, PDGF), dacomitinib (EGFR, Erbb2/Erbb4), neratinib (EGFR, Erbb2/Erbb4), varlitinib (EGFR, Erbb2/Erbb4), tucatinib (Erbb2), larotrectinib (Trk), erdafitinib (FGFR), infigratinib (FGFR), pemigatinib (FGFR), rogaratinib (FGFR), derazantinib (FGFR), E-7090 (FGFR), HMPL-453 (FGFR), zoligratinib (FGFR), futibatinib (FGFR), brivanib (FGFR, VEGFR), Ki 23057(FGFR), surufatinib (FGFR, VEGFR), pazopanib (GW 786034), cediranib (KIT, VEGFR, PDGFR), orantinib (FGF, PDGF, VEGF), H3B-6527, MAX-40279, ICP-105, telatinib (BAY-57-9352)(KIT, PDGFR, VEGFR), pegaptanib (VEGFR), semaxanib (MAPK, VEGFR), quizartinib (AC-220)(Flt3, KIT, PDGFR), crenolanib (CP 868596)(Flt3, PDGFR), lestaurtinib (multi kinase), Cabozantinib (XL-184)(VEGFR2, Axl, MET, RET), selpercatinib (RET), pralsetinib (RET), capmatinib (MET), tepotinib (MET), MK-2461 (MET), SU- 11274(MET), PHA-665752(MET), ibrutinib (Btk), acalabrutinib (Btk), asciminib (Bcr-Abl), flumatinib (Abl), zanubrutinib (Btk), pirtobrutinib (Btk), ruxolitinib (JAK), itacitinib (JAK), pacritinib (JAK), momelotinib (JAK), INCB-52793 (JAK), gusacitinib (JAK/SYK), ilginatinib (JAK), cerdulatinib (Syk, JAK), fedratinib (TG-101348)(Flt3, Jak2, RET), tandutinib (Flt3, KIT, PDGF), pexidartinib (KIT, Flt3), midostaurin (Flt3, KIT, PKC), zotiraciclib (FLT3), gilteritinib (Flt3), alectinib (ALK), crizotinib (ALK), ceritinib (ALK), lorlatinib (ALK,Ros1), entrectinib (ALK, Ros1, TRK), masitinib (multi kinase), sorafenib, sunitinib, vemurafenib (PLX4032 or RG7204), dabrafenib, encorafenib, regorafenib (BAY-73-4506)(FGFR3, KIT), selumetinib (AZD6244), trametinib (GSK121120212), binimetinib (BRAF, MEK), cobimetinib (MEK), mirdametinib (PD325901)(MEK), refametinib (MEK), uprosertib (AKT, MEK), pimasertib (MEK), dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), alpelisib (BYL719)(PI3), copanlisib (BAY- 80-6946), paxalisib (PI3K/mTOR/AKT pathway), S-49076 (multi kinase), rigosertib (multi kinase), rebastinib (multi kinase), ZSTK-474, fimepinostat (CUDC-907)(PI3K and HDAC), ‐ 49 ‐ Agent Ref: 12617.0003-00304 apitolisib (GDC-0980; RG-7422), pictilisib (GDC-0941, RG-7321, GNE-477), idelalisib (formerly CAL-101, GS 1101, GS-1101, IC87114), serabelisib (MLN1117, INK1117)(PI3K), sapanisertib (MLN0128 (INK128)), duvelisib (IPI-145, INK1197)(PI3K), ipatasertib (GDC- 0068), afuresertib, MK-2206, MK-8156, SKLB-1028, LY294002, SF1126 or PI-103, sonolisib (PX-866), GSK1059615(PI3K), pilaralisib (XL147)(PI3K), SF-1126 (multi kinase) or AT13148 or pan-Raf inhibitors such as PLX8394,RAF-265, or other signal transduction inhibitors such as mTOR inhibitors including temsirolimus, everolimus (RAD 001), and RAS inhibitors such as sotorasib (AMG-510), LY-3499446, adagrasib (MRTX-849), or ARS-3248, or isoprenyltransferase inhibitors such as antroquinonol); mitotic kinase inhibitors such as aurora kinase inhibitors (e.g., AT9283, barasertib (AZD1152), danusertib (PHA-739358), alisertib (MLN-8237), or CYC-116, or PLK (polo-like kinase inhibitors) such as PLK-1 or PLK-4, including rigosertib, onvansertib, CYC-140, GSK-461364, CFI-400945, or volasertib); CDK inhibitors (e.g., AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), abemaciclib, dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, PHA533533, ZK-304709, zotiraciclib or AZD-5438 and including CDK4 inhibitors such as palbociclib (PD332991), abemaciclib, dinaciclib, lerociclib, trilaciclib or ribociclib (LEE-011)); PI3K/AKT pathway inhibitors including PKA/B and/or PKB (akt) inhibitors, PI3K inhibitors, mTOR inhibitors, and/or calmodulin inhibitors (forkhead translocation inhibitors) (e.g., PI3K inhibitors such as apitolisib, buparlisib, copanlisib, pictilisib, dactolisib, idelalisib, serabelisib, duvelisib, ipatasertib, alpelisib, afuresertib, paxalisib, sonolisib, pilaralisib, fimepinostat (CUDC-907), SKLB-1028, GSK1059615 (PI3K), ZSTK-474, GSK-2636771, samotolisib (LY-3023414), LY294002, SF1126 and PI-103, mTOR inhibitors such as sirolimus (originally known as rapamycin), and rapamycin analogues such as RAD 001 (everolimus), CCI 779 (temsirolemus), AP23573 and ridaforolimus, or sapanisertib (MLN0128 (INK128), a dual inhibitor of the mTOR complex I (mTORCI) and mTORC2, PKA/B (or C) inhibitors such as perifosine, ipatasertib, uprosertib, afuresertib, MK-2206, MK-8156, AT13148, capivasertib (AZD5363), triciribine, Enzastaurin, XL-418, GSK-690693, or RX-0201); ERK inhibitors including ulixertinib, ASTX029, LY3214996, LTT462, MK-8353, SCH772984, AZD-0364, ASN-007, or KO-947; Hsp90 inhibitors (e.g., onalespib (AT13387), herbimycin, geldanamycin (GA), 17-allylamino-17- desmethoxygeldanamycin (17-AAG) (e.g., NSC-330507, Kos-953 and CNF-1010), 17- dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) (e.g., NSC- 707545 and Kos-1022), NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 an oral purine), alvespimycin, ganetespib (STA-9090), SNX-5422 (SC-102112) or IPI-504 or pimitespib); monoclonal antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents e.g., cytotoxic anticancer agents, such as antibody-drug conjugates), antibody derivatives, bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs™, ‐ 50 ‐ Agent Ref: 12617.0003-00304 Duobodies™, Bites™, XmAbs™, TandAbs™, or Fab derivatives), or other therapeutic proteins and related agents, such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR antibodies, for example rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), veltuzumab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ado- trastuzumab emtansine, fam-trastuzumab deruxtecan, ertumaxomab (HER2 and CD3), cetuximab (EGFR), matuzumab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), zalutumumab (EGFR), amivantamab (EGFR), bevacizumab (VEGF), ramucirumab (VEGFR), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab estafenatox (5T4), siltuximab (IL6), zanolimumab (CD4), SGN40 (CD40), ficlatuzumab, (anti-HGF), blinatumomab (CD3 modulator; B-lymphocyte antigen CD19 modulator), tafasitamab-cxix (CD19), loncastuximab tesirine (CD19), brentuximab vedotin (CD30), daratumumab (IgG1kappa antibody), moxetumomab, ranibizumab (anti-VEGF), enfortumab vedotin, sacituzumab govitecan, obinutuzumab (CD20), inotuzumab ozogamicin (CD22), belantamab mafodotin, brentuximab vedotin (CD30), obinutuzumab (CD20), teclistamabmogamulizumab (CCR4), polatuzumab vedotin (CD79b), isatuximab (CD38), dinutuximab (GD2), olaratumab (IMC 3G3, PDGF mAb), margetuximab, naxitamab (GD2), anti-FGFR MAbs (IMC-D11), anti-PDGF receptor-beta mAbs (1B3), aflibercept (AVE-0005)(VEGF trap), teclistamab (bispecific antibody BCMA and CD3), mosunetuzumab (bispecific antibody CD20 and CD3), tisotumab vedotin (antibody drug conjugate), mirvetuximab soravtansine (antibody drug conjugate), or immunomodulating antibodies, including check point inhibitors or agents such as CTLA-4 blocking antibodies and/or antibodies against PD-1 and PD-L1 and/or PD-L2 for example ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS- 936559 (anti- PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4); atezolizumab (anti-PDL1), durvalumab (anti-PDL1), avelumab (anti-PDL1), cemiplimab (anti-PD-1), pidilizumab (anti- PD-1); PDR- 001 (anti-PD-1), spartalizumab (anti-PD-1), dostarlimab (anti-PD-1), ipilumumab (anti-CTLA- 4), abatacept (antibody fragment and conjugate with CTLA-4), anti-LAG3, such as relatlimab, LAG-525, TSR-033, IBI-110 or FS-118, and anti-OX40 (CD134) agents (e.g., MOXR0916, MEDI6469, PF-04518600, MEDI0562, BMS 986178, ISB-830, KY-1005, or INCAGN-1949); estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, for example tamoxifen, fulvestrant, elacestrant, camizestrant, ‐ 51 ‐ Agent Ref: 12617.0003-00304 toremifene, droloxifene, faslodex, raloxifene or keoxifene; aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrozole, testolactone aminoglutethimide, mitotane or vorozole; fadrozole, liarozole, atamestane, formestane, dexaminoglutethimide, or trilostane; antiandrogens (i.e., androgen receptor antagonists) and related agents such as bicalutamide, nilutamide, flutamide, cyproterone, ketoconazole, apalutamide, darolutamide, or enzalutamide; hormones and analogues thereof such as medroxyprogesterone, diethylstilbestrol (a.k.a. diethylstilboestrol) or octreotide; finasteride, fludrocortisone, fluoxymesterone, arzoxifene, pasireotide, or vapreotide; steroids such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), fluoxymestrone, gossypol, calusterone, epitiostanol, or mepitiostane; steroidal cytochrome P450 17-alpha- hydroxylase-17,20-lyase inhibitor (CYP17) (e.g., abiraterone); fadrozole; gonadotropin releasing hormone agonists or antagonists (GnRAs) for example abarelix, relugolix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, deslorelin; leuprorelin, or nafarelin; glucocorticoids, for example prednisone, prednisolone, or dexamethasone; differentiating agents, such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane, alitretinoin, bexarotene, or tretinoin; fenretinide, isotretinoin, or RII retinamide; hedgehog pathway inhibitors, such as glasdegib, vismodegib, or sonidegib; dehydrogenase inhibitors such as isocitrate dehydrogenase inhibitors, including enasidenib, ivosidenib, vorasidenib, IDH-305, olutasidenib, DS-1001b, enfludenib, dihydroorotate dehydrogenase inhibitors including laflunimus, brequinar, ASLAN-003, AG-636, BAY-2402234, or PTC-299; or Pyruvate dehydrogenase inhibitors such as devimistat, or KULA-18; exportin 1 inhibitor such as selinexor, eltanexor, verdinexor, or felezonexor; polymerase inhibitors, such as DNA or RNA polymerase inhibitors, including lurbinectedin; farnesyltransferase inhibitors for example tipifarnib; chromatin targeted therapies such as histone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP-LAQ824), R306465/JNJ-16241199, JNJ-26481585, trichostatin A, vorinostat, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, apicidin; belinostat, panobinostat, romidepsin, resminostat, abexinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat, or fimepinostat; drugs targeting the ubiquitin-proteasome pathway including proteasome inhibitors for example bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), oprozomib, ubenimex CEP-18770, MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonist, idasanutlin (RG7388), HDM-201, KRT-232 (AMG-232), nutlin 3a, RG7112, CGM-097, ALRN-6924, MI-773 (SAR405838), milademetan (DS-3032b), APG-115, serdemetan, DS-5272,BI-0252, AM-7209, SP-141, SCH-1450206, RO-8994, RG- 7775 or BI-907828, or ASTX295 or UBX0101; inhibitors of deubiquitinases (DUBs); or ‐ 52 ‐ Agent Ref: 12617.0003-00304 inhibitors of ubiquitin-specific proteases such as HBX-41108; photodynamic drugs for example porfimer sodium or temoporfin; marine organism-derived anticancer agents such as trabectidin; eadiolabelled drugs for radioimmunotherapy for example with a beta particle- emitting isotope (e.g., Iodine-131, Yittrium-90) or an alpha particle-emitting isotope (e.g., Bismuth-213 or Actinium-225) for example ibritumomab, Iodine tositumomab, alpha radium 223; iobenguane, or lutetium Lu 177-dotatate; telomerase inhibitors for example telomestatin; matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat; recombinant interferons (such as interferon-γ and interferon-α) and interleukins (e.g., interleukin 2), for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b; selective immunoresponse modulators for example thalidomide, or thalidomide derivatives such as lenalidomide; or pomalidomide (ENMD 0995, CC-4047); therapeutic caccines such as sipuleucel-T (Provenge^TM) OncoVex, intravesical BCG live, mDC3 vaccine, PEPIDH1M vaccine, T-VEC or IDH1 targeting vaccine; cytokine-activating agents including picibanil, romurtide, sizofiran, virulizin, or thymosin; cytokine-conjugates, such as cytokine-toxin conjugates including tagraxofusp; arsenic trioxide; inhibitors of G- protein coupled receptors (GPCR) for example atrasentan; enzymes such as L-asparaginase, pegaspargase, rasburicase, or pegademase; DNA repair inhibitors such as PARP inhibitors for example, olaparib, rucaparib, veliparib, iniparib, niraparib, INO-1001, AG-014699, ONO- 2231; or talazoparib; agonists of death receptor (e.g., TNF-related apoptosis inducing ligand (TRAIL) receptor), such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008, apomab or recombinant TRAIL ligands such as recombinant Human TRAIL/Apo2 Ligand; other immunotherapies such as oncolytic viruses, such as talimogene laherparepvec (T-VEC); CAR-T cell therapy, such as anti-CD-19 CAR T cell therapy for example, tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene, idecabtagene, brexucabtagene autoleucel (KTE-X19); engineered T cell receptor (TCR-T) therapy; TLR agonists, such as motolimod, imiquimod, rintatolimod or resiquimod or immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors e.g. lazertinib, CA- 170, CCX-4503, PCC0208025 (BMS202), GS-4224, INCB-086550, or RRx-001; regulators of cell death (apoptosis) including Bcl-2 (B-cell lymphoma 2) antagonists such as venetoclax (ABT-199 or GDC-0199), ABT-737, ABT-263, TW-37, sabutoclax, obatoclax, and MIM1 and IAP antagonists including LCL-161 (Novartis), Debio-1143 (Debiopharma/Ascenta), AZD5582, Birinapant / TL-32711 (TetraLogic), CUDC-427 / GDC-0917 / RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech), ASTX660 or HGS-1029/AEG-40826 (HGS/ Aegera); and myeloid cell leukemia-1 (MCL-1 a member of the BCL2 family) inhibitors including AMG-176, MIK665, and S63845; gene modifiers or editors, such as CRISPR/ Cas9, zinc finger nucleases or synthetic nucleases, or TALENs; inhibitors ‐ 53 ‐ Agent Ref: 12617.0003-00304 of bromodomains including BET inhibitors such as GSK525762, GSK2820151, OTX-015/MK- 8628, BMS-986158, CPI-0610, RO6870810/TEN-010, RVX000222, FT-1101, ABBV-075, BAY1238097, INCB054329, INCB057643, PLX51107 or ZEN003694; radiotherapy for radical, palliative or prophylactic purposes (or, for adjuvant or neoadjuvant purposes); and prophylactic agents (adjuncts); i.e. agents that reduce or alleviate some of the side effects associated with chemotherapy agents, for example anti-emetic agents, agents that prevent or decrease the duration of chemotherapy-associated neutropenia and prevent complications that arise from reduced levels of platelets, red blood cells or white blood cells, for example interleukin-11 (e.g., oprelvekin), erythropoietin (EPO) (e.g., epoetin alfa, epoetin beta) or analogues thereof (e.g. darbepoetin alfa), colony-stimulating factor analogs such as granulocyte macrophage-colony stimulating factor (GM-CSF) (e.g., sargramostim), or granulocyte-colony stimulating factor (G-CSF) or analogues thereof (e.g., filgrastim, pegfilgrastim, lenograstim, leridistim, mirimostim, molgramostim, nartograstim), agents that inhibit bone resorption such as denosumab or bisphosphonates e.g., zoledronate, zoledronic acid, pamidronate or ibandronate, agents that suppress inflammatory responses such as dexamethasone, prednisone, or prednisolone, agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone- producing tumours, such as synthetic forms of the hormone somatostatin e.g. octreotide acetate lanreotide, antidote to drugs that decrease levels of folic acid such as leucovorin, or folinic acid, agents for pain e.g. opiates such as morphine, diamorphine or fentanyl, non- steroidal anti-inflammatory drugs (NSAID) such as COX-2 inhibitors for example celecoxib, etoricoxib or lumiracoxib, agents for mucositis e.g. palifermin, agents that modulate metabolism of anti-cancer drugs i.e. a PK enhancer for example a P450 (e.g.3A4 inhibitor) such as cobicistat or a cytidine deaminase inhibitor (e.g zebularine, tetrahydrouridine, or cedazuridine) or thymidine phosphorylase inhibitor (e.g. tipiracil); and/or agents for the treatment of side-effects including anorexia, cachexia, oedema or thromboembolic episodes, such as megestrol acetate. Each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes. As such, the posology of each of the two or more agents may differ: each may be administered at the same time or at different times. A person skilled in the art would know through common general knowledge the dosing regimens and combination therapies to use. For example, a compound of the invention may be used in combination with one or more other agents which are administered according to their existing combination regimen. Examples of standard combination regimens are provided below. ‐ 54 ‐ Agent Ref: 12617.0003-00304 Where a compound of the formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered in combination therapy with one, two, three, four, or more other therapeutic agents (typically one or two, more typically one), the compounds can be administered simultaneously or sequentially (in combined or by separate formulations through the same or different routes). In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. Suitably, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject undergoing treatment with one or more therapeutic compound. It will be appreciated that the typical method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The weight ratio of a compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration, general physical condition of the particular patient, the mode of administration, as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may also be administered in conjunction with suitable standard regimens of chemotherapy, which can be determined by those skilled in the art (for example as described in JCO Clin Cancer Inform 4:60-70), including, for example, PC (paclitaxel and carboplatin), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifphosfphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), RCVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), ICE-V (ICE plus vincristine), R-MCP (Rituximab-MCP), or FOLFOX or FLOX (folinic acid, fluorouracil and oxaliplatin). ‐ 55 ‐ Agent Ref: 12617.0003-00304 A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may also be administered in conjunction with non-chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy, surgery, and controlled diets. Radiotherapy may be for radical, palliative, adjuvant, neoadjuvant, or prophylactic purposes. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may also have therapeutic applications in sensitizing tumour cells for radiotherapy and chemotherapy. Hence a compound of formula (I) can be used as a "radiosensitizer" and/or a “chemosensitizer” or can be given in combination with another "radiosensitizer" and/or “chemosensitizer”. In some embodiments, a compound of formula (I) is for use as a chemosensitizer. The term "radiosensitizer" is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation. The term “chemosensitizer” is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with chemotherapeutics. Many cancer treatment protocols currently employ radiosensitizers in conjunction with radiation of x-rays. X-ray activated radiosensitizers are chosen from: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same. Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same. Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour with or without additional radiation; or other therapeutically effective compounds for treating cancer or other diseases. Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of chemosensitizers to the target cells, compounds which control ‐ 56 ‐ Agent Ref: 12617.0003-00304 the flow of therapeutics, nutrients, and/or oxygen to the target cells, chemotherapeutic agents which act on the tumour, or other therapeutically effective compounds for treating cancer or other disease. Calcium antagonists, for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumour cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies. For use in combination therapy with another chemotherapeutic agent, a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and one, two, three, four, or more other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four, or more therapeutic agents, i.e., in a unitary pharmaceutical composition containing all components. In an alternative, the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. In some embodiments, the present invention further provides a combination drug wherein a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and at least one or more therapeutic agents are physically associated. As used herein, the term “combination”, as applied to two or more compounds and/or agents, is intended to define material in which the two or more agents are associated. The terms “combined” and “combining” in this context are to be interpreted accordingly. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and at least one or more therapeutic agents are: (a) in admixture, (b) chemically/physicochemically linked, (c) chemically/physicochemically co-packaged, or (d) unmixed but co-packaged or co-presented. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and at least one or more therapeutic agents are non-physically associated. In some embodiments, this optionally further includes (a) instructions for the extemporaneous association of a compound of formula (I) and at least one or more therapeutic agents to form a physical association of the two or more compounds, or (b) instructions for combination therapy with a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and at least one or more therapeutic agents, or (c) instructions for administration to a patient population. When the individual agents are presented in the form of a kit, the kit may comprise two or more separate pharmaceutical compositions: a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, and one or more further pharmaceutical compounds. ‐ 57 ‐ Agent Ref: 12617.0003-00304 As used herein, the term “kit” defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g., measuring device) and/or delivery means (e.g., inhaler or syringe), optionally all contained within common outer packaging. In kits comprising a combination of two or more compounds/agents, the individual compounds/agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The kit may optionally further comprise instructions for use. The kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. Suitably, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional. ADVANTAGES The compounds of the invention may demonstrate advantages over known compounds, such as one or more of the following aspects: (i) potency; (ii) in vivo efficacy (iii) pharmacokinetic properties; (iv) metabolic stability; (v) oral bioavailability; (vi) physiochemical properties; and/or (vii) safety profile or therapeutic index (TI). CLAUSES The invention may be defined by the following clauses: Clause 1. A compound of formula (I): ‐ 58 ‐ Agent Ref: 12617.0003-00304 (I) or a ring A is a wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; R¹ is chosen from H, fluoro, chloro, CH₃, OCH₃, C₁haloalkyl, and OC₁haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached, join to form a cyclopropyl ring or oxetanyl ring; R³ is chosen from H, S(O)_1-2CH₃, S(O)₂N(R⁵)(R⁶), C(=O)N(R⁵)(R⁶), P(=O)(C_1-3alkyl)₂, CN, and C(CH₃)₂CN; R⁴ is chosen from H, OC_1-2alkyl, O-cyclopropyl, C₁haloalkyl, halo, CN, and OC_1- ₂haloalkyl; ‐ 59 ‐ Agent Ref: 12617.0003-00304 wherein when one of R³ or R⁴ is H, the other of R³ or R⁴ is not H; R⁵ is H or C_1-3alkyl; R⁶ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁵ and R⁶, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; R⁷ is chosen from C_1-4alkyl, C_3-6cycloalkyl, 4- to 7-membered heterocyclyl, and C(=O)CH₃, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH3, and wherein the C3-6cycloalkyl and 4- to 7-membered heterocyclyl are optionally substituted by one or two CH₃ groups; R⁸ is H or C_1-2alkyl; R⁹ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms wherein the second heteroatom is independently chosen from N, O, and S; and n is 0, 1, or 2. Clause 2. The pharmaceutically acceptable salt and/or solvate according to clause 1. Clause 3. The pharmaceutically acceptable salt and solvate according to clause 2. Clause 4. The pharmaceutically acceptable salt according to clause 2. Clause 5. The pharmaceutically acceptable solvate according to clause 2. Clause 6. The compound of formula (I) according to clause 1. Clause 7. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 6, wherein A is cyclohexyl. Clause 8. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 7, wherein n is 0. Clause 9. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 7, wherein n is 1. Clause 10. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 7, wherein n is 2. Clause 11. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 6, wherein A is piperidinyl. Clause 12. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 11, wherein A is 4-piperidinyl, i.e., ‐ 60 ‐ Agent Ref: 12617.0003-00304 wherein indicates the point and the numbers represent ring atom Clause The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 11, wherein A is 3-piperidinyl, i.e., wherein indicates the point of attachment and the numbers represent ring atom Clause 14. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 11, wherein A is 2-piperidinyl, i.e., wherein indicates the point of attachment and the numbers represent ring atom Clause 15. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 11 to 14, wherein n is 0. Clause 16. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 11 to 14, wherein n is 1. Clause 17. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 11 to 14, wherein n is 2. ‐ 61 ‐ Agent Ref: 12617.0003-00304 Clause 18. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 11 to 17, wherein the N atom of the piperidinyl ring is not substituted. Clause 19. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 11 to 17, wherein the N atom of the piperidinyl ring is substituted by R⁷. Clause 20. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 6, wherein A is oxanyl. Clause 21. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 20, wherein A is 4-oxanyl, i.e., indicates the point of attachment and the numbers represent ring atom Clause 22. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 20 or 21, wherein n is 0. Clause 23. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 20 or 21, wherein n is 1. Clause 24. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 20 or 21, wherein n is 2. Clause 25. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 6, wherein A is thianyl-1,1-dioxide. Clause 26. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 25, wherein A is 4-thianyl-1,1-dioxide, i.e., ‐ 62 ‐ Agent Ref: 12617.0003-00304 wherein indicates the point of attachment and the numbers represent ring atom Clause The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 25 or 26, wherein n is 0. Clause 28. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 25 or 26, wherein n is 1. Clause 29. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 25 or 26, wherein n is 2. Clause 30. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 29, wherein X¹ is C and X² is N such that the compounds of formula (I) have the following structure: . Clause 31. The salt and/or solvate thereof any one is N and X² is C such that the compounds of formula (I) have the following structure: . Clause 32. The salt and/or solvate thereof according to any one of clauses 1 to 31, wherein Z is C(=O)CH₃. ‐ 63 ‐ Agent Ref: 12617.0003-00304 Clause 33. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate R⁴ V¹ thereof according to any one of clauses 1 to 31, . Clause 34. The compound of formula (I) or solvate thereof according to clause 33, wherein V¹ is CH. Clause 35. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ is N. Clause 36. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 33 to 35, wherein V² is CH. Clause 37. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 33 to 35, wherein V² is N. Clause 38. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 33 to 37, wherein V³ is CH. Clause 39. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 33 to 37, wherein V³ is CF. Clause 40. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 33 to 37, wherein V³ is N. Clause 41. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 33 to 40, wherein at least one of V¹, V², and V³ is not N. Clause 42. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹, V², and V³ are each CH. Clause 43. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ and V² are each CH and V³ is N. Clause 44. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ and V³ are each CH and V² is N. Clause 45. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V² and V³ are each CH and V¹ is N. Clause 46. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ and V² are each N and V³ is CH. Clause 47. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ and V³ are each N and V² is CH. Clause 48. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V² and V³ are each N and V¹ is CH. ‐ 64 ‐ Agent Ref: 12617.0003-00304 Clause 49. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ is CH, V³ is CF, and V² is N. Clause 50. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V² is CH, V³ is CF, and V¹ is N. Clause 51. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 33, wherein V¹ and V² are each N and V³ is CF. Clause 52. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is H. Clause 53. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is fluoro. Clause 54. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is chloro. Clause 55. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is CH₃. Clause 56. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is OCH3. Clause 57. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is C₁haloalkyl. Clause 58. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 57, wherein R¹ is C₁fluoroalkyl. Clause 59. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 58, wherein R¹ is CF₃. Clause 60. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 51, wherein R¹ is OC₁haloalkyl. Clause 61. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 60, wherein R¹ is OC₁fluoroalkyl. Clause 62. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 61, wherein R¹ is OCF₃. Clause 63. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 62, wherein R² is attached at the 3-position of ring A, and wherein the 3-position of ring A is as defined in any one of clauses 14, 21, or 26. Clause 64. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is fluoro. Clause 65. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is chloro. ‐ 65 ‐ Agent Ref: 12617.0003-00304 Clause 66. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is CH₃. Clause 67. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is C₁haloalkyl. Clause 68. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 67, wherein at least one R² is C₁fluoroalkyl. Clause 69. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 68, wherein at least one R² is CF₃. Clause 70. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one at least one R² is CH₂OH. Clause 71. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is oxo. Clause 72. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is OH. Clause 73. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is OCH3. Clause 74. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is OC₁haloalkyl. Clause 75. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 74, wherein at least one R² is OC₁fluoroalkyl. Clause 76. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 75, wherein at least one R² is OCF₃. Clause 77. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein at least one R² is N(R⁸)(R⁹). Clause 78. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is fluoro. Clause 79. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is chloro. Clause 80. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is CH₃. Clause 81. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is C1haloalkyl. ‐ 66 ‐ Agent Ref: 12617.0003-00304 Clause 82. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 81, wherein when n is 2, the second R² group is C₁fluoroalkyl. Clause 83. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 82, wherein when n is 2, the second R² group is CF₃. Clause 84. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is CH₂OH. Clause 85. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is oxo. Clause 86. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is OH. Clause 87. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is OCH3. Clause 88. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is OC₁haloalkyl. Clause 89. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 88, wherein when n is 2, the second R² group is C₁fluoroalkyl. Clause 90. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 89, wherein when n is 2, the second R² group is CF₃. Clause 91. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 77, wherein when n is 2, the second R² group is N(R⁸)(R⁹). Clause 92. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached, join to form a cyclopropyl ring, i.e., . ‐ 67 ‐ Agent Ref: 12617.0003-00304 Clause 93. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 63, wherein two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached, join to form an oxetanyl ring: indicates the point of attachment. Clause The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 93, wherein the oxetanyl is 2-oxetanyl: indicates the point of attachment. Clause The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 93, wherein the oxtetanyl is 3-oxetanyl: indicates the point of attachment. ‐ 68 ‐ Agent Ref: 12617.0003-00304 Clause 96. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 91, wherein when n is 2, two R² groups are attached to different carbon atoms in ring A. Clause 97. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 91, wherein when n is 2, two R² groups are attached to the same carbon atom in ring A. Clause 98. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 97, wherein two fluoro groups are attached to the same carbon atom in ring A. Clause 99. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 97, wherein two methyl groups are attached to the same carbon atom in ring A. Clause 100. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is S(O)CH₃. Clause 101. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is S(O)2CH3. Clause 102. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is S(O)₂N(R⁵)(R⁶). Clause 103. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is C(=O)N(R⁵)(R⁶). Clause 104. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is P(=O)(C_1-3alkyl)₂. Clause 105. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 104, wherein R³ is P(=O)(CH₃)₂. Clause 106. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is CN. Clause 107. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is C(CH₃)₂CN. Clause 108. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 99, wherein R³ is H. Clause 109. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 107 wherein R⁴ is H. Clause 110. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 107, wherein neither R³ nor R⁴ is H. Clause 111. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 108, wherein R⁴ is OC1-2alkyl. ‐ 69 ‐ Agent Ref: 12617.0003-00304 Clause 112. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 111, wherein R⁴ is OCH₃. Clause 113. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 111, wherein R⁴ is OCD₃. Clause 114. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 111 wherein R⁴ is O-cyclopropyl. Clause 115. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 111, wherein R⁴ is C₁haloalkyl. Clause 116. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 115, wherein R⁴ is C₁fluoroalkyl. Clause 117. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 116, wherein R⁴ is CF₃. Clause 118. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 111, wherein R⁴ is halo. Clause 119. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 118, wherein R⁴ is fluoro. Clause 120. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 111, wherein R⁴ is CN. Clause 121. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 111, wherein R⁴ is OC_1-2haloalkyl. Clause 122. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 121, wherein R⁴ is OC₁fluoroalkyl. Clause 123. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 122, wherein R⁴ is OCF₃. Clause 124. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 123, wherein R⁵ is H. Clause 125. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 123, wherein R⁵ is C_1-3alkyl. Clause 126. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 125, wherein R⁵ is methyl. Clause 127. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 125, wherein R⁵ is ethyl. Clause 128. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 125, wherein R⁵ is propyl. Clause 129. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 128, wherein R⁶ is H. ‐ 70 ‐ Agent Ref: 12617.0003-00304 Clause 130. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 128, wherein R⁶ is C_1-2alkyl which is optionally substituted by one OCH₃. Clause 131. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 130, wherein R⁶ is unsubstituted C_1-2alkyl. Clause 132. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 131, wherein R⁶ is unsubstituted methyl. Clause 133. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 131, wherein R⁶ is unsubstituted ethyl. Clause 134. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 131, wherein R⁶ is C_1-2alkyl and is substituted by one OCH₃. Clause 135. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 134, wherein R⁶ is methyl and is substituted by one OCH₃. Clause 136. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 134, wherein R⁶ is ethyl and is substituted by one OCH₃. Clause 137. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 123, wherein R⁵ and R⁶, together with the nitrogen to which they are attached, join to form a 6-membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S. Clause 138. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 137, wherein R⁵ and R⁶, together with the nitrogen with which they are attached, join to form a 6-membered heterocyclyl containing one heteroatom, wherein the one heteroatom is the N atom of the S(O)₂N(R⁵)(R⁶) or the C(=O)N(R⁵)(R⁶) group. Clause 139. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 137, wherein R⁵ and R⁶, together with the nitrogen to which they are attached, join to form a 6-membered heterocyclyl containing two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S. Clause 140. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 139, wherein the 6-membered heterocyclyl contains two nitrogen heteroatoms. Clause 141. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 139, wherein the 6-membered heterocyclyl contains one nitrogen heteroatom and one oxygen heteroatom. Clause 142. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 139, wherein the 6-membered heterocyclyl contains one nitrogen heteroatom and one sulfur heteroatom. ‐ 71 ‐ Agent Ref: 12617.0003-00304 Clause 143. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 137 to 142, wherein R⁵ and R⁶ join to form morpholinyl, piperidinyl, piperidinonyl, piperazinonyl, or piperazinyl. Clause 144. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 143, wherein the piperidinyl is chosen from piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl. Clause 145. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 143, wherein R⁵ and R⁶ join to form morpholinyl. Clause 146. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 145, wherein R⁷ is C_1-4alkyl, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH₃. Clause 147. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 146, wherein R⁷ is methyl. Clause 148. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 146, wherein the C_1-4alkyl group is not substituted. Clause 149. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 146, wherein the C_1-4alkyl group is substituted by one or more OH and/or one or more OCH₃. Clause 150. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 149, wherein the C_1-4alkyl group is substituted by one or more OH. Clause 151. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 150, wherein the C_1-4alkyl group is substituted by one OH. Clause 152. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 149, wherein the C_1-4alkyl group is substituted by one or more OCH₃. Clause 153. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 152, wherein the C_1-4alkyl group is substituted by one OCH₃. Clause 154. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 149, wherein the C1-4alkyl group is substituted by one or more OH and one or more OCH₃. Clause 155. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 154, wherein the C_1-4alkyl group is substituted by one OH and one OCH₃. Clause 156. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 145, wherein R⁷ is C_3-6cycloalkyl. ‐ 72 ‐ Agent Ref: 12617.0003-00304 Clause 157. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 156, wherein R⁷ is C₃cycloalkyl. Clause 158. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 156, wherein R⁷ is C₄cycloalkyl. Clause 159. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 156, wherein R⁷ is C₅cycloalkyl. Clause 160. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 156, wherein R⁷ is C₆cycloalkyl. Clause 161. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 145, wherein R⁷ is 4- to 7-membered heterocyclyl. Clause 162. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 161, wherein R⁷ is 4-membered heterocyclyl. Clause 163. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 161, wherein R⁷ is 5-membered heterocyclyl. Clause 164. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 161, wherein R⁷ is 6-membered heterocyclyl. Clause 165. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 161, wherein R⁷ is 7-membered heterocyclyl. Clause 166. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 165, wherein the 7-membered heterocyclyl is a 7-membered heterospirocyclyl. Clause 167. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 166, wherein the 7-membered heterospirocyclyl contains one nitrogen atom and one oxygen atom. Clause 168. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 167, wherein the 7-membered heterospirocyclyl is 2-oxa-6- azaspiro[3.3]heptane. Clause 169. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 161 to 166, wherein the 4- to 7-membered heterocyclyl group contains one heteroatom chosen from N, S, and O. Clause 170. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 169, wherein the 4- to 7-membered heterocyclyl group contains one nitrogen heteroatom. Clause 171. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 169, wherein the 4- to 7-membered heterocyclyl group contains one oxygen heteroatom. ‐ 73 ‐ Agent Ref: 12617.0003-00304 Clause 172. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 169, wherein the 4- to 7-membered heterocyclyl group contains one sulfur heteroatom. Clause 173. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 161 to 166, wherein the 4- to 7-membered heterocyclyl group may contain two heteroatoms chosen from N, S, and O. Clause 174. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 173, wherein the 4- to 7-membered heterocyclyl group contains two nitrogen heteroatoms. Clause 175. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 173, wherein the 4- to 7-membered heterocyclyl group contains one nitrogen heteroatom and one oxygen heteroatom. Clause 176. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 173, wherein the 4- to 7-membered heterocyclyl group contains one nitrogen heteroatom and one sulfur heteroatom. Clause 177. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 173, wherein the 4- to 7-membered heterocyclyl group contains one oxygen heteroatom and one sulfur heteroatom. Clause 178. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 156 to 160, wherein the C_3-6cycloalkyl group is not substituted. Clause 179. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 178, wherein the C₃cycloalkyl group is not substituted. Clause 180. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 178, wherein the C₄cycloalkyl group is not substituted. Clause 181. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 178, wherein the C₅cycloalkyl group is not substituted. Clause 182. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 178, wherein the C6cycloalkyl group is not substituted. Clause 183. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 156 to 160, wherein the C_3-6cycloalkyl group is substituted by one or two CH₃ groups. Clause 184. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 183, wherein the C_3-6cycloalkyl group is substituted by one CH₃ group. ‐ 74 ‐ Agent Ref: 12617.0003-00304 Clause 185. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 183, wherein the C₃cycloalkyl group is substituted by one or two CH₃ groups. Clause 186. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 185, wherein the C₃cycloalkyl group is substituted by one CH₃ group. Clause 187. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 183, wherein the C₄cycloalkyl group is substituted by one or two CH3 groups. Clause 188. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 187, wherein the C₄cycloalkyl group is substituted by one CH₃ group. Clause 189. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 183, wherein the C₅cycloalkyl group is substituted by one or two CH₃ groups. Clause 190. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 189, wherein the C₅cycloalkyl group is substituted by one CH₃ group. Clause 191. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 183, wherein the C₆cycloalkyl group is substituted by one or two CH₃ groups. Clause 192. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 191, wherein the C₆cycloalkyl group is substituted by one CH₃ group. Clause 193. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 161 to 177, wherein the 4- to 7-membered heterocyclyl group is not substituted. Clause 194. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 193, wherein the 4-membered heterocyclyl group is not substituted. Clause 195. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 193, wherein the 5-membered heterocyclyl group is not substituted. Clause 196. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 193, wherein the 6-membered heterocyclyl group is not substituted. ‐ 75 ‐ Agent Ref: 12617.0003-00304 Clause 197. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 177, wherein the 7-membered heterocyclyl group is not substituted. Clause 198. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 161 to 177, wherein the 4- to 7-membered heterocyclyl group is substituted by one or two CH₃ groups. Clause 199. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 198, wherein the 4- to 7-membered heterocyclyl group is substituted by one CH3 group. Clause 200. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 198, wherein the 4- membered heterocyclyl group is substituted by one or two CH₃ groups. Clause 201. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 200, wherein the 4- membered heterocyclyl group is substituted by one CH₃ group. Clause 202. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 198, wherein the 5- membered heterocyclyl group is substituted by one or two CH₃ groups. Clause 203. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 201, wherein the 5- membered heterocyclyl group is substituted by one CH₃ group. Clause 204. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 198, wherein the 6- membered heterocyclyl group is substituted by one or two CH₃ groups. Clause 205. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 204, wherein the 6- membered heterocyclyl group is substituted by one CH₃ group. Clause 206. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 198, wherein the 7- membered heterocyclyl group is substituted by one or two CH₃ groups. Clause 207. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 206, wherein the 7- membered heterocyclyl group is substituted by one CH₃ group. Clause 208. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 145, wherein R⁷ is C(=O)CH₃. ‐ 76 ‐ Agent Ref: 12617.0003-00304 Clause 209. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 208, wherein R⁸ is H. Clause 210. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 208, wherein R⁸ is C_1-2alkyl. Clause 211. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 210, wherein R⁸ is methyl. Clause 212. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 210, wherein R⁸ is ethyl. Clause 213. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 212, wherein R⁹ is H. Clause 214. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 212, wherein R⁹ is C_1-2alkyl which is optionally substituted by one OCH₃. Clause 215. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 214, wherein the C_1-2alkyl group is not substituted. Clause 216. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 215, wherein R⁹ is methyl and is not substituted. Clause 217. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 215, wherein R⁹ is ethyl and is not substituted. Clause 218. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 214, wherein the C_1-2alkyl group is substituted by OCH₃. Clause 219. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 218, wherein R⁹ is methyl and is substituted by one OCH₃. Clause 220. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 219, wherein R⁹ is ethyl and is substituted by one OCH₃. Clause 221. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 208, wherein R⁸ and R⁹, together with the nitrogen to which they are attached, join to form a 6-membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S. Clause 222. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 221, wherein R⁸ and R⁹, together with the nitrogen to which they are attached, join to form a 6-membered heterocyclyl containing one heteroatom, wherein the one heteroatom is the N atom of the N(R⁸)(R⁹) group. Clause 223. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 221, wherein R⁸ and R⁹, together with the nitrogen to which they ‐ 77 ‐ Agent Ref: 12617.0003-00304 are attached, join to form a 6-membered heterocyclyl containing two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S. Clause 224. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 223, wherein the 6-membered heterocyclyl contains two nitrogen heteroatoms. Clause 225. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 223, wherein the 6-membered heterocyclyl contains one nitrogen heteroatom and one oxygen heteroatom. Clause 226. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 223, wherein the 6-membered heterocyclyl contains one nitrogen heteroatom and one sulfur heteroatom. Clause 227. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 221 to 226, wherein R⁸ and R⁹ join to form morpholinyl, piperidinyl, piperidinonyl, piperazinonyl, and piperazinyl. Clause 228. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 227, wherein the piperidinyl is chosen from piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl. Clause 229. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 227, wherein R⁸ and R⁹ can join to form morpholinyl. Clause 230. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 1, wherein the compound of formula (I) is a compound of formula (Ic): wherein: X¹ is C and X² is N such that ring B or ‐ 78 ‐ Agent Ref: 12617.0003-00304 X¹ is N and X² is C such that ring B ; Y is chosen from NH, NCH3 and SO2; ; NHCH₃, and P(=O)(CH₃)₂; and n is 0 or 1. Clause 231. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 230, wherein the compound of formula (I) is a compound of formula (Id): ; wherein R¹, R², X¹, Clause 232. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 230, wherein the compound of formula (I) is a compound of formula (Ie): Y ; ‐ 79 ‐ Agent Ref: 12617.0003-00304 wherein R¹, R², X¹, X², B, Y, and Z are as defined in clause 229. Clause 233. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 232, wherein X¹ is C and X² is N such that ring B . Clause 234. The solvate according to any one of clauses 230 to 232, wherein X¹ is N and X² is C such that ring B . Clause 235. The compound of formula (I) or salt and/or solvate thereof according to any one of clauses 230 to NH. Clause 236. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 234, wherein Y is NCH₃. Clause 237. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 234, wherein Y is SO₂. Clause 238. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 237, wherein Z is C(=O)CH₃. Clause 239. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 237, . Clause 240. The compound of formula (I) or pharmaceutically solvate thereof according to any one of clauses 230 to 239, wherein R² is fluoro. Clause 241. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 240, wherein R³ is SO₂CH₃. Clause 242. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 240, wherein R³ is C(=O)NHCH₃. Clause 243. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 to 240, wherein R³ is P(=O)(CH₃)₂. Clause 244. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 and 233 to 243, wherein n is 0. Clause 245. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 230 and 233 to 243, wherein n is 1. ‐ 80 ‐ Agent Ref: 12617.0003-00304 Clause 246. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to clause 1, wherein the compound of formula (I) is chosen from: 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; 4-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine; 3-methoxy-N-methyl-4-[(3-{7-[(oxan-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; 4-[(3-{7-[(1,1-dioxo-1λ⁶-thian-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)-1-methylpiperidin-4-amine; N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)-1-methylpiperidin-4-amine; (3S,4R)-N-[2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl]-3-fluoro-1-methylpiperidin-4-amine; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine; 4-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; N-(3-{7-[(piperidin-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2- yn-1-yl)acetamide; N-(3-{7-[(oxan-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1- yl)acetamide; ‐ 81 ‐ Agent Ref: 12617.0003-00304 N-[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl]acetamide; 3-methoxy-N-methyl-4-[(3-{7-[(1-methylpiperidin-4-yl)amino]-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; 5-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylpyridine-2-carboxamide; 3-methoxy-N-methyl-4-((3-(8-((1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)acetamide; 3-methoxy-N-methyl-4-((3-(8-(piperidin-4-ylamino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1- yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine; N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzonitrile; 3-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylpicolinamide; (3-cyclopropoxy-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (3-(difluoromethoxy)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; 3-chloro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; ‐ 82 ‐ Agent Ref: 12617.0003-00304 2-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylbenzamide; (3-(difluoromethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; 3-cyano-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxypyridin-2-yl)dimethylphosphine oxide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxypyrimidin-2-yl)dimethylphosphine oxide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)dimethylphosphine oxide; 4-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-methoxy-4-((3-(8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 4-((3-(8-((1-(2-hydroxyethyl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((2-(3-((4-methoxypyridin-3-yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-8-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide; (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; 4-((3-(8-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide; 4-((3-(8-(((3S,4R)-1,3-dimethylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-methoxy-N-methyl-4-((3-(8-((5-methyl-5-azaspiro[2.5]octan-8-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; ‐ 83 ‐ Agent Ref: 12617.0003-00304 (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyridin-2- yl)dimethylphosphine oxide; (4-((3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((Trans)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(morpholino)methanone; N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; N-(3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-6-(methylsulfonyl)pyridin-3- yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine; (4-((3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((3R,4R)-3-(hydroxymethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; 1-cyclopropyl-3-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-2-one; 4-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-1-methylpiperidin-2-one; (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2- yl)dimethylphosphine oxide; (3-fluoro-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; ‐ 84 ‐ Agent Ref: 12617.0003-00304 (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; N-((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine; 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 5-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; 4-((3-(8-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; and (4-((3-(7-(((1r,4r)-4-aminocyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. Clause 247. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, and a pharmaceutically acceptable excipient. Clause 248. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use as a medicament. Clause 249. Use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 in the manufacture of a medicament. Clause 250. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder affected by p53 mutation. Clause 251. Use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder affected by p53 mutation. Clause 252. A method for the prophylaxis or treatment of a disease or disorder affected by p53 mutation, said method comprising administering to a subject a compound of formula (I) or ‐ 85 ‐ Agent Ref: 12617.0003-00304 a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246. Clause 253. The compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 250 to 252 wherein the disease or disorder affected by p53 mutation is a proliferative disease or disorder. Clause 254. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof increases the ability of the p53 mutant to bind to DNA. Clause 255. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of increasing the ability of the p53 mutant to bind to DNA. Clause 256. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof reactivates p53 function. Clause 257. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of reactivating p53 function. Clause 258. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof induces a conformational change in the p53 mutant. Clause 259. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of inducing a conformational change in the p53 mutant. Clause 260. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof alters (e.g., increases) the stability of a p53 mutant. Clause 261. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of altering (e.g., increasing) the stability of a p53 mutant. ‐ 86 ‐ Agent Ref: 12617.0003-00304 Clause 262. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof restores wild type-function to mutant p53. Clause 263. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of restoring wild type-function to mutant p53. Clause 264. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is a Y220C reactivator. Clause 265. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of reactivating Y220C. Clause 266. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof reactivates wild type p53 function in cancerous cells. Clause 267. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of a disease or disorder, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is capable of reactivating wild type p53 function in cancerous cells. Clause 268. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, compound for use, use, or method according to any one of clauses 250 to 255 and 258 to 263, wherein the p53 mutant includes a Y220C mutation. Clause 269. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, compound for use, use, or method according to any one of clauses 250 to 255 and 258 to 263, wherein the p53 mutant carries a Y220C mutation. Clause 270. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, compound for use, use, or method according to any one of clauses 250 to 255 and 258 to 263, wherein the p53 mutant carries only a Y220C mutation. Clause 271. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 250 to 253, wherein the disease or disorder is cancer. ‐ 87 ‐ Agent Ref: 12617.0003-00304 Clause 272. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to clause 271, wherein the cancer is a haematological cancer. Clause 273. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to clause 271, wherein the cancer is a non- haematological cancer. Clause 274. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to clause 273, wherein the cancer is a solid cancer. Clause 275. A compound for use, use, or method according to clause 274, wherein the cancer comprises lesions or a tumour. Clause 276. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 271 to 275, wherein the cancer is chosen from: tumours of epithelial origin (e.g., adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas), carcinomas of the bladder and urinary tract (including urothelial carcinoma), breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, bowel, colorectal, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney (e.g., renal cell carcinoma), lung (e.g., adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (e.g., cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity, and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testes, cervix, myometrium, endometrium, thyroid (e.g., thyroid follicular carcinoma), brain, adrenal, prostate, skin and adnexae (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e., leukaemias and lymphomas), premalignant haematological disorders, and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (e.g., acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, T-cell lymphomas and leukaemias, natural killer (NK) cell lymphomas, Hodgkin’s lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (e.g., acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML), chronic myelomonocytic leukaemia (CMML), hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary ‐ 88 ‐ Agent Ref: 12617.0003-00304 myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukaemia); tumours of mesenchymal origin (e.g., sarcomas of soft tissue, bone, or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi’s sarcoma, Ewing’s sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans); tumours of the central or peripheral nervous system (e.g., astrocytomas (e.g. gliomas), neuromas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas); endocrine tumours (e.g., pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid); ocular and adnexal tumours (e.g., retinoblastoma); germ cell and trophoblastic tumours (e.g., teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); paediatric and embryonal tumours (e.g., medulloblastoma, neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); and syndromes, congenital or otherwise, which leave the subject susceptible to malignancy (e.g., Xeroderma Pigmentosum or Li-Fraumeni Syndrome). Clause 277. The compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 271 to 276, wherein the cancer is a cancer which is characterised by a p53 mutation such as a Y220C mutation. Clause 278. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the treatment of a lesion or tumour in which p53 carries a Y220C mutation. Clause 279. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 in the manufacture of a medicament for the treatment of a lesion or tumour in which p53 carries a Y220C mutation. Clause 280. A method for the treatment of a lesion or tumour in which p53 carries a Y220C mutation comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246. Clause 281. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the treatment of a haematological cancer in which p53 carries a Y220C mutation. Clause 282. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 in the manufacture of a medicament for the treatment of a haematological cancer in which p53 carries a Y220C mutation. Clause 283. A method for the treatment of a haematological cancer in which p53 carries a Y220C mutation comprising administering to a subject a compound of formula (I) or a ‐ 89 ‐ Agent Ref: 12617.0003-00304 pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246. Clause 284. A method for treating a cell in which p53 carries a Y220C mutation, said method comprising administering to the cell a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246. Clause 285. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 for use in the prophylaxis or treatment of cancer in a subject chosen from a sub-population possessing cancers which are p53 mutant. Clause 286. Use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 in the manufacture of a medicament for the prophylaxis or treatment of cancer in a subject chosen from a sub-population possessing cancers which are p53 mutant. Clause 287. A method for the prophylaxis or treatment cancer in a subject chosen from a sub-population possessing cancers which are p53 mutant, said method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246. Clause 288. The compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 248 to 287, wherein the compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof is provided in the form of a pharmaceutical composition according to clause 247. Clause 289. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 248 to 288, for the treatment of a disease or disorder. Clause 290. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 248 to 288, for the prophylaxis of a disease or disorder. Clause 291. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246 which is administered in a combination therapy with one of more other compounds (or therapies) also suitable for the treatment or prophylaxis of the diseases and disorders listed herein. Clause 292. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to clause 291, wherein the combination therapy comprises a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and one or more other anticancer compounds (or therapies) for treatment of cancer. Clause 293. A compound of formula (II): ‐ 90 ‐ Agent Ref: 12617.0003-00304 or a salt and/or solvate wherein X¹, X², B, and Z are 1 to 246 and Q² is a leaving group such as halo, e.g. chloro or bromo. Clause 294. A compound of formula (V): or a salt and/or solvate thereof; wherein X¹, X², and B are as any one 1 to 246, Q¹ is a leaving group such as halogen e.g., iodo, or trifluoromethanesulfonate and Q² is a leaving group such as halo, e.g. chloro or bromo. Clause 295. A compound of formula (VI): or a salt and/or solvate wherein A, B, R¹, R², n, X¹, and X² are as defined in any one of clauses 1 to 246 and Q¹ is a leaving group such as halogen e.g., iodo, or trifluoromethanesulfonate. Clause 296. A process for the preparation of compound of formula (I) or a salt and/or solvate thereof according to any one of clauses 1 to 247 which comprises the step of: reacting a compound of formula (II): ‐ 91 ‐ Agent Ref: 12617.0003-00304 ; or salt and/or solvate thereof; wherein X¹, X², B, and Z are as 1 to 246 and Q² is a leaving group such as halo, e.g., chloro or bromo; with a compound of formula (III): or salt and/or solvate thereof; 2 wherein R and A are as defined 1 to 246. Clause 297. A process for the preparation of compound of formula (I) or a salt and/or solvate thereof according to any one of clauses 1 to 246 which comprises the step of: reacting a compound of formula (VI): or a salt and/or solvate wherein A, B, R¹, R², n, X¹, and X² are as defined in any one of clauses 1 to 246 and Q¹ is a leaving group, such as halogen, e.g., iodo, or trifluoromethanesulfonate; with a compound of formula (IV): or a salt and/or solvate thereof; wherein Z is as defined in any one of clauses 1 to 247. Clause 298. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, compound of formula (I) or pharmaceutically ‐ 92 ‐ Agent Ref: 12617.0003-00304 acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 248 to 292, compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 293 to 295, or process according to clause 296 or 297 which is in a natural isotopic form. Clause 299. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 1 to 246, compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof for use, use, or method according to any one of clauses 248 to 292, compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of clauses 293 to 295, or process according to clause 296 or 297 which is in a natural isotopic form other than deuterium (i.e., ²H or D) replacement of a hydrogen atom. EXAMPLES Compounds are named in accordance with protocols utilized by chemical naming software packages. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. Abbreviations MeCN, ACN acetonitrile AcOEt, EtOAc Ethyl acetate AMU Atomic mass units aq. aqueous Boc tert-butyloxycarbonyl Cy cyclohexane CyHex cyclohexane DIPEA N,N-Diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EC₅₀ half maximal effective concentration ESI Electrospray ionisation EtOH ethanol Et₂O diethyl ether FBS Fetal bovine serum FC Flash chromatography ‐ 93 ‐ Agent Ref: 12617.0003-00304 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium HATU hexafluorophosphate) HCl hydrochloric acid HCOOH Formic acid HEPES N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid HPLC high pressure liquid chromatography IC₅₀ Half-maximal inhibitory concentration LCMS Liquid chromatography-mass spectrometry MeOH methanol mins. minutes MS mass spectrometry MW microwave Na₂S₂O₃ sodium thiosulfate Na₂S₂O₅ sodium metabisulfite Ni-NTA Nickel- Nitrilotriacetic NMP N-methyl-2-pyrrolidinone NMR nuclear magnetic resonance o/n overnight PDA photodiode array detection Pd(OAc)₂ palladium (2) acetate Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium (0) petrol petroleum ether fraction with boiling point range 40 – 60 °C ppm parts per million RT, rt, r.t. room temperature SiO₂ silica RP reverse phase RPMI medium Roswell Park Memorial Institute medium sat. saturated SPR Surface plasmon resonance TCEP tris(2-carboxyethyl)phosphine TBTU N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate TEA triethylamine TEV Tobacco Etch Virus TFA trifluoroacetic acid THF tetrahydrofuran ‐ 94 ‐ Agent Ref: 12617.0003-00304 TMP 2,2,6,6-Tetramethylpiperidinyl TMS trimethylsilane UV Ultraviolet UPLC Ultra High Performance Liquid Chromatography XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl General Experimental Details and methods Analytical methods Instruments, materials and methods employed for analyses 1H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency), equipped with: a self-shielded Z-gradient coil 5 mm ¹H/nX broadband probe head for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with transmitter offset frequency shift, or on AgilentVNMRS-500 or on a Bruker Avance 400 spectrometers. Chemical shifts are reported in ppm relative to trimethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation (s= singlet, d= doublet, t= triplet, q= quartet, m= multiplet, br. s= broad singlet, br. d= broad doublet, br. t= broad triplet, dd= double- doublet, ddd= double-double-doublet, td= triple doublet). LC/UV/MS Analytical Methods LCMS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on UPLC/PDA/MS Acquity^TM system coupled with Micromass ZQ^TM or Waters SQD single quadrupole mass spectrometer operated in positive and/or negative electron spray ES ionization mode and/or Fractionlynx system used in analytical mode coupled with ZQ^TM single quadrupole operated in positive and/or negative ES ionisation mode. Quality Control methods used operated under low pH conditions or under high pH conditions. Data described herein are measured values (found). Molecular ion peaks of a free form (such as [M+H]+ and [M-H]-), molecular ion peaks of a free form [M]+ or fragment ion peaks thereof, or sodium-adduct ion peaks of a free form [M+Na]+ are typically observed. Preparative HPLC Methods Method 1, MDAP Waters with mass spectrometry detection (MS:ZQ2000). Column: xBridge C18 (30x100mm, 3µm). Conditions: [A2: 10 mM ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia]; [B2: MeCN]. Gradient: from 50% B2 to 70.0% B2 in 10min (flow: 40.00mL/min). Detection: UV/Vis detection range 210 nm to 350nm MS(ES+/ES-) Scan range 100 to 1000 AMU. ‐ 95 ‐ Agent Ref: 12617.0003-00304 Method 2, MDAP Waters with mass spectrometry detection (MS:ZQ2000). Column: CSH C18 (30x100mm, 3µm). Conditions: [A1: Waters + 0.1% HCOOH]; [B1: MeCN]. Gradient: from 65.0% B1 to 70.0% B1 in 10min (flow: 40.00mL/min). Detection: UV/Vis + MS(ES+). Method 3, MDAP Waters with mass spectrometry detection (MS:ZQ2000). Column: CSH C18 (30x100mm, 3µm). Conditions: [A1: Waters + 0.1% HCOOH]; [B1: MeCN]. Gradient: from 48.0% B1 to 49.0% B1 in 10min (flow: 40.00mL/min). Detection: UV/Vis detection range 210 nm to 350nm MS(ES+/ES-) Scan range 100 to 1000 AMU. Method 4, MDAP Waters with mass spectrometry detection (MS:ZQ2000). Column: CSH C18 (30x100mm, 3µm). Conditions: [A1: Waters + 0.1% HCOOH]; [B1: MeCN]. Gradient: from 53.0% B1 to 60.0% B1 in 10min (flow: 40.00mL/min). Detection: UV/Vis + MS(ES+). Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Flash chromatography is carried out using an Isolera MPLC system (manufactured by Biotage) using pre-packed silica gel or reverse-phase cartridges (supplied by Biotage or Sepachrom). Many of the compounds described in the following Examples have been prepared from stereochemically pure starting materials. When reference is made to the use of a “similar” or “analogous” procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions, or chromatographic purification conditions. By following methods similar and/or analogous to general procedures below, the compounds set out below were prepared. The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesized according to the step in the description given. Where a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocenter is not specified and is represented by straight lines. As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may exist as a solvate e.g., hydrate, and/or contain residual solvent or minor impurities. Compounds isolated as a salt form, may be integer stoichiometric i.e., mono- or di-salts, or of intermediate stoichiometry. Synthesis of Intermediates Intermediate 1: 7-chloro-2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridine ‐ 96 ‐ Agent Ref: 12617.0003-00304 in an ice bath to 0 °C, boron trifluoride diethyl etherate (28.73 mL, 232.77 mmol) was added dropwise keeping the temperature below 5 °C (ca. 20 min), then the reaction was stirred in the ice bath for 45 min. The mixture was cooled to -70 °C in a dry ice/acetone bath and TMPMgCl ^LiCl (1M in THF/toluene; 253.9 mL, 253.94 mmol) was added dropwise keeping the temperature below -65 °C (ca.50 min). Then the mixture was stirred at -70 °C for 2 h. A solution of iodine (80.6 g, 317.42 mmol) in THF (125 mL) was added dropwise keeping the temperature below -65 °C (50 min), then it was left to return slowly to r.t., stirring overnight. The reaction mixture was quenched with sat. Na₂CO₃ (250 mL) and water (250 mL), and the mixture was stirred for 1 h. The mixture was extracted with Et₂O (250 mL x 2). The organic phases were merged and poured into 500 mL of 0.66 M Na₂S₂O₅. The mixture was stirred until complete colour change was observed then the organic phase was recovered, and the aqueous phase extracted with 125 mL of Et₂O. The organic phases were merged, dried (Na₂SO₄), filtered, and concentrated in vacuo. The product was purified by column chromatography (Biotage D Sfar Silica 350 g, from 100 % CyHex to 95:5 CyHexEtOAc) to obtain 2-iodopyrazolo[1,5-a]pyridine (37.96 g, 73.51% yield). MS (m/z) 245.0 [M+H]+. Step 2 2-Iodopyrazolo[1,5-a]pyridine (37.96 g, 155.55 mmol) was dissolved in THF (314 mL) and cooled to -70 °C in a dry ice/acetone bath. TMPMgCl ^LiCl (1M in THF/toluene; 211.24 mL, 211.24 mmol) was added dropwise keeping the temperature below -65 °C (ca. 45 min). Then the mixture was stirred at -70 °C for 30 min. A solution of 1,1,1,2,2,2-hexachloroethane (53.6 g, 226.32 mmol) in THF (70.3 mL) was added dropwise keeping the temperature below -65 °C (ca.15 min). The reaction mixture was slowly warmed to r.t. (in about 1 h), then stirred for 1 h at rt. The reaction mixture was then quenched with an aqueous 10 % Na2S2O3 solution (300 mL) and extracted with Et₂O (150 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to obtain an oil which was purified via column chromatography (silica gel, Sfar D 200 g, 0-5% ethyl acetate in cyclohexane) to obtain 7- chloro-2-iodo-pyrazolo[1,5-a]pyridine (39.2 g, 93.3 % yield) . MS (ESI) m/z = 278.9 - 281.0 [M+H]+. Step 3 ‐ 97 ‐ Agent Ref: 12617.0003-00304 7-chloro-2-iodo-pyrazolo[1,5-a]pyridine (5.0 g, 17.95 mmol) and 1,1-dioxo-2- (trifluoromethylsulfanyl)-1,2-benzothiazol-3-one (7.6g, 26.93 mmol) were dissolved in MeCN (90 mL) under nitrogen. Chloro(trimethyl)silane (3.42 mL, 26.93 mmol) was added dropwise (1-2 min), and the resulting mixture was heated to 60 °C and stirred for 30 min, then it was concentrated in vacuo. The residue was re-dissolved in DCM (50 mL), 1M NaOH (50 mL) was added at r.t. and the mixture was stirred for 5 min. The organic phase was recovered, and the aqueous one was extracted again with DCM (15 ml). The organic phases were merged, dried (Na₂SO₄) and concentrated in vacuo to obtain 7-chloro-2-iodo-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridine (6.12 g, 16.17 mmol, 90.05% yield) . MS (m/z) 379.0 [M+H]+.¹H NMR (400 MHz, CDCl₃) δ 7.71 (dd, J = 8.9, 1.2 Hz, 1H), 7.37 (dd, J = 8.8, 7.4 Hz, 1H), 7.04 (dd, J = 7.4, 1.2 Hz, 1H). Intermediate 2: 8-bromo-2-iodo-3-(trifluoromethylsulfanyl)imidazo[1,2-a]pyridine Step 1 In a 500 mL round bottom flask equipped with an air refrigerator, a solution of 3-bromo-2- pyridinamine (10.0 g, 57.8 mmol) in 2-bromoacetic acid ethyl ester (50.0 mL, 450.9 mmol) was stirred at 50 °C overnight (16 hours) under nitrogen atmosphere. The reaction mixture became a suspension. The reaction mixture was diluted with Et₂O and filtered. The resulting solid was washed with Et₂O and dried under high vacuum affording 2-amino-3-bromo-1-(2-ethoxy-2- oxoethyl)pyridin-1-ium (1:1 Bromide), 19.52 g ( 99.33% yield).¹H NMR (400 MHz, DMSO) δ 1.26 (t, J = 7.1 Hz, 3H), 4.21 (q, J = 7.1 Hz, 2H), 5.30 (s, 2H), 6.94 (dd, J = 7.7, 6.7 Hz, 1H), 8.16 (dd, J = 6.7, 1.4 Hz, 1H), 8.43 (dd, J = 7.7, 1.4 Hz, 1H), 8.73 (s, 2H). Step 2 In a 500 mL round bottom flask equipped with an air refrigerator, a suspension of 2-amino-3- bromo-1-(2-ethoxy-2-oxoethyl)pyridin-1-ium (1:1 Bromide) (9.75 g, 28.68 mmol) in Phosphorus(V) oxychloride (40.0 mL, 429.14 mmol) was refluxed (105 °C) for 3 hours under ‐ 98 ‐ Agent Ref: 12617.0003-00304 nitrogen atmosphere. The UPLC analysis showed complete conversion of the starting material to the presumed desired product (88%) and to the bis-brominated side product (12%). POCl₃ was evaporated under reduced pressure with a rotary evaporator connected to a basic trap (NaOH 1M) cooled with an ice bath. The round bottom flask was then cooled with an ice bath; the residual POCl₃ was quenched carefully with crushed ice and ammonium hydroxide solution until pH 8 was reached. The resulting suspension was filtered, washed with water and cyclohexane. The resulting material was then dried in an oven at 50 °C overnight affording 8- bromo-2-chloro-imidazo[1,2-a]pyridine (6.76 g, 29.2 mmol, quant. yield). (ESI) m/z = 230.94/232.94/234.94 [M+H]⁺ (Combined bromine/chlorine pattern). ¹H NMR (400 MHz, DMSO) δ 6.90 – 6.95 (m, 1H), 7.68 (dd, J = 7.5, 1.0 Hz, 1H), 8.20 (s, 1H), 8.54 (dd, J = 6.8, 1.0 Hz, 1H). Step 3 In a 40 mL vial, sodium iodide (2410.56 mg, 16.08 mmol) and 8-bromo-2-chloro-imidazo[1,2- a]pyridine (744.0 mg, 3.21 mmol) were degassed with three vacuum nitrogen cycles. Anhydrous MeCN (4 mL) was added, and the resulting suspension was degassed as above. Hydriodic acid (3.0 mL, 39.87 mmol) was added; the resulting suspension was degassed as above and heated at 85 °C overnight. Complete conversion to the presumed desired product was observed. The reaction was cooled with an ice-bath and a 2:1 solution 12 M NaOH/saturated Na₂S₂O₃ was added until pH 10-12 was reached. The resulting suspension was filtered, washed with water and cyclohexane, and dried in an oven at 50 °C overnight affording 8-bromo-2-iodo-imidazo[1,2-a]pyridine (890 mg, 2.756 mmol, 85.75% yield). (ESI) m/z = 322.98/324.98 [M+H]+ (Bromine pattern).¹H NMR (400 MHz, DMSO) δ 6.85 (t, J = 7.4, 6.8 Hz, 1H), 7.60 (dd, J = 7.4, 1.0 Hz, 1H), 8.27 (s, 1H), 8.52 (dd, J = 6.8, 1.0 Hz, 1H). Step 4 In a 40 mL vial, 8-bromo-2-iodo-imidazo[1,2-a]pyridine (400.0 mg, 1.24 mmol) and 1,1-dioxo- 2-(trifluoromethylsulfanyl)-1,2-benzothiazol-3-one (456.11 mg, 1.61 mmol) were dissolved in MeCN (6 mL) and 3 vacuum/nitrogen cycles were performed. Chloro(trimethyl)silane (205.44 mg, 1.89 mmol) was added, and the resulting mixture was stirred at r.t. overnight. The reaction mixture was diluted with water and DCM. The aqueous phase was extracted with DCM (x3). The organic phases were collected, dried with sodium sulfate, filtered on a phase separator, and evaporated under reduced pressure. The resulting crude material was purified on a Biotage Sfär D 50g cartridge (gradient: cyclohexane/AcOEt from 100:0 to 89:11) affording 8- bromo-2-iodo-3-(trifluoromethylsulfanyl)imidazo[1,2-a]pyridine (479 mg, 1.132 mmol, 91.42% yield). (ESI) m/z = 422.93/424.94 [M+H]+ (Bromine pattern). ¹H NMR (400 MHz, ‐ 99 ‐ Agent Ref: 12617.0003-00304 DMSO) δ 7.12 (dd, J = 7.5, 6.8 Hz, 1H), 7.89 (dd, J = 7.5, 1.0 Hz, 1H), 8.71 (dd, J = 6.7, 1.0 Hz, 1H). Intermediate 3a: tert-butyl N-[2-methoxy-4-(methylcarbamoyl)phenyl]-N-(prop-2-yn-1- yl)carbamate; Intermediate 3b: 3-methoxy-N-methyl-4-(prop-2-ynylamino)benzamide Step 1 3-Methoxy-4-aminobenzoic acid methyl ester (91.2 g, 503 mmol), heptane (900mL) was combined and heated at 90 °C under N₂ for 1 hour. The mixture was then cooled in an ice bath and the supernatant was removed by decantation set aside. Di-tert-butyl dicarbonate (132 g, 604 mmol), isopropyl acetate (900 mL), and 4-dimethylaminopyridine (0.615 g, 5.03 mmol) were then added to the residue, and the mixture was heated at 90 °C overnight. The mixture was cooled to RT and concentrated in vacuo. The mixture was then stirred in petrol (450 mL) for 1 hr, and then collected by filtration to give 102.2 g of product. The product was combined with potassium carbonate (69.6 g, 503 mmol) and methanol (MeOH) (270.0 mL), and the mixture heated at 70°C for 4 hours before then being allowed to cool to RT overnight. Water (90 mL) was added, and the mixture stirred for 1 h. The resulting solid was collected by filtration, washed (1:1 MeOH / water) and dried to give the product (119.1 g, 84%). NMR was consistent. MS (ESI) m/z = 226.20 [M-tBu]+ (acidic). Step 2 Methyl 4-{[(tert-butoxy)carbonyl]amino}-3-methoxybenzoate (10.1 g, 35.9 mmol), cesium carbonate (17.5 g, 53.8 mmol), and dimethylformamide (DMF) (50.0 mL) were added to a reaction vessel, stirring under N₂. Propargyl bromide (4.80 mL, 43.1 mmol) was added, and the mixture stirred under N₂ for 2.5 days at RT. Water (100mL) was then added and the ‐ 100 ‐ Agent Ref: 12617.0003-00304 products extracted with EtOAc (100mL x 3). Combined organics were washed with brine (100 mL), dried (MgSO₄), and concentrated to give the product (13.5 g). This was purified on Isolera Sfär100 (eluted with a gradient 5-30% EtOAc/petrol) to give the product (10.97 g). MS (ESI) m/z = 264.15 [M-tBu]+. Step 3 Lithium hydroxide monohydrate (2.88 g, 68.7 mmol) in water (H₂O) (11.0 mL) was added to a solution of methyl 4-{[(tert-butoxy)carbonyl](prop-2-yn-1-yl)amino}-3-methoxybenzoate (11.0 g, 34.3 mmol) in tetrahydrofuran (THF) (55.0 mL). The mixture was aged at RT overnight. The mixture was diluted with water (55 mL) and extracted with EtOAc (110 mL). The organic layer was extracted with 1M NaOH (50 mL) and then the combined aqueous basic fractions were acidified with the dropwise addition of conc. HCl (ca.8 mL) to pH 4. The aqueous mixture was extracted with EtOAc (110 mL x 3), and the combined organics were washed with brine (110 mL), dried (MgSO₄), and concentrated in vacuo at 40 °C to give 4-{[(tert- butoxy)carbonyl](prop-2-yn-1-yl)amino}-3-methoxybenzoic acid (3a) (10.42 g), 99%. MS (ESI) m/z = 206.09 [M-Boc]+. Step 4 Methylamine hydrochloride (4.84 g, 71.7 mol), TBTU (16.4 g, 51.2 mmol), and 4-{[(tert- butoxy)carbonyl](prop-2-yn-1-yl)amino}-3-methoxybenzoic acid (10.4 g, 34.1 mmol) were combined in a reaction flask. Dimethylformamide (DMF) (100 mL) was added, followed by N,N-diisopropylethylamine (29.7 mL, 171 mmol), and the resulting solution was stirred at RT, under N₂, for 2.5 days. The mixture was diluted with water (100 mL) and EtOAc (100 mL), and the mixture adjusted to pH 4 by addition of 2M HCl (40 mL). The phases were separated, and the aqueous layer further extracted with EtOAc (100 mL x 4). The combined organic layers were washed successively with 5% lithium chloride (50 mL) and brine (100 mL), dried (MgSO₄), and concentrated in vacuo at 40 °C to give 17.82 g of product. The product was dissolved in EtOAc (100 mL), washed with sat. NaHCO₃ (100 mL) and the basic (pH 9) aqueous was extracted with further EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried (MgSO₄), and concentrated in vacuo to give the product (11.39 g). MS (m/z) 263.15 [M-tBu]+ (acidic).¹H NMR (400 MHz, DMSO, 298 K) δ 8.51 – 8.44 (m, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.1, 1.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.60 – 4.06 (br. m, 2H), 3.84 (s, 3H), 3.13 (m, 1H), 2.79 (d, J = 4.4 Hz, 3H), 1.30 (br. s, 9H).1H NMR (400 MHz, DMSO, 363 K) δ 8.12 (br. s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 8.1, 1.9 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 2.5 Hz, 2H), 3.86 (s, 3H), 2.90 (t, J = 2.5 Hz, 1H), 2.82 (d, J = 4.6 Hz, 3H), 1.35 (s, 9H). Step 5 ‐ 101 ‐ Agent Ref: 12617.0003-00304 tert-butyl N-[2-methoxy-4-(methylcarbamoyl)phenyl]-N-prop-2-ynyl-carbamate (300.0 mg, 0.940 mmol) was dissolved in TFA (2.4 mL) and DCM (7 mL), and the resulting mixture was stirred for 30 min. The mixture was concentrated in vacuo at r.t. The mixture was then partitioned between EtOAc and sat. K₂CO₃. The organic phase was recovered, dried over Na₂SO₄, filtered-off, and concentrated in vacuo to afford 3-methoxy-N-methyl-4-(prop-2- ynylamino)benzamide (3b) (236 mg). MS (m/z) 219.1 [M+H]+.¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.02 (s, 1H), 4.00 (d, J = 2.4 Hz, 2H), 3.90 (s, 3H), 2.99 (d, J = 4.8 Hz, 3H), 2.23 (t, J = 2.4 Hz, 1H). Intermediate 3c: 2-methoxy-4-methylsulfonyl-N-prop-2-ynyl-aniline To a suspension and potassium carbonate (8.24 g, was a of 3-bromo-1-propyne (3.2 mL, 29.91 mmol) in anhydrous DMF (8 mL) at r.t., and the mixture then heated at 70 °C overnight. The mixture was cooled and diluted with a saturated solution of NaHCO₃. The aqueous phase was extracted with EtOAc (x3). The organic phases were collected, dried with sodium sulfate, filtered on a phase separator, and evaporated under reduced pressure. The resulting crude material was purified on two piled Biotage Sfär D 100 g cartridges (gradient: cyclohexane/EtOAc from 100:0 to 50:50) affording 4-methanesulfonyl-2-methoxy-N-(prop-2- yn-1-yl)aniline (2.33 g, 9.737 mmol, 49% yield). LCMS: r.t.0.77 min (ESI) m/z = 240.07 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 3.07 (t, J = 2.4 Hz, 1H), 3.10 (s, 3H), 3.88 (s, 3H), 4.00 (dd, J = 6.2, 2.4 Hz, 2H), 6.29 (t, J = 6.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H). Intermediate 3d: 4-dimethylphosphoryl-2-methoxy-N-prop-2-ynyl-aniline 4- in DMF (5 mL). 3-Bromo-1-propyne (80 WT % in toluene; 0.21 mL, 1.86 mmol) and potassium carbonate (641.13 mg, 4.64 mmol) were added, and the reaction mixture was then heated at 70 °C and stirred overnight. The mixture was then allowed to reach rt and then partitioned between EtOAc and H₂O. The aqueous layers was further extracted with EtOAc(x3) and then ‐ 102 ‐ Agent Ref: 12617.0003-00304 DCM:MeOH 9:1 (x3). The combined organic factions were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified through FC (Biotage, RP C18; eluting with gradient from [H₂O+0.1% NH₄OH] to [H₂O+0.1% NH₄OH]:[ACN+0.1% NH₄OH] 7:3) to afford 4-dimethylphosphoryl-2-methoxy-N-prop-2-ynyl-aniline (175 mg). MS (ESI) m/z = 238.45 [M+H]+. Intermediate 3e: N-(prop-2-yn-1-yl)acetamide Acetyl chloride (1.16 solution of 2-propyn- 1-amine (1.16 mL, , triethylamine (2.78 mL, 19.97 mmol) in DCM (33 mL). The reaction mixture was stirred at rt, then DCM (33 mL) and aqueous NaOH 1M (66 mL) were added: phases were separated. The aqueous phase was extracted 3 times with DCM (33 mL each wash). Organics were combined and dried over sodium sulfate. Volatiles were removed to give N-(prop-2-yn-1-yl)acetamide (1680 mg, 17.3 mmol, 95.28% yield) . MS (ESI) m/z = 98.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) d ppm 1.81 - 1.84 (3H, m) 3.07 - 3.09 (1H, m) 3.80 - 3.86 (2H, m) 8.26 (1H, t, J=6.27 Hz). Intermediate 3f: 4-methoxy-N-methyl-5-[(prop-2-yn-1-yl)amino]pyridine-2-carboxamide Step 1 To a solution of methyl 5-bromo-4-methoxy-pyridine-2-carboxylate (2000.0 mg, 8.13 mmol) in THF (40 mL) was added carbamic acid tert-butyl ester (1428.31 mg, 12.19 mmol), followed by XPhos (Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane) (774.97 mg, 1.63 mmol), (1E,4E)-1,5-diphenyl-3-penta-1,4-dienone;palladium (744.31 mg, 0.810 mmol), and ‐ 103 ‐ Agent Ref: 12617.0003-00304 Cs₂CO₃ (5329.43 mg, 16.26 mmol), and the resulting mixture was degassed with three vacuum/nitrogen cycles. The reaction was heated at reflux for 6 hrs. The reaction mixture was allowed to cool to RT and water was added, and the mixture was extracted with EtOAc (3x). The combined organic phases were washed with water, dried over sodium sulfate, filtered, and concentrated, and the residue was purified by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-60% EtOAc in CyHex) to provide methyl 5-(tert-butoxycarbonylamino)-4- methoxy-pyridine-2-carboxylate (2336 mg, 8.275 mmol, 101.81% yield). MS (ESI) m/z = 283.2 [M+H]+ .¹H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 9H), 3.86 (s, 3H), 3.95 (s, 3H), 7.65 (s, 1H), 8.57 (s, 1H), 8.87 (s, 1H). Step 2 To a solution of methyl 5-(tert-butoxycarbonylamino)-4-methoxy-pyridine-2-carboxylate (2236.0 mg, 7.92 mmol) in DMF (15 mL) were added Cs₂CO₃ (3895.2 mg, 11.88 mmol) and 3-bromo-1-propyne 80% in toluene (1.06 mL, 9.51 mmol). The resulting mixture was stirred at RT for 4 hr. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic phases were washed with brine (3x), dried over sodium sulfate, filtered, and concentrated, and the residue was purified by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-100% EtOAc in CyHex) to provide methyl 5-[tert-butoxycarbonyl(prop-2- ynyl)amino]-4-methoxy-pyridine-2-carboxylate. MS (ESI) m/z = 321.2 [M+H]+.¹H NMR (400 MHz, DMSO-d6) δ 1.32 (s, 9H), 3.18 (t, J = 2.46 Hz, 1H), 3.89 (s, 3H), 3.97 (s, 3H), 4.33 (s, 2H), 7.73 (s, 1H), 8.41 (s, 1H). Step 3 Lithium hydroxide hydrate (369.79 mg, 8.61 mmol) was added to a solution of methyl 5-[tert- butoxycarbonyl(prop-2-ynyl)amino]-4-methoxy-pyridine-2-carboxylate (2754.0 mg, 7.82 mmol) in a mixture of methanol (10.82 mL), THF (3.092 mL), and water (3.092 mL), and the resulting reaction mixture was stirred at RT for 2 hrs. Solvents were removed under vacuum, the residue was co-evaporated 3 times with toluene, and dried to provide crude lithio 5-{[(tert- butoxy)carbonyl](prop-2-yn-1-yl)amino}-4-methoxypyridine-2-carboxylate (2466 mg, 7.898 mmol, 100.9% yield). MS (ESI) m/z = 307.2 [M+H]+.¹H NMR (400 MHz, DMSO-d6) δ 1.28 (s, 9H), 3.17 (d, J = 2.50 Hz, 1H), 3.92 (s, 3H), 4.16 (d, J = 54.58 Hz, 2H), 7.66 (s, 1H), 8.15 (s, 1H). Step 4 To a solution of lithio 5-{[(tert-butoxy)carbonyl](prop-2-yn-1-yl)amino}-4-methoxypyridine-2- carboxylate (2366.0 mg, 7.58 mmol) in DMF (18.94 mL) were added N,N- Diisopropylethylamine (2.64 mL, 15.15 mmol) and TBTU (3649.36 mg, 11.37 mmol). The resulting mixture was stirred at RT for 30 mins, then methanamine 2M solution in THF (11.37 mL, 22.73 mmol) was added and stirring was carried on at RT overnight. The mixture was ‐ 104 ‐ Agent Ref: 12617.0003-00304 diluted with water, extracted with EtOAc (3x), and then the combined organic phases were washed repeatedly with sat. NaHCO₃ solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-100% EtOAc in CyHex) to provide impure material, which was purified again by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-3% MeOH in DCM) to provide tert-butyl N-[4-methoxy-6-(methylcarbamoyl)-3-pyridyl]-N- prop-2-ynyl-carbamate (1993 mg, 6.241 mmol, 82.36% yield). , MS (ESI) m/z = 320.2 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 1.31 (s, 9H), 2.82 (d, J = 4.87 Hz, 3H), 3.18 (t, J = 2.52 Hz, 1H), 3.96 (s, 3H), 4.30 (d, J = 6.27 Hz, 2H), 5.75 (s, 1H), 7.70 (s, 1H), 8.33 (s, 1H), 8.75 (d, J = 5.01 Hz, 1H). Step 5 A solution of tert-butyl N-[4-methoxy-6-(methylcarbamoyl)-3-pyridyl]-N-prop-2-ynyl-carbamate (1993.0 mg, 6.24 mmol) in DCM (23.4 mL) and trifluoroacetic acid (7.8 mL) was stirred for 1 hr at RT until complete conversion was achieved. The solvents were removed under vacuum, and the residue was co-evaporated with toluene to provide a crude residue, which was purified twice by RP-FC on 60 g Biotage Sfär C18 D Duo 100 Å 30 μm cartridge (eluent: 2-30% MeCN+0.1% HCOOH in water+0.1% HCOOH) to provide 4-methoxy-N-methyl-5-(prop-2- ynylamino)pyridine-2-carboxamide ( 1006 mg, 4.589 mmol, 73.53% yield). MS (ESI) m/z = 220.4 [M+H]+.¹H NMR (400 MHz, DMSO-d6) δ 2.81 (d, J = 4.82 Hz, 3H), 3.12 (t, J = 2.42 Hz, 1H), 3.96 (s, 3H), 4.05 (d, J = 2.52 Hz, 2H), 6.24 (s, 1H), 7.58 (s, 1H), 7.86 (s, 1H), 8.53 – 8.58 (m, 1H). Intermediate 5a: tert-butyl 4-({2-iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7- yl}amino)piperidine-1-carboxylate g, 7.92 mmol), 4-amino-1-boc-piperidine (1.91 g, 9.51 mmol), N-methyl-2-pyrrolidinone (NMP) (26.4 mL), and triethylamine (2.76 mL, 19.8 mmol) were combined and heated to 130°C. After 4 hours, additional 4-amino-1-boc-piperidine (1.59 g, 7.92 mmol) was added, and the reaction ‐ 105 ‐ Agent Ref: 12617.0003-00304 stirred overnight. The reaction was cooled to RT, diluted with EtOAc, washed with water and brine, and then the organic phase was dried over sodium sulfate. The solution was concentrated under reduced pressure then columned on a 50g Sfar column eluting with petrol:EtOAc, 10-50% over 10 column volumes. The resultant solution was concentrated under reduced pressure then diluted in MeCN and water. This solution was frozen then the solvent lyophilised to give tert-butyl 4-({2-iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-7-yl}amino)piperidine-1-carboxylate (3.90 g). m/z = 541 [M-H]-. Intermediate 5c: 2-iodo-N-(1-methyl-4-piperidyl)-3-(trifluoromethylsulfanyl)pyrazolo[1,5- a]pyridin-7-amine A mixture of 1- mL), 7-chloro-2- iodo-3- mg, mmol), and DIPEA (0.21 mL, 1.19 mmol) was stirred at 130 °C for 16 h. The mixture was cooled to r.t., suspended in water (2 mL), and stirred for 10 min. The aqueous phase was removed, then the mixture was diluted with diethyl ether and 1M HCl. The mixture was stirred for 5 min, then the aqueous phase was recovered. The organic phase was washed with HCl 1M (2 mL), repeating the previous step.1M NaOH was added to the aqueous phase until pH 12 was reached, then it was extracted with DCM (2x). The organic phase was recovered, dried over sodium sulfate, and concentrated in vacuo to afford 2-iodo-N-(1-methyl-4-piperidyl)-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-amine (366 mg). MS (m/z) 457.1 [M+H]+. Intermediate 5d: tert-butyl (3S,4R)-3-fluoro-4-({2-iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo [1,5-a]pyridin-7-yl}amino)piperidine-1-carboxylate; Intermediate 5e: (3S,4R)-3-fluoro-N-{2- iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl}piperidin-4-amine ‐ 106 ‐ Agent Ref: 12617.0003-00304 (3S,4R)-1-Boc-3-fluoropiperidine-4-amine (2306.44 mg, 10.57 mmol) was dissolved in NMP (2.642 mL). 7-Chloro-2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridine (2000.0 mg, 5.28 mmol) and DIPEA (1.38 mL, 7.93 mmol) were added, and the resulting mixture was heated at 130 °C for 48 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (30 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2x10 mL), dried over sodium sulfate and concentrated in vacuo to obtain a product. The product was dissolved in EtOAc and washed with 1 M HCl. The organic phase was recovered, dried over sodium sulfate, and concentrated in vacuo to obtain tert-butyl (3S,4R)- 3-fluoro-4-[[2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]amino]piperidine-1- carboxylate (2310 mg, 4.122 mmol, 78.03% yield) . MS (ESI) (m/z): 561.03 [M+H]+, 559.24 [M-H]-.¹H NMR (400 MHz, DMSO) δ 1.42 (s, 9H), 1.76 – 1.97 (m, 2H), 2.82 – 3.24 (m, 2H), 3.92 – 4.17 (m, 2H), 4.22 – 4.39 (m, 1H), 4.66 – 5.25 (m, 1H), 6.47 (dd, J = 8.15, 1.08 Hz, 1H), 6.61 (d, J = 8.87 Hz, 1H), 7.06 (d, J = 8.48 Hz, 1H), 7.52 (t, J = 8.23 Hz, 1H). Step 2 tert-butyl (3S,4R)-3-fluoro-4-[[2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7- yl]amino]piperidine-1-carboxylate (741.0 mg, 1.24 mmol) was dissolved in trifluoroacetic acid (3.108 mL) and DCM (9.323 mL), and the resulting mixture was stirred for 30 min. It was concentrated in vacuo at r.t., and then evaporated to dryness. The mixture was then partitioned between EtOAc and sat. K₂CO₃ solution and stirred for 30 min. The organic phase was recovered, dried over Na₂SO₄, filtered-off and concentrated in vacuo to afford 2-iodo-N- [rac-(3S,4R)-3-fluoro-4-piperidyl]-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-amine (565 mg, 1.228 mmol, 98.76% yield). MS (m/z) 461.0 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 1.69 – 1.86 (m, 2H), 1.97 (br s, 1H), 2.56 – 2.66 (m, 1H), 2.80 (dd, J = 40.0, 14.6 Hz, 1H), 2.92 – 3.04 (m, 1H), 3.07 – 3.22 (m, 1H), 3.87 – 4.07 (m, 1H), 4.78 (d, J = 50.7 Hz, 1H), 6.37 – 6.50 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H). Intermediate 5f: 2-iodo-N-(oxan-4-yl)-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7- amine 7-chloro-2-iodo- 2.64 mmol), 4- oxanamine (0.53 g, 5.28 mmol), and DIPEA (0.69 mL, 3.96 mmol) in NMP (1.321 mL) were heated at 130 °C for 16 h. The reaction mixture was diluted with ethyl acetate and brine. Layers ‐ 107 ‐ Agent Ref: 12617.0003-00304 were separated, and the aqueous layer was further extracted with ethyl acetate. Organic layers were combined, washed with ammonium chloride, dried over sodium sulfate, and concentrated in vacuo to obtain a product. The product was purified by flash chromatography (silica 25g+25g, Cy/EtOAc from 9:1 to 7:3) to give 2-iodo-N-tetrahydropyran-4-yl-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-amine (0.883 g, 1.992 mmol, 75.41% yield). MS (ESI) m/z= 444.5 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) d ppm 1.69 - 1.83 (2 H, m) 1.83 - 1.92 (2 H, m) 3.40 - 3.50 (2 H, m) 3.73 - 3.85 (1 H, m) 3.87 - 3.95 (2 H, m) 6.33 - 6.38 (1 H, m) 6.94 - 6.99 (1 H, m) 6.99 - 7.05 (1 H, m) 7.43 - 7.50 (1 H, m). Intermediate 5g: (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-7-yl}-1-methylpiperidin-4-amine A mixture of 7- (2000.0 mg, 5.28 mmol), - (2167.27 mg, 10.57 mmol) and DIPEA (5.06 mL, 29.06 mmol) in NMP (1.000 mL) was heated at 130 °C for 48 h. The mixture was cooled to r.t., suspended in water (2 mL), and stirred for 10 min. The supernatant aqueous phase was removed, then the mixture was diluted with diethyl ether and 1M HCl. The mixture was stirred for 5 min, then the aqueous phase was recovered. The organic phase was extracted again with HCl 1M (2 mL). The acidic aqueous phases were merged and basified with 1M NaOH (until pH 12 was reached). The aqueous mixture was then extracted with DCM (2x). The organic phase was recovered, dried over sodium sulfate, and concentrated in vacuo to afford (3S,4R)-3-fluoro-N-{2-iodo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl}-1-methylpiperidin-4-amine (1920 mg, 4.048 mmol, 76.62% yield). MS (m/z) 475.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 1.98 – 2.42 (m, 7H), 2.95 (d, J = 11.3 Hz, 1H), 3.24 (t, J = 10.7 Hz, 1H), 3.53 – 3.73 (m, 1H), 4.88 (d, J = 48.8 Hz, 1H), 5.95 (d, J = 7.7 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H). Intermediate 5h: 8-bromo-6-fluoro-2-iodo-3-((trifluoromethyl)thio)imidazo [1,2- a]pyridine Step 1 ‐ 108 ‐ Agent Ref: 12617.0003-00304 To a solution added ethyl 2- bromoacetate . was filtered and washed with Et₂O (300 mL) to afford ethyl 2-(2-amino-3-bromo-5-fluoro-1l4-pyridin-1- yl)acetate (5.5 g, 19.86 mmol, 83.8%). MS (ESI) m/z 278 [M+H]⁺. Step 2 Br Br NH₂ _O ^POCl ₃ N C^l A solution of ethyl (5.5 g, 19.8 mmol) in POCl₃(30 mL) added ice water (300 mL) and ammonia to adjust to pH 8, filtered and washed with H₂O (500 mL) and cyclohexane (500 mL) to afford 8-bromo-2-chloro-6-fluoroimidazo[1,2-a]pyridine (5.7 g, 22.99 mmol, 80% purity). MS (ESI) m/z 249/251 [M+H]⁺. Step 3 To a solution of 8- g, 22.97 mmol) in MeCN (70 mL) was added NaI (17.23 g, 114.94 mmol) and HI (36.53 g, 285.59 mmol). The mixture was stirred at 85°C o/n under N₂. The mixture was added NaOH (12M) adjust to pH 10-12, extracted with EtOAc (300 mL*2), washed with Na₂S₂O₃ (200 mL*2) and brine (200 mL*2), dried over Na₂SO₄, filtered, and concentrated to afford 8-bromo-6-fluoro-2-iodoimidazo[1,2- a]pyridine.( 4 g, 11.77 mmol, 51%). MS (ESI) m/z 341/343 [M+H]⁺. Step 4 To a solution of 8- g, 10.3 mmol) in MeCN (140 mL) was added 2-((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (4.99 g, 17.5 mmol) and TMSCl (1.68 g, 15.4 mmol). The mixture was stirred at 60°C for 1h. The ‐ 109 ‐ Agent Ref: 12617.0003-00304 mixture was concentrated, added NaOH (1M), extracted with EtOAc (200 mL*2), washed with brine (200 mL*2) and H₂O (200 mL), dried over Na₂SO₄, filtered, concentrated, and purified by column silica gel to afford 8-bromo-6-fluoro-2-iodo-3-((trifluoromethyl)thio)imidazo [1,2- a]pyridine.(3.7g, 8.4mmol, 35%). MS (ESI) m/z 441/443 [M+H]⁺. Intermediate 6a: 4-[3-[8-bromo-3-(trifluoromethylsulfanyl)imidazo[1,2-a]pyridin-2-yl]prop-2- ynylamino]-3-methoxy-N-methyl-benzamide 8- , copper (I) , ₄ , methyl-4- (prop-2-ynylamino)benzamide (1.38 g, 6.33 mmol) were degassed applying three vacuum/nitrogen cycles, then diisopropylamine (6.91 mL, 49.28 mmol) and DMSO (9.6 mL) were added and degassed as above, then the resulting mixture was stirred at rt for 15 min. The reaction mixture was poured into a sat. aq. solution of NaHCO₃, then EtOAc was added. The phases were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered-off and concentrated in vacuo. Crude material was purified by flash chromatography (Biotage® Sfär Silica D-Duo 60 μm 200 g, Cy/EtOAc from 60:40 to 0:100 and then EtOAc:EtOH 90:10) affording 4-[3-[8-bromo-3-(trifluoromethylsulfanyl)imidazo[1,2- a]pyridin-2-yl]prop-2-ynylamino]-3-methoxy-N-methyl-benzamide (2.068 g, 4.029 mmol, 76.42% yield). MS (ESI) m/z= 513.4, 515.5 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 2.76 (d, J = 4.5 Hz, 3H), 3.85 (s, 3H), 4.35 (d, J = 6.3 Hz, 2H), 6.00 (t, J = 6.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 7.15 (dd, J = 7.5, 6.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.93 (dd, J = 7.5, 1.0 Hz, 1H), 8.09 (d, J = 4.7 Hz, 1H), 8.62 – 8.67 (m, 1H). Intermediate 6b: N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop- 2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline ‐ 110 ‐ Agent Ref: 12617.0003-00304 8- mmol), 4- , copper (I) iodide (151.62 mg, 0.790 mmol) and palladium tetrakis triphenylphosphine (212.27 mg, 0.180 mmol) were degassed with three vacuum/nitrogen cycles. A degassed solution of diisopropylamine (2.34 mL, 16.6 mmol) in anhydrous DMSO (5.227 mL) was added; the reaction mixture was degassed as above and left stirring at RT for 2 hours. Reaction was quenched by slow addition of 20 mL of water keeping the temperature at RT using a water bath. Mixture obtained was further diluted with water (100 mL) and extracted with EtOAc (3x100 mL). Organics were collected, washed with brine, filtered over a phase separator, and dried under vacuum. Crude was purified by FCC on a 25g silica gel column (eluent gradient: from Cy to 80% EtOAc) to afford N-[3-[8-bromo-3-(trifluoromethylsulfanyl)imidazo[1,2- a]pyridin-2-yl]prop-2-ynyl]-2-methoxy-4-methylsulfonyl-aniline (616 mg, 1.153 mmol, 65.06% yield). MS (ESI) m/z= 534.1 [M+H]⁺.¹H-NMR (400 MHz, DMSO) δ 3.09 (s, 3H), 3.90 (s, 3H), 4.39 (d, J = 6.3 Hz, 2H), 6.51 (t, J = 6.3 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 7.11 – 7.17 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.92 (dd, J = 7.4, 1.0 Hz, 1H), 8.64 (d, J = 6.8 Hz, 1H). Intermediate 6c: tert-butyl N-[3-[7-chloro-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2- yl]prop-2-ynyl]-N-[2-methoxy-4-(methylcarbamoyl)phenyl]carbamate A MW a]pyridine (600.0 mg, 1.59 mmol), tert-butyl N-[2-methoxy-4-(methylcarbamoyl)phenyl]-N-prop-2-ynyl- carbamate (605.55 mg, 1.9 mmol), copper (I) iodide (132.0 mg, 0.690 mmol), and Pd(PPh₃)₄ (192.32 mg, 0.170 mmol). The vial was sealed, and it was degassed by 5 cycles of nitrogen/vacuum. DMSO (13.33 mL) and diisopropylamine (1499.31 mg, 14.82 mmol) were added, and after degassing again with 5 cycles of nitrogen/vacuum, the reaction mixture was ‐ 111 ‐ Agent Ref: 12617.0003-00304 stirred at r.t. for 1 hour. The reaction was combined with that from a second batch, and the combined mixture was partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc (x3). The combined organic portions were dried (sodium sulfate), and the solvent was evaporated under reduced pressure. Crude was purified by column chromatography (Sfar C18 D, 60g; Water + 0.1% HCOOH/CH₃CN + 0.1% HCOOH from 10/0 to 4/6 as eluent) obtaining tert-butyl N-[3-[7-chloro-3-(trifluoromethylsulfanyl)pyrazolo[1,5- a]112yridine-2-yl]prop-2-ynyl]-N-[2-methoxy-4-(methylcarbamoyl)phenyl]carbamate (1480 mg). MS (ESI) (m/z): 513.16 [M-tBu]⁺. Intermediate 6d: N-[3-[7-chloro-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2- ynyl]-2-methoxy-4-methylsulfonyl-aniline 7- 0.660 mmol), copper mg, , mmol), and 2-methoxy-4-methylsulfonyl-N-prop-2-ynyl-aniline (189.64 mg, 0.790 mmol) were degassed with three vacuum/nitrogen cycles. DMSO was added and the reaction mixture further degassed as above. Pd(PPh₃)₄ (80.13 mg, 0.070 mmol) was added, and the mixture degassed again as above. The mixture was left stirring for 4 h at r.t., and then it was quenched with water and extracted with EtOAc (3x). The combined organic phase was dried over sodium sulfate, filtered-off, and concentrated in vacuo. Crude material was purified by FC (Biotage D Sfar 10 g, from 100 % CyHex to 30:70 CyHex:EtOAc) affording N-[3-[7-chloro-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]-2-methoxy-4-methylsulfonyl- aniline (261 mg). MS (m/z) 490.1 [M+H]⁺. The following intermediate was made in an analogous fashion to Intermediates 6a to 6d: Intermediate 6e I) = ‐ 112 ‐ Agent Ref: 12617.0003-00304 1H NMR (400 MHz, DMSO) δ 1.87 (s, , , J , , , . I) = .4 ‐ 113 ‐ Agent Ref: 12617.0003-00304 MS (ESI) 1 I) = I) = 00 O- m ), ), ‐ 114 ‐ Agent Ref: 12617.0003-00304 3.93 (s, 3H), 4.40 (d, J=6.4 Hz, 2H), 6.20 z, (t, z, d, z, d, 2, s, d, H) I) .9 00 O) s, s, s, d, z, , J ), = ), = z, s, d, z, R z, 64 .7 ), d, 1 ‐ 115 ‐ Agent Ref: 12617.0003-00304 H), 7.14 (t, J=7.1 Hz, 1 H) 6.57 - 2 br 35 ), 3 I) = 9. R z, 56 59 84 H, - H, (1 27 (1 d, 97 - H, - H, - H, - H, I) 3- 00 O- m (3 - m) (2 (1 38 - m) (1 - m) (1 ‐ 116 ‐ Agent Ref: 12617.0003-00304 H, m) 8.40 (1 H, q, J=4.47 Hz) 8.62 - ). /z 4- ]⁺ Alkynes Syntheses Alkyne Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide, for use in the synthesis of Intermediate 6g, Step 1 O O O₂N O To a mixture of 3-methoxy-4-nitrobenzoic acid (2.14 g, 0.011 mol) in DMF (50 mL) was added HATU (6.19 g, 0.016 mol), dimethylamine (2M, THF) (10.9 mL, 0.022 mol), and DIPEA (4.21 g, 0.033 mol). The mixture was stirred for 16 h at RT. The resulted mixture was diluted with EA (500 mL), washed with brine (500 mL*3), dried over Na₂SO₄ and concentrated to afford 3- methoxy-N,N-dimethyl-4-nitrobenzamide (4.80 g, 40% purity, 0.009 mol). MS (ESI) m/z = 225 [M+H]⁺. Step 2 To a solution of 3-methoxy-N,N-dimethyl-4-nitrobenzamide (5.52 g, 40% purity, 0.010 mol) in EtOH (20 mL) and water (10 mL) was added Fe (6.87 g, 0.123mol) and NH₄Cl (6.58 g, 0.123 mol). The mixture was stirred for 4h at 90 °C. The solids were filtrated out. The solution was concentrated and diluted with EA (200 mL), washed with brine (200 mL*3), dried over Na₂SO₄ and concentrated to afford 4-amino-3-methoxy-N,N-dimethylbenzamide (3.47 g, 50% purity, 0.009 mol). MS (ESI) m/z = 195 [M+H]⁺. Step 3 ‐ 117 ‐ Agent Ref: 12617.0003-00304 To a 0.008 mol) in CHCl₃ (30 mL) was added 3-bromoprop-1-yne (1.31 g, 0.011 mol) and DIPEA (4.27 g, 0.033 mol). The mixture was stirred for 16h at 60 °C. The resulted mixture was concentrated and purified by silica gel column (EtOAc/PE=1/10-1/1) to afford 3-methoxy-N,N-dimethyl-4-(prop- 2-yn-1-ylamino)benzamide (1.1g, 95% purity). MS (ESI) m/z = 233 [M+H]⁺. Alkyne Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)benzonitrile, for use in the synthesis of Intermediate 6h Step 1 (50 mL) was added 3-bromoprop-1-yne (6.43 g, 54.054 mmol) and DIPEA (5.23 g, 40.539 mmol). The mixture was stirred for 16h at 70 °C. The resulted mixture was concentrated and purified by silica gel column (EtOAc/PE=1/100-1/5) to afford 3-methoxy-4-(prop-2-yn-1- ylamino)benzonitrile (0.99 g, 5.320 mmol). MS (ESI) m/z = 186 [M+H]⁺. Alkyne Synthesis of 3-fluoro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide, for use in the synthesis of Intermediate 6i Step 1 To a solution of 4-amino-3-fluoro-N-methylbenzamide (0.5 g, 2.98 mmol) in CHCl₃ (10 mL) was added DIPEA (1.2 g, 9.30 mmol) and 3-bromoprop-1-yne (0.71 g, 5.95 mmol). The mixture was stirred at 70°C for 16h. The mixture was filtered, concentrated, extracted with ‐ 118 ‐ Agent Ref: 12617.0003-00304 EtOAC and water, dried over Na₂SO₄, purified by column silica gel to afford 3-fluoro-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (220 mg, 1.07 mmol). MS (ESI) m/z = 207 [M+H]⁺. Alkyne Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)picolinamide, for use in the synthesis of Intermediate 6j Step 1 To a mixture (50 mL) was added HATU g, , g, mmol) and NaHCO₃ (1.25 g, 14.839 mmol). The mixture was stirred for 4 h at RT. The resulted mixture was diluted with EA (300 mL), washed with brine (300 mL*3), dried over Na₂SO₄ and concentrated to afford 6-methoxy-N-methyl-5-nitropicolinamide (3.90 g, 35% purity, 6.464 mmol). MS (ESI) m/z = 212 [M+H]⁺ Step 2 To a mmol) in MeOH (50 mL) and water (25 mL) was added Fe (4.46 g, 72.695 mmol) and NH₄Cl (3.89 g, 72.695 mmol). The mixture was stirred for 4h at 80 °C. The solids were filtrated out. The solution was concentrated and diluted with EA (200 mL), washed with brine (200 mL*3), dried over Na₂SO₄ and concentrated to afford 5-amino-6-methoxy-N-methylpicolinamide (1.54 g, 50% purity, 4.249 mmol). MS (ESI) m/z = 182 [M+H]⁺. Step 3 mmol) in CHCl₃ (30 mL) was added 3-bromoprop-1-yne (3.70 g, 31.126 mmol) and DIPEA (3.02 g, 23.344 mmol). The mixture was stirred for 36h at 70 °C. The resulted mixture was ‐ 119 ‐ Agent Ref: 12617.0003-00304 concentrated and purified by silica gel column (EtOAc/PE=1/10-1/1) to afford 6-methoxy-N- methyl-5-(prop-2-yn-1-ylamino)picolinamide (1.30 g, 60% purity). MS (ESI) m/z = 220 [M+H]⁺. Alkyne Synthesis of (3-cyclopropoxy-4-(prop-2-yn-1- ylamino)phenyl)dimethylphosphine oxide, for use in the synthesis of Intermediate 6k Step 1 To a mixture of in THF (20 mL) was added NaH g, , g, . The mixture was stirred for 4 h at RT. The resulted mixture was diluted with EA (300 mL), washed with brine (300 mL*3), dried over Na₂SO₄ and concentrated; the residue was purified by silica gel column (EtOAc/PE=1/30-1/1) to afford 4-bromo-2-cyclopropoxy-1-nitrobenzene (2.06 g, 7.982 mmol). MS (ESI) m/z = 258/260 [M+H]⁺. Step 2 To a mixture of 4- in DMF (50 mL) was added dimethylphosphine oxide (708 mg, 9.067 mmol), Pd(AcO)₂ (170 mg, 0.756 mmol), Xantphos ((9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)) (525 mg, 0.907 mmol) and K₃PO₄ (1.25 g, 14.839 mmol). The mixture was stirred for 16h at 120^oC under N₂. After cooled to RT, the mixture was diluted with EA (300 mL), washed with brine (300 mL*3), dried over Na₂SO₄ and concentrated, the residue was purified by silica gel column (EtOAc/PE=1/15-1/1) to afford to (3-cyclopropoxy-4-nitrophenyl)dimethylphosphine oxide (1.50 g, 5.878 mmol). MS (ESI) m/z = 256 [M+H]⁺. Step 3 ‐ 120 ‐ Agent Ref: 12617.0003-00304 To a solution of g, 5.293 mmol) in EtOH (20 mL) and NH₄Cl (1.42 g, 26.463 mmol). The mixture was stirred for 4h at 80 °C. The solids were filtrated out. The solution was concentrated and diluted with EA (200 mL), washed with brine (200 mL*3), dried over Na₂SO₄ and concentrated to afford (4-amino-3-cyclopropoxyphenyl)dimethylphosphine oxide (1.19 g, 95% purity, 1.131 mmol). MS (ESI) m/z = 226 [M+H]⁺. Step 4 To a (1.16 g, 5.150 mmol) in CHCl₃ (30 mL) was added 3-bromoprop-1-yne (2.45 g, 20.601 mmol) and DIPEA (2.00 g, 15.451 mmol). The mixture was stirred for 16h at 70 °C. The resulted mixture was concentrated and purified by silica gel column (EtOAc/PE=1/10-1/1) to afford (3-cyclopropoxy- 4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (2.30 g, 50% purity). MS (ESI) m/z = 264 [M+H]⁺. Alkyne Synthesis of (3-(difluoromethoxy)-4-(prop-2-yn-1- ylamino)phenyl)dimethylphosphine oxide, for use in the synthesis of Intermediate 6l Step 1 To a solution of 5- was added H₂O (50 mL), KOH (19.3 g, 344 mmol) and diethyl (bromodifluoromethyl) phosphonate (9.8 g, 36.7 ‐ 121 ‐ Agent Ref: 12617.0003-00304 mmol) at -25°C. The mixture was stirred at R.T. for 2h. The mixture was concentrated, extracted with EtOAc (200 mL*2), dried over Na₂SO₄, filtered, and concentrated to afford 4- bromo-2-(difluoromethoxy)-1-nitrobenzene ( 5.7 g, 21.35 mmol). MS (ESI) m/z = 268 [M+H]⁺. Step 2: F F F O O F O To a in DMF (100 mL) was g, , ₂ mg,1.07 mmol), Xantphos (741.3 mg,1.28 mmol), K₃PO₄ (6.8 g, 32 mmol). The mixture was stirred at 120°C for 5h under N₂. The mixture was extracted with EtOAc (200 mL*2), washed with brine (200 mL), dried over Na₂SO₄, filtered, concentrated, and purified by column silica gel to afford (3- (difluoromethoxy)-4-nitrophenyl)dimethylphosphine oxide ( 2.5 g, 9.43 mmol). MS (ESI) m/z = 266 [M+H]⁺. Step 3 To a (1.85 g, 6.95 mmol) in EtOH/H₂O (40mL/20mL) was added Fe (1.95 g, 34.9 mmol) and NH₄Cl (1.87 g, 34.9 mmol). The mixture was stirred at 70 °C for 5h. The mixture was filtered and concentrated, extracted with EtOAc (200 mL*2), washed with brine (200 mL), dried over Na₂SO₄, filtered and concentrated to afford (4-amino-3-(difluoromethoxy)phenyl)dimethylphosphine oxide (1.6 g, 6.8 mmol). (MS (ESI) m/z = 236 [M+H]⁺. Step 4 ‐ 122 ‐ Agent Ref: 12617.0003-00304 To a solution of (4-amino-3-(difluoromethoxy)phenyl)dimethylphosphine oxide (700 mg, 2.97 mmol) in DMF (20 mL) was added 3-bromoprop-1-yne (2.12 g, 17.8 mmol) and K₂CO₃ (821.3 mg, 5.94 mmol). The mixture was stirred at 110°C o/n. The mixture was filtered and concentrated, extracted with EtOAc (100 mL*2), washed with brine (100 mL), dried over Na₂SO₄, filtered, concentrated, and purified by column silica gel to afford (3-(difluoromethoxy) -4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (525 mg, 1.9mmol). MS (ESI) m/z = 274 [M+H]⁺. Alkyne Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide, for use in the synthesis of Intermediate 6m To a solution in CHCl₃ (50 mL) was added yne g, g, 37.689 mmol). The mixture was stirred for 16h at 70 °C. The resulting mixture was concentrated and purified by silica gel column (EtOAc/PE=1/100-1/5) to afford 3-chloro-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (1.50 g, 6.757 mmol). MS (ESI) m/z = 223 [M+H]⁺. Alkyne Synthesis of 2-fluoro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide, for use in the synthesis of Intermediate 6n Step 1 O O MeNH₂.HCl O To a solution in DMF (40 mL) was added DIPEA (3.6g, 27.9mmol), HATU (4.2 g, 11.2 mmol), and methanamine hydrochloride (0.759g, 9.3mmol). The mixture was stirred at R.T. for 10h. The mixture was poured into water, extracted with EtOAc (200 mL*3), dried over Na₂SO₄, concentrated and column silica gel to afford 2-fluoro-5-methoxy-N-methyl-4-nitrobenzamide (2.2 g, 9.6 mmol). MS (ESI) m/z = 229[M+H]⁺. Step 2 ‐ 123 ‐ Agent Ref: 12617.0003-00304 To a solution of g, 8.68mmol) in EtOH/H₂O (1.88 g, 34.81 mmol). The mixture was stirred at 80 °C for 2h. The mixture was filtered and concentrated, purified by column silica gel to afford 4-amino-2-fluoro-5-methoxy-N-methylbenzamide (1.7 g, 8.59 mmol). MS (ESI) m/z = 199 [M+H]⁺. Step 3 To a solution mmol) in CH₃CN (8 mL) was added K₂CO₃ (2.1 g, 15.22 mmol) and 3-bromoprop-1-yne (1.2 g, 10.08 mmol). The mixture was stirred at 100°C for 16h in a sealed tube. The mixture was filtered and concentrated, purified by column silica gel to afford 2-fluoro-5-methoxy-N-methyl-4-(prop-2- yn-1-ylamino)benzamide (545 mg, 0.19 mmol), (260 mg, 1.10 mmol, 90%) and (175 mg, 0.74 mmol, 78%). MS (ESI) m/z = 237 [M+H]⁺. Alkyne Synthesis of (3-(difluoromethyl)-4-(prop-2-yn-1- ylamino)phenyl)dimethylphosphine oxide, for use in the synthesis of Intermediate 6o Step 1 To a solution of 5- in DCM (5.434 mL) at 0 °C, N-ethyl-N-(trifluoro-$l^{4}-sulfanyl)ethanamine (0.14 mL, 1.09 mmol) was added the reaction mixture was stirred at r.t. for 1 hour. UPLC-MS analysis showed complete conversion of starting material in the desired product. A saturated solution of NaHCO₃ was added to the reaction mixture, and the aqueous phase was extracted with DCM (x3). The organic portions were collected, residual water was removed by sodium sulfate, and the solvent was ‐ 124 ‐ Agent Ref: 12617.0003-00304 evaporated under reduced pressure. Crude was purified by column chromatography (Biotage™ Sfär Silica D-Duo 60 μm, 5g; Cyclohexane/EtOAc from 10/0 to 9/1 as eluent) obtaining 4-bromo-2-(difluoromethyl)-1-nitro-benzene (221 mg, 0.877 mmol). ¹H NMR (400 MHz, DMSO) δ 7.44 (t, J = 53.9 Hz, 1H), 8.07 (m, 2H), 8.12 – 8.18 (m, 1H). Step 2 A MW vial (50.0 mg, 0.200 mmol), , 9,9-dimethyl- 4-xanthenyl)-diphenylphosphine (25.26 mg, 0.040 mmol) and palladium (2⁺) diacetate (4.94 mg, 0.020 mmol). The vial was sealed, and it was degassed by 5 cycles of nitrogen/vacuum. DMF (0.441 mL) and N,N-Diisopropylethylamine (0.07 mL, 0.400 mmol) were added, and after degassing again with 5 cycles of nitrogen/vacuum, the reaction mixture was stirred 120 °C for 1 hour. UPLC-MS analysis showed incomplete consumption of starting material and formation of the presumed desired product. Stirring continued for 3 hours more at the same temperature after which complete consumption of starting material was observed. After cooling to r.t., water was added to the reaction mixture. The suspension was filtered, and the filtrate was evaporated under reduced pressure obtaining 2-(difluoromethyl)-4-dimethylphosphoryl-1- nitro-benzene (77 mg, 0.309 mmol) as a crude product that was used in the next step without further purification. MS (ESI) m/z = 249.89 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 1.75 (s, 3H), 1.79 (s, 3H), 7.50 (t, J = 54.0 Hz, 1H), 8.19 – 8.29 (m, 2H), 8.29 – 8.35 (m, 1H). Step 3 To a mg, 0.310 mmol) in DMF (1.545 mL), hypodiboric acid (83.12 mg, 0.930 mmol) was added in one portion followed by the addition of 4,4′−dipyridyl (0.48 mg, 0 mmol). The exothermic reaction was controlled with a water bath. The reaction was stirred at r.t. for 10 minutes, and after this time UPLC-MS analysis showed complete conversion of starting material in the presumed desired product. The reaction mixture was evaporated under reduced pressure obtaining 2- (difluoromethyl)-4-dimethylphosphoryl-aniline (72 mg, 0.329 mmol) as a crude product that was used in the next step without further purification. MS (ESI) m/z = 219.92 [M+H]⁺.¹H NMR ‐ 125 ‐ Agent Ref: 12617.0003-00304 (400 MHz, DMSO-d6) δ 1.54 (s, 3H), 1.57 (s, 3H), 5.94 (s, 2H), 6.80 (dd, J = 8.39, 2.39 Hz, 1H), 7.05 (t, J = 54.78 Hz, 1H), 7.50 (ddt, J = 10.31, 8.35, 1.77 Hz, 1H), 7.62 (dd, J = 11.80, 1.78 Hz, 1H). Step 4 In was , 9.31 mmol) and potassium carbonate (1.29 g, 9.31 mmol) were added, and the reaction mixture was stirred at 80 °C for 1 hour. UPLC-MS analysis showed low formation of the presumed desired product, so further 3-bromo-1-propyne (1.5 eq.) was added and stirring continued for 1.5 hours at 100 °C. After this time, further formation of the presumed desired product and trace of the bis-alkylated derivative were observed. The reaction was allowed to stir overnight at the same temperature. The day after UPLC-MS analysis showed further consumption of starting material and formation of the presumed desired product (1:1 ratio). 3-bromo-1- propyne (1.5 eq.) was added and stirring continued at 100 °C for 1.5 hours. After the reaction check further 3-bromo-1-propyne (1.5 eq.) was added again and stirring continued for 1.5 hours at the same temperature. Even if the starting material consumption was not complete, the reaction was stopped. Water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (x3). The organic portions were collected, residual water was removed by sodium sulfate and the solvent was evaporated under reduced pressure. Crude was purified by column chromatography (Biotage™ Sfär Silica D-Duo 60 μm, 50g; Cyclohexane/EtOAc from 10/0 to 0/10 +DCM/MeOH from 10/0 to 7/3 as eluent) obtaining 2- (difluoromethyl)-4-dimethylphosphoryl-N-prop-2-ynyl-aniline (307 mg, 1.194 mmol). MS (ESI) m/z = 257.94 [M+H]⁺. Alkyne Synthesis of 3-cyano-N-methyl-4-(prop-2-yn-1-ylamino)benzamide, for use in the synthesis of Intermediate 6p ‐ 126 ‐ Agent Ref: 12617.0003-00304 To a solution of 4-amino-3-cyano-N-methylbenzamide (0.49 g, 2.80 mmol) in DMF (8 mL) was added TEA (848 mg, 8.40 mmol) and 3-bromoprop-1-yne (2.3 g, 19.30 mmol). The mixture was stirred at 100°C for 16h in a sealed tube. The mixture was poured into water, extracted with EtOAC, dried with Na₂SO₄ and concentrated, purified by column silica gel to afford 3- cyano-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (220 mg, 1.03 mmol). MS (ESI) m/z = 214 [M+H]⁺. Alkyne Synthesis of (4-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2- yl)dimethylphosphine oxide, for use in the synthesis of Intermediate 6q Step 1 Split in two 100 mL 2,4-dibromo-5-nitro- pyridine (10.0 g, 35.47 was a (40 mL) and MeOH (25 mL). The solution was cooled with an ice bath and a solution of sodium methoxide (2.4 g, 42.21 mmol) in MeOH (25 mL) was added dropwise during 10 minutes. The reaction mixture was maintained at that temperature for 1 hour. The UPLC analysis after that time showed almost complete conversion to the presumed desired product. A mixture of the two possible regioisomers was observed. Water was added, and the resulting precipitates coming from the two reactions were separately filtered off and dried under high vacuum affording batches 2- bromo-4-methoxy-5-nitro-pyridine (3.88 g, 16.65 mmol) and 2-bromo-4-methoxy-5-nitro- pyridine (3.79 g, 16.26 mmol). Due to the presence of the other regioisomer, the resulting precipitates were put together and purified by FC (Biotage™ Sfar Silica D-Duo 60 um, 100 g, gradient: cyclohexane/AcOEt) affording the presumed product 2-bromo-4-methoxy-5-nitro- pyridine (4.6 g, 19.74 mmol) and the presumed undesired regioisomer 4-bromo-2-methoxy-5- nitro-pyridine (0.750 g, 3.219 mmol). Due to column overloading, tailing of the chromatographic peak was observed, and the tail was recovered separately affording 2- bromo-4-methoxy-5-nitro-pyridine (1.323 g, 5.678 mmol). A structural elucidation was requested, and the structure was confirmed by ¹H NMR. MS (ESI) m/z = 234.91 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6 ) δ ppm 4.06 (s, 3 H), 7.74 (s, 1H), 8.84 (s, 1 H). Step 2 ‐ 127 ‐ Agent Ref: 12617.0003-00304 Split in three 40 (3500.0 mg, 15.02 mmol), palladium(2⁺) diphenylphosphino-9,9- dimethyl-4-xanthenyl)-diphenylphosphine (2085.83 mg, 3.6 mmol) were degassed with three vacuum/nitrogen cycles. Anhydrous DMF (21 mL) was added, followed by N,N- diisopropylethylamine (5.95 mL, 34.16 mmol). The reaction mixture was degassed as above. A degassed solution of dimethylphosphine oxide (3500.0 mg, 44.84 mmol) in anhydrous DMF (7 mL) was added; the resulting solution was degassed as above, placed on a preheated plate (80 °C) and left stirring at that temperature for 2 hours. The UPLC analysis after that time showed traces of starting material and the formation of the presumed desired product as dominant species. The reaction mixtures were cooled down to r.t. and left for 1 hour at -20 °C and then filtered. The eluate was discarded, and the resulting precipitate was washed with DCM; the organic phase was concentrated under reduced pressure affording the desired product 2-dimethylphosphoryl-4-methoxy-5-nitro-pyridine (2400 mg, 10.43 mmol). Low levels of contamination by residual DIPEA were observed by ¹H NMR. The material was used as such in the next synthetic step without further purification.¹H NMR data currently not available. MS (ESI) m/z = 231.03. Step 3 an air condenser, 2- dimethylphosphoryl-4-methoxy-5-nitro-pyridine (337.0 mg, 1.46 mmol), ammonium chloride (344.61 mg, 6.44 mmol) and iron (269.86 mg, 4.83 mmol) were degassed with three vacuum/nitrogen cycles. Ethanol (3 mL) and water (0.500 mL) were added; the resulting suspension was degassed as above and heated at 80 °C for 2 hours. The UPLC analysis after that time showed complete conversion of the starting material to the presumed desired product. The reaction mixture was cooled down to r.t. and filtered. The solid was washed with fresh ethanol. Organics were concentrated under reduced pressure, dissolved in ACN and filtered again. The acetonitrile solution was concentrated affording 6-dimethylphosphoryl-4- methoxy-pyridin-3-amine (280 mg, 1.399 mmol). However, due to the presence of iron, the ¹H NMR was inconclusive. The material was purified on a 10g SCX cartridge using NH₃2M in ‐ 128 ‐ Agent Ref: 12617.0003-00304 MeOH. The appropriate fraction was concentrated affording the desired product 6- dimethylphosphoryl-4-methoxy-pyridin-3-amine (200 mg, 0.999 mmol) that was used as such in the next synthetic step. MS (ESI) m/z = 201.02 [M+H]+. ¹H NMR (400 MHz, DMSO- d6) δ ppm 1.53 (s, 3 H), 1.57 (s, 3 H), 3.88 (s, 3 H), 5.35 (s, 2 H), 7.30 (d, J=5.94 Hz, 1 H), 7.97 - 8.03 (s, 1 H). Step 4 6-dimethylphosphoryl-4- (414.28 mg, 3 mmol) were degassed with three vacuum/nitrogen cycles. Anhydrous DMF (2.8 mL) was added, followed by addition of 3-bromo-1-propyne 80 wt % soln in toluene (0.4 mL, 3.59 mmol). The reaction mixture was heated at 70 °C for 6 hours. The UPLC analysis showed almost complete conversion to the presumed desired product (low amounts of residual starting material and bis-alkylated byproduct). The reaction mixture was concentrated under reduced pressure, and residual DMF was stripped away with cyclohexane. The crude material was dissolved in MeOH and dry loaded on a Biotage Sfar C1830g cartridge (gradient: water + 0.1% HCOOH/ ACN + 0.1% HCOOH from 100:0 to 80:20) affording 6-dimethylphosphoryl-4- methoxy-N-prop-2-ynyl-pyridin-3-amine (92 mg, 0.386 mmol), 6-dimethylphosphoryl-4- methoxy-N-prop-2-ynyl-pyridin-3-amine (89 mg, 0.374 mmol) and 6-dimethylphosphoryl-4- methoxy-N-prop-2-ynyl-pyridin-3-amine (90 mg, 0.378 mmol). ¹H NMR signals for 6- dimethylphosphoryl-4-methoxy-N-prop-2-ynyl-pyridin-3-amine were not coherent; the fractions were put together affording 6-dimethylphosphoryl-4-methoxy-N-prop-2-ynyl-pyridin- 3-amine (230 mg, 0.965 mmol) which was used as such in the next synthetic step. MS (ESI) m/z = 239.4 [M+H]+. Alkyne Synthesis of 2-dimethylphosphoryl-4-methoxy-N-prop-2-ynyl-pyrimidin-5- amine for use in the synthesis of Intermediate 6r Step 1 O O ‐ 129 ‐ Agent Ref: 12617.0003-00304 A MW vial was loaded with 2-chloro-4-methoxy-pyrimidin-5-amine (100.0 mg, 0.630 mmol), Pd(OAc)₂ (14.07 mg, 0.060 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (141.5 mg, 0.250 mmol). It was sealed and 3 vacuum/nitrogen cycles were performed. Then DMF (3.917 mL), DIPEA (0.05 mL, 0.310 mmol) and dimethylphosphine oxide (63.59 mg, 0.810 mmol) were added, and 3 more cycles were performed. The reaction was heated at 120 °C for 2 h. Practically full conversion was observed after that time. The DMF solution passed through a 5 g SCX cartridge, washing with MeOH and eluting with 1M ammonia in MeOH. The eluted solution was concentrated in vacuo to obtain 2-dimethylphosphoryl-4-methoxy-pyrimidin-5- amine (96.1 mg, 0.478 mmol). The compound was used for the next step without further purification. MS (ESI) m/z = 202.1 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 1.65 (d, J = 13.46 Hz, 6H), 3.98 (s, 3H), 5.64 (s, 2H), 7.94 (s, 1H). Step 2 2- was dissolved in DMF (0.837 . mg, was added, followed by 3-bromo-1-propyne (0.051 mL, 0.458 mmol). The mixture was heated at 70 °C for 2 h. LCMS analysis showed partial conversion (about 30% starting material left), and it was heated for 6 h more at 70 °C. Full conversion was observed after that time, and only <10% a/a of bis- alkylated product was observed by LCMS. EtOH (2 mL) was added to precipitate potassium carbonate, and it was filtered. The filtrate was purified by SCX (Strata 5 g cartridge), eluting with 1M ammonia in MeOH to afford 2-dimethylphosphoryl-4-methoxy-N-prop-2-ynyl- pyrimidin-5-amine (9.0 mg, 0.037 mmol). The compound was used for the next step without further purification. MS (ESI) m/z = 240.5 [M+H]⁺. Alkyne Synthesis of (6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2- yl)dimethylphosphine oxide for use in the synthesis of Intermediate 6s Step 1 To a mixture of 2,6- THF (50 mL) was added MeONa (632 mg, 0.0117 mol). The mixture was stirred for 16 h at RT. The resulted mixture was diluted with EA (300 mL), washed with brine (300 mL*3), dried over Na₂SO₄ and ‐ 130 ‐ Agent Ref: 12617.0003-00304 concentrated, the residue was purified by silica gel column (EtOAc/PE=1/20-1/1) to afford 6- bromo-2-methoxy-3-nitropyridine (2.1 g, 9.0121 mmol). MS (ESI) m/z = 233/235 [M+H]⁺. Step 2 mmol) in MeOH (30 mL) (2.66 g, 49.7811 mmol). The mixture was stirred for 5h at 60^oC. The solids were filtrated out. The solution was concentrated and diluted with EA (200 mL), washed with brine (200 mL*3), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel column to afford 6-bromo-2- methoxypyridin-3-amine (1.67 g, 95% purity, 8.2250 mmol, 83%). MS (ESI) m/z = 203/205 [M+H]⁺. Step 3 To a mixture in DMF (50 mL) was added dimethylphosphine oxide (678 mg, 8.6879 mmol), Pd(AcO)₂ (163 mg, 0.7240 mmol), Xantphos (503 mg, 0.8688 mmol), and K₃PO₄ (3.07 g, 14.4799 mmol). The mixture was stirred for 6h at 120 °C under N₂. After cooled to RT, the mixture was diluted with EA (300 mL), washed with brine (300 mL*3), dried over Na₂SO₄ and concentrated, the residue was purified by silica gel column (EtOAc/PE=1/15-1/1) to afford to (5-amino-6-methoxypyridin-2- yl)dimethylphosphine oxide (1.68 g, 80% purity, 8.3924 mmol). MS (ESI) m/z = 201 [M+H]⁺. Step 4 To a (1.25 g, 6.2444 mmol) in DMF (50 mL) was added 3-bromoprop-1-yne (3.71 g, 31.2219 mmol) and K₂CO₃ ‐ 131 ‐ Agent Ref: 12617.0003-00304 (2.59 g, 18.7331 mmol). The mixture was stirred for 16h at 80 °C. The resulted mixture was diluted with EA (200 mL), washed with brine (200 mL*3), dried over Na₂SO₄ and concentrated, the residue was purified by silica gel column to (6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2- yl)dimethylphosphine oxide (900 mg, 3.7779 mmol). MS (ESI) m/z = 239 [M+H]⁺. Alkyne Synthesis of 4-methoxy-N-(prop-2-yn-1-yl)pyridin-3-amine, for use in the synthesis of Intermediate 6t, Step 1 To a mixture of 3- and 4-methoxypyridin-3- amine (518.0 mg, 4.17 , 90.49 mmol) was added, and the mixture was stirred heating to 40 °C for 1 hour. Sodium triacetoxyborohydride (3208.98 mg, 16.69 mmol) was then added, and the mixture was stirred heating to 35 °C o/n. The mixture got to a gel consistency, and UPLC/MS check showed 5% a/a by UV of product. The mixture was diluted with 20 mL of DCM and left stirring at 35 °C for 6 hours. UPLC/MS showed no improvement. Sodium triacetoxyborohydride (1203.37 mg, 6.26 mmol) was added, and the mixture was stirred heating to 35 °C for further 16 hours. UPLC/MS check showed mainly product. The mixture was cooled to RT, diluted with brine and extracted with DCM (2x), the combined organic phase was washed with Na₂CO₃ s.s., dried using a phase separation cartridge and evaporated to give 4-methoxy-N-(3-trimethylsilylprop-2-ynyl)pyridin-3-amine (993 mg, 4.237 mmol). MS (ESI) m/z = 235.2 [M+H]; ¹H NMR (400 MHz, DMSO) δ 0.09 (s, 9H), 3.83 (s, 3H), 3.97 (d, J = 6.31 Hz, 3H), 5.38 (t, J = 6.35 Hz, 1H), 6.86 (d, J = 5.36 Hz, 1H), 7.84 (d, J = 5.28 Hz, 1H), 7.86 (s, 1H). Step 2 To a solution of 4- 3-amine (993.0 mg, 3.77 mmol) in THF (25 mL) at 0 °C, TBAF 1M in THF (3.77 mL, 3.77 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. UPLC/MS check showed ‐ 132 ‐ Agent Ref: 12617.0003-00304 complete conversion to product. The mixture was diluted with DCM, washed with brine, and the aqueous phase further extracted with DCM (2x). The combined organic phase was dried using a phase separation cartridge and evaporated. The crude was purified by FC (SfarD, 25 g, MeOH/DCM 0-5%) to afford 4-methoxy-N-prop-2-ynyl-pyridin-3-amine (324 mg, 1.998 mmol). MS (ESI) m/z = 163.1 [M+H]; ¹H NMR (400 MHz, DMSO) δ 3.04 (t, J = 2.40 Hz, 1H), 3.83 (s, 3H), 3.95 (dd, J = 6.51, 2.37 Hz, 2H), 5.40 (t, J = 6.46 Hz, 1H), 6.86 (d, J = 5.29 Hz, 1H), 7.84 (d, J = 5.28 Hz, 1H), 7.87 (s, 1H). Alkyne Synthesis of 4-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)picolinamide, for use in the synthesis of Intermediate 6u Step 1 In a suitable round- of methyl 5-bromo-4- methoxy-pyridine-2- mg, mL) was added carbamic acid tert-butyl ester (1428.31 mg, 12.19 mmol), followed by XPhos (774.97 mg, 1.63 mmol), (1E,4E)-1,5-diphenyl-3-penta-1,4-dienone; palladium (744.31 mg, 0.810 mmol) and dicesium carbonate (5329.43 mg, 16.26 mmol), and the resulting mixture was degassed with three vacuum/nitrogen cycles. The reaction proceeded at reflux for 6 hrs to complete conversion. The reaction mixture was allowed to cool to RT. Water was added and the mixture was extracted with EtOAc (3x), the combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated and the residue was purified by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-60% EtOAc in CyHex) to provide methyl 5-(tert- butoxycarbonylamino)-4-methoxy-pyridine-2-carboxylate (2336 mg, 8.275 mmol). MS (ESI) m/z = 283.2 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 9H), 3.86 (s, 3H), 3.95 (s, 3H), 7.65 (s, 1H), 8.57 (s, 1H), 8.87 (s, 1H). Step 2 ‐ 133 ‐ Agent Ref: 12617.0003-00304 To a solution of methyl 5-(tert-butoxycarbonylamino)-4-methoxy-pyridine-2-carboxylate (2236.0 mg, 7.92 mmol) in DMF (15 mL) were added dicesium carbonate (3895.2 mg, 11.88 mmol) and 3-bromo-1-propyne 80% in toluene (1.06 mL, 9.51 mmol). The resulting mixture was stirred at RT for 4 hrs to complete conversion. The reaction mixture was diluted with water and extracted with EtOAc (3x). The organic phases were washed with brine (3x), dried over sodium sulfate, filtered and concentrated, and the residue was purified by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-100% EtOAc in CyHex) to provide methyl 5-[tert- butoxycarbonyl(prop-2-ynyl)amino]-4-methoxy-pyridine-2-carboxylate (2754 mg, 8.597 mmol). MS (ESI) m/z = 321.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 1.32 (s, 9H), 3.18 (t, J = 2.46 Hz, 1H), 3.89 (s, 3H), 3.97 (s, 3H), 4.33 (s, 2H), 7.73 (s, 1H), 8.41 (s, 1H). Step 3 Lithium hydroxide a solution of methyl 5-[tert- butoxycarbonyl(prop-2-ynyl)amino]-4-methoxy-pyridine-2-carboxylate (2754.0 mg, 7.82 mmol) in a mixture of methanol (10.82 mL), THF (3.092 mL) and water (3.092 mL), and the resulting reaction mixture was stirred at RT for 2 hrs to complete conversion. Solvents were removed under vacuum, and the residue was co-evaporated 3 times with toluene and dried to provide crude lithium 5-[tert-butoxycarbonyl(prop-2-ynyl)amino]-4-methoxy-pyridine-2- carboxylate (2466 mg, 7.898 mmol). MS (ESI) m/z = 307.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d6) δ 1.28 (s, 9H), 3.17 (d, J = 2.50 Hz, 1H), 3.92 (s, 3H), 4.16 (d, J = 54.58 Hz, 2H), 7.66 (s, 1H), 8.15 (s, 1H). Step 4 To a solution of lithium 5-[tert-butoxycarbonyl(prop-2-ynyl)amino]-4-methoxy-pyridine-2- carboxylate (2366.0 mg, 7.58 mmol) in DMF (18.94 mL) were added N,N- ‐ 134 ‐ Agent Ref: 12617.0003-00304 disopropylethylamine (2.64 mL, 15.15 mmol) and TBTU (3649.36 mg, 11.37 mmol), and the resulting mixture was stirred at R for 30 mins, then methanamine 2M solution in THF (11.37 mL, 22.73 mmol) was added, and stirring was carried on at RT o/n, with incomplete conversion and formation of some minor impurities. The mixture was diluted with water and extracted with EtOAc (3x), then the combined organic phases were washed repeatedly with sat. NaHCO₃ solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-100% EtOAc in CyHex) to provide impure target, which was purified again by FC on 50 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-3% MeOH in DCM) where it co-eluted with previous impurities. Opportune fractions were collected and concentrated to provide tert- butyl N-[4-methoxy-6-(methylcarbamoyl)-3-pyridyl]-N-prop-2-ynyl-carbamate (1993 mg, 6.241 mmol). MS (ESI) m/z = 320.2 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ 1.31 (s, 9H), 2.82 (d, J = 4.87 Hz, 3H), 3.18 (t, J = 2.52 Hz, 1H), 3.96 (s, 3H), 4.30 (d, J = 6.27 Hz, 2H), 5.75 (s, 1H), 7.70 (s, 1H), 8.33 (s, 1H), 8.75 (d, J = 5.01 Hz, 1H). Step 5 A solution of tert-butyl N- -N-prop-2-ynyl-carbamate (1993.0 mg, 6.24 mmol) in DCM (23.4 mL) and trifluoroacetic acid (7.8 mL) was stirred for 1 hr at RT until complete conversion was achieved. The solvents were removed under vacuum, and the residue was co-evaporated with toluene to provide a crude residue, which was purified twice by RP-FC on 60 g Biotage Sfär C18 D Duo 100 Å 30 μm cartridge (eluent: 2-30% MeCN+0.1% HCOOH in water+0.1% HCOOH). Opportune fractions were collected and concentrated to dryness to provide 4-methoxy-N-methyl-5-(prop-2-ynylamino)pyridine-2- carboxamide (1006 mg, 4.589 mmol). MS (ESI) m/z = 220.4 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ 2.81 (d, J = 4.82 Hz, 3H), 3.12 (t, J = 2.42 Hz, 1H), 3.96 (s, 3H), 4.05 (d, J = 2.52 Hz, 2H), 6.24 (s, 1H), 7.58 (s, 1H), 7.86 (s, 1H), 8.53 – 8.58 (m, 1H). Synthesis of Examples ‐ 135 ‐ Agent Ref: 12617.0003-00304 Example 1: 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A prop-2- 0.390 mmol), (3S,4R)-3-fluoro-1-methyl-piperidin-4-amine;dihydrochloride (239.73 mg, 1.17 mmol), Cs₂CO₃ (894.11 mg, 2.73 mmol), [1-(2-diphenylphosphino-1-naphthalenyl)-2- naphthalenyl]-diphenylphosphine (145.56 mg, 0.230 mmol) and palladium diacetate (26.48 mg, 0.120 mmol) in 1,4-dioxane (2.997 mL) was degassed with 3 vacuum/nitrogen cycles and then stirred at 100 °C for 2h, in a preheated heating plate. The reaction mixture was cooled and stored at -20 °C for 16 h. It was then warmed to r.t., diluted with EtOAc and filtered over a phase separator, washing with further EtOAc (30 mL overall), and the filtrate was concentrated in vacuo. It was purified by reverse phase FC (Biotage™ Sfär C18 D-Duo 100 Å 30 μm, from 97:3 to 70:30 of 0.1 % v/v HCOOH in water: 0.1 % v/v HCOOH in MeCN). The appropriate fractions were combines and concentrated at 30 ºC to remove residual MeCN, then sat. aq. K₂CO₃ was added until pH 10-11 was reached and the product was extracted with EtOAc (3 x 25 mL). The recovered organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered-off and concentrated in vacuo to afford 4-[3-[8-[[(3S,4R)-3-fluoro-1- methyl-4-piperidyl]amino]-3-(trifluoromethylsulfanyl)imidazo[1,2-a]pyridin-2-yl]prop-2- ynylamino]-3-methoxy-N-methyl-benzamide (122 mg, 0.285 mmol, 56 % yield) . MS (ESI) m/z= 565.7 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.73 - 1.80 (m, 1 H), 1.86 (qd, J=12.0, 3.7 Hz, 1 H), 2.04 - 2.13 (m, 1 H), 2.19 - 2.31 (m, 1 H), 2.18 (s, 3 H), 2.75 (d, J=4.5 Hz, 3 H), 2.74 - 2.81 (m, 1 H), 3.02 (br t, J=10.8 Hz, 1 H), 3.62 - 3.81 (m, 1 H), 3.84 (s, 3 H), 4.32 (d, J=6.3 Hz, 2 H), 4.82 (d, J=49.8 Hz, 1 H), 5.59 (d, J=8.9 Hz, 1 H), 6.00 (t, J=6.3 Hz, 1 H), 6.61 (d, J=7.7 Hz, 1 H), 6.75 (d, J=8.2 Hz, 1 H), 7.01 (t, J=7.2 Hz, 1 H), 7.34 (d, J=1.6 Hz, 1 H), 7.41 (dd, J=8.2, 1.6 Hz, 1 H), 7.86 (d, J=6.6 Hz, 1 H), 8.10 (q, J=4.1 Hz, 1 H). Example 2: (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine ‐ 136 ‐ Agent Ref: 12617.0003-00304 N- - 4- methylsulfonyl-aniline (166.0 mg, 0.290 mmol), tert-butyl (3S,4R)-4-amino-3-fluoro-piperidine- 1-carboxylate (187.14 mg, 0.860 mmol), Cs₂CO₃ (281.08 mg, 0.860 mmol), [1-(2- diphenylphosphino-1-naphthalenyl)-2-naphthalenyl]-diphenylphosphine (71.18 mg, 0.110 mmol) and palladium(2+) diacetate (12.95 mg, 0.060 mmol) were degassed with three vacuum/nitrogen cycles. Then anhydrous 1,4-Dioxane (2.263 mL) was added; the resulting suspension was degassed further as above and heated at 90 °C for 2 hours. The reaction mixture was cooled and diluted with EtOAc and filtered on a phase separator. The organic phase was evaporated under reduced pressure. The resulting crude material was purified by FCC on silica gel 10g column (eluent gradient from Cy to 80% EtOAc) to afford tert-butyl (3S,4R)-3-fluoro-4-[[2-[3-(2-methoxy-4-methylsulfonyl-anilino)prop-1-ynyl]-3- (trifluoromethylsulfanyl)imidazo[1,2-a]pyridin-8-yl]amino]piperidine-1-carboxylate (156 mg, 0.232 mmol, 81.26% yield). MS (ESI) m/z = 672.2 [M+H]⁺. Step 2 Trifluoroacetic acid (0.5 mL, 6.53 mmol) was added to a solution of tert-butyl (3S,4R)-3-fluoro- 4-[[2-[3-(2-methoxy-4-methylsulfonyl-anilino)prop-1-ynyl]-3- (trifluoromethylsulfanyl)imidazo[1,2-a]pyridin-8-yl]amino]piperidine-1-carboxylate (156.0 mg, 0.230 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature overnight. Solvent was evaporated, and the residue was purified with 2g SCX (eluent MeOH/Ammonia 1M in MeOH). This was further purified with 6g C18 cartridge (eluent from water + 0.1% formic acid to MeCN + 0.1% formic ac. 25%) to afford product (58 mg). Further purification by preparative LCMS afforded (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine (24 mg, 0.042 mmol, 18.08% yield). MS (ESI) m/z = 572.1 [M+H]⁺. ¹H ‐ 137 ‐ Agent Ref: 12617.0003-00304 NMR (400 MHz, DMSO-d6) δ 1.58 – 1.78 (m, 2H), 1.92 (s, 1H), 2.59 (t, J = 12.24 Hz, 1H), 2.77 (dd, J = 39.55, 14.59 Hz, 1H), 2.95 (d, J = 13.46 Hz, 1H), 3.10 (s, 3H), 3.12 – 3.21 (m, 1H), 3.91 (s, 4H), 4.37 (d, J = 6.24 Hz, 2H), 4.72 (d, J = 50.24 Hz, 1H), 5.57 (d, J = 9.04 Hz, 1H), 6.49 (t, J = 6.23 Hz, 1H), 6.59 – 6.66 (m, 1H), 6.88 (d, J = 8.39 Hz, 1H), 7.02 (dd, J = 7.69, 6.71 Hz, 1H), 7.26 (d, J = 1.98 Hz, 1H), 7.40 (dd, J = 8.35, 1.99 Hz, 1H), 7.86 (d, J = 6.64 Hz, 1H). Example 3: 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide 3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]-N-[2-methoxy-4- (methylcarbamoyl)phenyl]carbamate (250.0 mg, 0.440 mmol), (3S,4R)-3-fluoro-1-methyl- piperidin-4-amine;dihydrochloride (270.34 mg, 1.32 mmol), Cs₂CO₃ (720.21 mg, 2.2 mmol), [1-(2-diphenylphosphino-1-naphthalenyl)-2-naphthalenyl]-diphenylphosphine (109.43 mg, 0.180 mmol) and Pd(OAc)₂ (19.91 mg, 0.090 mmol). The vial was sealed, and it was degassed by 5 cycles of nitrogen/vacuum.1,4-Dioxane (2.9 mL) was added, and after degassing again with 5 cycles of nitrogen/vacuum, the reaction mixture was stirred overnight at 100 °C. After cooling to r.t., the reaction mixture was diluted with EtOAc and water. The two phases were separated and the aqueous one was extracted with EtOAc (x2). The combined organic portions were collected, washed with brine, dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The resulting residue was purified by SCX cartridge first washing with MeOH and then eluted with NH₃ (1M in MeOH) obtaining tert-butyl N-[3-[7- ‐ 138 ‐ Agent Ref: 12617.0003-00304 [[(3S,4R)-3-fluoro-1-methyl-4-piperidyl]amino]-3-(trifluoromethylsulfanyl)pyrazolo[1,5- a]pyridin-2-yl]prop-2-ynyl]-N-[2-methoxy-4-(methylcarbamoyl)phenyl]carbamate (177 mg). MS (ESI) (m/z): 665.17 [M+H]⁺. Step 2 To a solution of tert-butyl N-[3-[7-[[(3S,4R)-3-fluoro-1-methyl-4-piperidyl]amino]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]-N-[2-methoxy-4- (methylcarbamoyl)phenyl]carbamate (177.0 mg) in DCM (2.6 mL) was added TFA (0.2 mL, 2.66 mmol) and the reaction mixture was stirred at r.t. for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (Sfar C18 D, 30g; Water + 0.1% HCOOH/CH₃CN + 0.1% HCOOH from 10/0 to 5/5 as eluent). Appropriate fractions were collected, and the organic phase was evaporated. The remaining aqueous solution was basified with a saturated solution of NaHCO₃ and extracted twice with EtOAc. The combined organics were dried (Na₂SO₄) and concentrated under reduced pressure affording 4-[3-[7-[[(3S,4R)-3-fluoro-1-methyl-4-piperidyl]amino]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynylamino]-3-methoxy-N-methyl- benzamide (76.1 mg, 50.62% yield). MS (ESI) (m/z): 565.17 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 1.74 – 1.87 (m, 1H), 1.98 (qd, J = 12.02, 3.77 Hz, 1H), 2.13 (t, J = 11.43 Hz, 1H), 2.18 – 2.40 (m, 4H), 2.71 – 2.87 (m, 4H), 3.05 (t, J = 11.57 Hz, 1H), 3.72 – 3.99 (m, 4H), 4.35 (d, J = 6.28 Hz, 2H), 4.87 (d, J = 49.56 Hz, 1H), 6.01 (t, J = 6.29 Hz, 1H), 6.48 (d, J = 8.87 Hz, 1H), 6.51 (dd, J = 8.24, 1.09 Hz, 1H), 6.77 (d, J = 8.25 Hz, 1H), 7.01 (dd, J = 8.57, 0.97 Hz, 1H), 7.35 (d, J = 1.87 Hz, 1H), 7.41 (dd, J = 8.25, 1.87 Hz, 1H), 7.51 (t, J = 8.23 Hz, 1H), 8.09 (q, J = 4.07 Hz, 1H). Example 4: (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine ‐ 139 ‐ Agent Ref: 12617.0003-00304 2- ynyl]-2-methoxy-4-methylsulfonyl-aniline (250.0 mg, 0.460 mmol), Cs₂CO₃ (456.71 mg, 1.39 mmol), Pd(OAc)₂ (21.04 mg, 0.090 mmol), [1-(2-diphenylphosphino-1-naphthalenyl)-2- naphthalenyl]-diphenylphosphine (115.66 mg, 0.190 mmol) and (3S,4R)-1-Boc-3- fluoropiperidin-4-amine (304.07 mg, 1.39 mmol) were added, and the resulting mixture was degassed with three vacuum/nitrogen cycles. 1,4-Dioxane (4.55 mL) was then added, the mixture was further degassed with 3 cycles N₂/vacuum, and it was stirred heating to 100 °C o/n. The mixture was cooled to RT, filtered through a pad of diatomaceous earth washing with EtOAc and the filtrate was evaporated. The crude was purified by FC (Sfar D 25 g, EtOAc/Cy- Hex, 0-50%) affording tert-butyl (3S,4R)-3-fluoro-4-[[2-[3-(2-methoxy-4-methylsulfonyl- anilino)prop-1-ynyl]-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]amino]piperidine-1- carboxylate (102 mg). The latter was triturated using pentane and purified a second time by RP (Sfar C18, MeCN/water + 0.1% NH₄OH) giving tert-butyl (3S,4R)-3-fluoro-4-[[2-[3-(2- methoxy-4-methylsulfonyl-anilino)prop-1-ynyl]-3-(trifluoromethylsulfanyl)pyrazolo[1,5- a]pyridin-7-yl]amino]piperidine-1-carboxylate (87 mg, 27.89% yield). m/z: 694.4 [M+Na]⁺. Step 2 To a solution of tert-butyl (3S,4R)-3-fluoro-4-[[2-[3-(2-methoxy-4-methylsulfonyl-anilino)prop- 1-ynyl]-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]amino]piperidine-1-carboxylate (86.0 mg, 0.130 mmol) in DCM (1 mL), trifluoroacetic acid (0.1 mL, 1.27 mmol) was added, and the mixture was stirred for 1 hour. Volatiles were evaporated, and the crude was taken up in DCM and a saturated solution of Na₂CO₃. The aqueous phase was further extracted with DCM (2x), and the combined organic phase was dried using a phase separation cartridge and ‐ 140 ‐ Agent Ref: 12617.0003-00304 evaporated. The compound was triturated using pentane, then the solid was suspended in water filtered and dried under vacuum to obtain (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl- 2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7- yl)piperidin-4-amine (60 mg, 82.82% yield). The latter was solubilized with a 1/1 mixture of MeOH/MeCN, transferred in a 40 mL vial, and dried using the V10 affording N-[(3S,4R)-3- fluoro-4-piperidyl]-2-[3-(2-methoxy-4-methylsulfonyl-anilino)prop-1-ynyl]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-amine (55 mg, 75.91% yield); m/z: 572.3 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 1.73 – 1.82 (m, 2H), 2.58 – 2.68 (m, 1H), 2.74 – 2.91 (m, 1H), 2.94 – 3.01 (m, 1H), 3.09 (s, 3H), 3.13 – 3.22 (m, 1H), 3.87 – 4.03 (m, 4H), 4.39 (d, J = 6.24 Hz, 2H), 4.67 – 4.86 (m, 1H), 6.47 – 6.53 (m, 3H), 6.88 (d, J = 8.40 Hz, 1H), 7.00 (d, J = 8.41 Hz, 1H), 7.25 (d, J = 1.99 Hz, 1H), 7.38 (dd, J = 8.35, 2.00 Hz, 1H), 7.50 (t, J = 8.21 Hz, 1H), NH exchangeable proton not visible. Example 5: 4-[(3-{7-[(1,1-dioxo-1λ⁶-thian-4-yl)amino]-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide A microwave (MW) vial was charged with tert-butyl N-[3-[7-chloro-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]-N-[2-methoxy-4- (methylcarbamoyl)phenyl]carbamate (200.0 mg, 0.350 mmol), 4-aminotetrahydro-2H- thiopyran-1,1-dioxide hydrochloride (195.79 mg, 1.05 mmol), Cs₂CO₃ (460.93 mg, 1.41 mmol), [1-(2-diphenylphosphino-1-naphthalenyl)-2-naphthalenyl]-diphenylphosphine (87.55 mg, 0.140 mmol) and Pd(OAc)₂ (15.92 mg, 0.070 mmol). The vial was sealed, and it was degassed ‐ 141 ‐ Agent Ref: 12617.0003-00304 by 5 cycles of nitrogen/vacuum.1,4-Dioxane (2.3 mL) was added and after degassing again with 5 cycles of nitrogen/vacuum, the reaction mixture was stirred for 6 hours at 100 °C. After cooling to r.t., water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (x3). The organic portions were collected, dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (Sfar C18 D, 30g; Water + 0.1% HCOOH/CH₃CN + 0.1% HCOOH from 100/0 to 75/25 as eluent). Appropriate fractions were collected, and the organic phase was evaporated. The aqueous fraction was basified with a saturated solution of NaHCO₃ and extracted twice with EtOAc. Combined organics were dried over a phase separator and concentrated under reduced pressure affording tert-butyl N-[3-[7-[(1,1-dioxothian-4-yl)amino]- 3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]-N-[2-methoxy-4- (methylcarbamoyl)phenyl]carbamate (160 mg, 67 % yield). MS (ESI) (m/z): 682.16 [M+H]⁺. Step 2 To a solution of tert-butyl N-[3-[7-[(1,1-dioxothian-4-yl)amino]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]-N-[2-methoxy-4- (methylcarbamoyl)phenyl]carbamate (160.0 mg, 0.230 mmol) in DCM (2.347 mL), TFA (0.18 mL, 2.35 mmol) was added and the reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (Sfar C18 D, 30g; Water + 0.1% HCOOH/CH₃CN + 0.1% HCOOH from 100/0 to 45/65 as eluent). Appropriate fractions were collected, and the organic phase was evaporated. The aqueous solution was basified with a saturated solution of NaHCO₃ and extracted twice with EtOAc. The combined organics were dried over a phase separator and concentrated under reduced pressure. Purification by preparative HPLC afforded 4-[(3-{7- [(1,1-dioxo-1λ6-thian-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop- 2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (51.2 mg, 37.51% ). MS (ESI) (m/z): 582.25 [M+H]+.¹H NMR (400 MHz, DMSO-d6) δ 2.09 – 2.31 (m, 4H), 2.75 (d, J = 4.51 Hz, 3H), 3.00 – 3.23 (m, 2H), 3.32 – 3.38 (m, 2H), 3.85 (s, 3H), 3.89 – 4.03 (m, 1H), 4.35 (d, J = 6.32 Hz, 2H), 6.01 (t, J = 6.25 Hz, 1H), 6.31 – 6.45 (m, 1H), 6.75 (d, J = 8.25 Hz, 1H), 6.96 (dd, J = 8.58, 0.96 Hz, 1H), 7.35 (d, J = 1.86 Hz, 1H), 7.41 (dd, J = 8.30, 1.83 Hz, 2H), 7.51 (t, J = 8.23 Hz, 1H), 8.09 (q, J = 4.60 Hz, 1H). The following examples were made in an analogous fashion to Examples 1 to 5, using the appropriate intermediates. Example Intermediate; Structure & Name; characterising data ‐ 142 ‐ Agent Ref: 12617.0003-00304 z, z, ), - ), 81 – s, 23 98 54 ‐ 143 ‐ Agent Ref: 12617.0003-00304 1H NMR (400 MHz, DMSO-d6) δ 1.73 (qd, J = 11.80, 4.39 Hz, 2H), 1.82 – 1.89 (m, 2H), 2.76 (d, J = 4.48 Hz, 3H), 3.44 (td, J = 11.72, 2.14 Hz, 2H), 3.70 – 3.81 J = 1 ). - – 08 z, – – e z, 87 .2 m, ‐ 144 ‐ Agent Ref: 12617.0003-00304 4, 0, z, 98 m, 76 – ), z, ), d, = ‐ 145 ‐ Agent Ref: 12617.0003-00304 – br m, ), 01 85 z, z, z, d, ‐ 146 ‐ Agent Ref: 12617.0003-00304 N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide (t, J ), 88 2- 41 38 98 = d, t, ), ‐ 147 ‐ Agent Ref: 12617.0003-00304 = 28.0 Hz, 1H), 3.50 (d, J = 11.4 Hz, 1H), 3.17 (dd, J = 26.7, 13.4 Hz, 2H), 3.05 (s, 3H), 2.98 – 2.89 (m, 1H), 2.06 – 1.83 (m, 2H). d, z, J 7 ‐ 148 ‐ Agent Ref: 12617.0003-00304 - 7 (t, ), ‐ 149 ‐ Agent Ref: 12617.0003-00304 3-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N- ‐ 150 ‐ Agent Ref: 12617.0003-00304 8.1, 3.0 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.92 (t, J = 6.3 Hz, 1H), 5.57 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 3.92 (dd, J = 6.1, 3.3 Hz, 1H), 6) 9 J ‐ 151 ‐ Agent Ref: 12617.0003-00304 = 11.4 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.2 Hz, 1H), 2.19 (s, 3H), 2.09 (t, J = 11.0 Hz, 1H), 1.90 – 1.65 (m, 2H). ‐ 152 ‐ Agent Ref: 12617.0003-00304 d, .7 H), .4 93 (t, (d, ‐ 153 ‐ Agent Ref: 12617.0003-00304 (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- 98 82 - 05 = , 7 3 ‐ 154 ‐ Agent Ref: 12617.0003-00304 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.36 – 2.22 (m, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.4 Hz, 1H), 2.00 – 1.88 (m, 1H), 1.78 – 1.69 (m, 1H). - 8 - - H, - s) - d, ‐ 155 ‐ Agent Ref: 12617.0003-00304 ), d, 61 34 11 1- J (t, = s, ‐ 156 ‐ Agent Ref: 12617.0003-00304 (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- (1 32 84 24 z) m) d, m) H, 79 - ‐ 157 ‐ Agent Ref: 12617.0003-00304 1H NMR (500 MHz, DMSO-d6) δ ppm 1.73 - 1.80 (m, 1 H), 1.86 (qd, J=12.0, 3.6 Hz, 1 H), 2.09 (br t, J=10.7 Hz, 1 H), 2.24 (dd, J=39.2, 12.9 Hz, 1 H), 2.19 ), .9 1 ). .6 .2 1 1 - ), 34 85 1 35 ‐ 158 ‐ Agent Ref: 12617.0003-00304 (d, J=1.8 Hz, 1 H), 7.40 (dd, J=8.2, 1.6 Hz, 1 H), 7.80 (d, J=6.6 Hz, 1 H), 8.10 (q, J=4.2 Hz, 1 H). a]pyridin-2-yl}prop-2-yn-1-yl)acetamide Step tert- 1- carboxylate (Intermediate 5a, 250 mg, 0.461 mmol), N-(prop-2-ynyl)acetamide (Intermediate 3e 51.5 mg, 0.530 mmol), Pd(PPh₃)₄ (26.6 mg, 0.023 mmol) and copper (i) iodide (26.3 mg, 0.138 mmol) were placed in a 5 mL microwave vial and sealed. The vial was placed under nitrogen using three vacuum/nitrogen cycles. To this was added anhydrous degassed tetrahydrofuran (1.3 mL) and triethylamine (0.225 mL, 1.61 mmol) and the flask stirred at room temperature for 68 hours. The reaction was then diluted in EtOAc and washed with saturated NaHCO₃ then brine and dried over sodium sulfate. The solvent was removed under reduced pressure and product purified on a 10g Sfaur column eluting with petrol:acetone from 5-50% acetone to give a green solution. The solution was then diluted in MeOH and run through an equilibrated Tris-amine solid supported column. The compound was further purified using a reverse phase 12g Sfaur C18 column eluting with water 0.1% TFA/ MeCN + 0.1% TFA from 5-95% MeCN. Product containing fractions were combined, frozen and solvent lyophilised to give tert-butyl 4-{[2-(3-acetamidoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-7-yl]amino}piperidine-1-carboxylate (90.0 mg, 0.176 mmol, 38.2% yield) as an off white solid. m/z = 510 [M-H]-. ‐ 159 ‐ Agent Ref: 12617.0003-00304 Step 2 tert-butyl 4-{[2-(3-acetamidoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin- 7-yl]amino}piperidine-1-carboxylate (90.0 mg, 0.176 mmol) was dissolved in methanol (MeOH) (4.00 mL) then 4M hydrochloric acid in dioxane (3.00 mL) was added and stirred for 2 hours. The mixture was then evaporated under reduced pressure to give N-(3-{7-[(piperidin- 4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)acetamide (1:1 Hydrochloride) (60.0 mg, 0.134 mmol, 76.1% yield) as a pale brown solid. m/z = 412 [M+H]⁺ _. ¹H NMR (DMSO-d6) 8.99 (m, 1H), 8.57 (m, 1H), 8.51 (t, J = 5.7 Hz, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.6, 1H), 6.48-6.41 (m, 1H), 4.21 (d, J = 5.7 Hz, 2H), 3.93-3.81 (m, 1H), 3.38-3.30 (m, 2H), 3.08-3.96 (m, 2H), 2.12-2.04 (m, 2H), 1.98- 1.85 (m, 5H) F19 NMR (DMSO-d6) -44.00 (s). Example 15: N-[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]acetamide A mixture of pyrazolo[1,5- a]pyridin-7-amine (300.0 mg, 0.650 mmol), copper (I) iodide (52.79 mg, 0.280 mmol), Pd tetrakis triphenylphosphine (225.97 mg, 0.200 mmol) and diisopropylamine (0.86 mL, 6.09 mmol) was degassed, then DMSO (2.875 mL) and N-prop-2-ynylacetamide (84.41 mg, 0.780 mmol) were added. The mixture was degassed again and then stirred at rt for 1h, then it was quenched with water and extracted with EtOAc (2 x). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was purified by FC, reverse phase (Biotage C18 Sfar 30g+30g, water + 0.1% formic acid / MeCN + 0.1% formic acid, from 98:2 to 7:3). The product was partitioned between EtOAc and a sat. aq solution of NaHCO₃. The organic layer was dried over sodium sulfate, filtered and evaporated. The product was dissolved in water/MeCN and evaporated to N-[3-[7-[[(3S,4R)-3-fluoro-4-piperidyl]amino]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynyl]acetamide (89 mg, 0.207 mmol, 31.79% yield) as yellowish solid. MS (ESI) m/z= 430.5 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) d ppm 1.74 - 1.83 (2 H, m) 1.84 - 1.91 (3 H, m) 2.55 - 2.66 (1 H, m) 2.73 - 2.92 (1 H, m) 2.93 - 3.04 (1 H, m) 3.17 (1 H, t, J=11.55 Hz) 3.90 - 4.08 (1 H, m) 4.16 - 4.25 (2 H, m) 4.69 - 4.88 (1 H, m) 6.47 - 6.58 (2 H, m) 7.00 - 7.07 (1 H, m) 7.50 - 7.57 (1 H, m) 8.48 (1 H, t, J=5.50 Hz). ‐ 160 ‐ Agent Ref: 12617.0003-00304 Example 16: 3-methoxy-N-methyl-4-[(3-{7-[(1-methylpiperidin-4-yl)amino]-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide 2-Iodo- amine (150.0 , , (0.43 mL, 3.07 mmol) and 3-methoxy-N-methyl-4-(prop-2-ynylamino)benzamide (86.1 mg, 0.390 mmol) were degassed with three vacuum/nitrogen cycles. DMSO was added, and the reaction mixture further degassed as above. Pd(PPh₃)₄ (39.89 mg, 0.030 mmol) was added and the mixture degassed again as above. The mixture was left stirring for 1 h at r.t., then water was added observing the formation of a precipitate. The solid was collected by filtration, washed with water, and then dried in vacuo. It was dissolved in DCM, filtered again over a phase separator and concentrated in vacuo, affording crude 3-methoxy-N-methyl-4-[3-[7-[(1-methyl- 4-piperidyl)amino]-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2- ynylamino]benzamide (230 mg). Crude material was purified by NH-functionalized FC (Biotage D Sfar Amino 28 g, from 100 % DCM to 98:2 DCM:MeOH) affording 3-methoxy-N- methyl-4-[3-[7-[(1-methyl-4-piperidyl)amino]-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin- 2-yl]prop-2-ynylamino]benzamide (84.5 mg, 47.02% yield). MS (m/z) 547.6 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 8.08 (d, J = 4.7 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.40 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.98 – 6.86 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 6.00 (t, J = 6.3 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 3.56 – 3.40 (m, 1H), 2.81 – 2.69 (m, 5H), 2.16 (s, 3H), 2.07 – 1.95 (m, 2H), 1.85 (d, J = 12.3 Hz, 2H), 1.79 – 1.64 (m, 2H). Example 17: 5-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylpyridine-2-carboxamide ‐ 161 ‐ Agent Ref: 12617.0003-00304 In a round-bottom flask were placed 2-iodo-N-[(3S,4R)-3-fluoro-1-methyl-4-piperidyl]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-7-amine (200.0 mg, 0.420 mmol), 4-methoxy-N- methyl-5-(prop-2-ynylamino)pyridine-2-carboxamide (110.95 mg, 0.510 mmol), copper (I) iodide (34.5 mg, 0.180 mmol) and palladium tetrakis triphenylphosphine (51.69 mg, 0.040 mmol). The flask was sealed, and 3 vacuum/nitrogen cycles were performed, then anhydrous DMSO (3.125 mL) and diisopropylamine (0.56 mL, 3.96 mmol) were added and the mixture was degassed again. The mixture was heated to 50 ºC for 5 hrs, further 4-methoxy-N-methyl- 5-(prop-2-ynylamino)pyridine-2-carboxamide (56 mg, 0.255 mmol) was added and the mixture was stirred at 50 ºC overnight. Water was added and the resulting mixture was extracted with EtOAc (3x), then the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by FC on 25 g Biotage Sfär Silica D 60 μm cartridge (eluent: 0-7% MeOH in DCM), then by RP-FC on 30 g Biotage Sfär C18 D Duo 100 Å 30 μm cartridge (eluent: 3-40% MeCN+0.1% HCOOH in water+0.1% HCOOH), then again by FC on 25 g Biotage Sfär Silica D 60 μm cartridge (gradient: 0-100% of EtOAc/EtOH 3:1 in CyHex in 10 CV, then 18 CV of EtOAc/EtOH 3:1 to elute target compound) to give 107 mg of product. The product was further purified by preparative HPLC to provide 5-[3-[7-[[(3S,4R)-3-fluoro-1-methyl-4-piperidyl]amino]-3- (trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-ynylamino]-4-methoxy-N-methyl- pyridine-2-carboxamide (68.2 mg, 0.121 mmol, 28.59% yield). MS (ESI) m/z = 220.4 [M+H]+. ¹H NMR (400 MHz, DMSO-d6) δ 1.77 – 1.84 (m, 1H), 1.91 – 2.05 (m, 1H), 2.11 (t, J = 11.57 Hz, 1H), 2.19 (s, 3H), 2.19 – 2.35 (m, 1H), 2.76 (d, J = 4.88 Hz, 3H), 2.77 – 2.83 (m, 1H), 3.05 (t, J = 11.52 Hz, 1H), 3.78 – 3.91 (m, 1H), 3.93 (s, 3H), 4.43 (d, J = 6.45 Hz, 2H), 4.86 (d, J = 49.47 Hz, 1H), 6.22 (t, J = 6.43 Hz, 1H), 6.44 – 6.54 (m, 2H), 6.97 – 7.03 (m, 1H), 7.46 – 7.54 (m, 2H), 7.99 (s, 1H), 8.40 (q, J = 4.77 Hz, 1H). Example 47: (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyridin-2- yl)dimethylphosphine oxide ‐ 162 ‐ Agent Ref: 12617.0003-00304 (300 mg, 2.17 mmol) in DMF (2.0 mL) was treated with an 80% solution of 3-bromoprop-1- yne in toluene (275 mg, 1.85 mmol). The reaction mixture was warmed to 60 °C and stirred for 2 hours, then the reaction mixture was filtered and purified by reverse phase chromatography (2-16% MeCN/water with 0.1% TFA) gave the desired product (dimethyl(5- (prop-2-yn-1-ylamino)pyridin-2-yl)phosphine oxide). MS (EI) (m/z): 209.2 [M+H]⁺. Step 2 A mixture containing Intermediate 5g (N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine) (15 mg, 0.032 mmol) in DMSO (1.0 mL) was treated with dimethyl(5-(prop-2-yn-1-ylamino)pyridin-2-yl)phosphine oxide (15 mg, 0.072 mmol) and then deoxygenated by bubbling Argon gas for 5 min. Hunig's base (30 mg, 0.23 mmol), palladiumtetrakis (4.0 mg, 0.0035 mmol), and copper(I) iodide (3.0 mg, 0.016 mmol) were added, and the reaction mixture was stirred for 2 h at 50 °C. The reaction mixture was filtered and purified by reverse phase chromatography (12-42% MeCN/water with 0.1% TFA) to provide desired product, (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyridin-2- yl)dimethylphosphine oxide.¹H NMR (500 MHz, DMSO) δ 9.85 (br m, 1H), 8.26 (br m, 1H), 7.70 (br m, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.07 (m, 2H), 6.51 (d, J = 7.7 Hz, 1H), 5.17-5.26 (m, 1H), 4.41 (s, 2H), 3.87 (m, 2H), 3.52 (m, 2H), 3.22 (m, 1H), 2.83 (s, 3H), 2.35 (m, 1H), 2.08 (m, 1H), 1.60 (m, 6H). MS (EI) (m/z): 555.2 [M+H]⁺. Example 48: (4-((3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide. ‐ 163 ‐ Agent Ref: 12617.0003-00304 MeO SCF₃ SCF HN P ₃ O - 3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)piperidine-1-carboxylate (265 mg, 0.473 mmol) and Intermediate 3d, (3-methoxy-4-(prop-2-yn-1- ylamino)phenyl)dimethylphosphine oxide (225 mg, 0.948 mmol) in DMSO (3.0 mL) was deoxygenated by bubbling Argon gas for 10 min. Hunig's base (371 mg, 2.87 mmol), copper(I) iodide (45 mg, 0.236 mmol). and palladiumtetrakis (55 mg, 0.476 mmol) were added, and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then diluted with DCM, washed with sat. NH₄Cl. Organic layer was dried (Na₂SO₄) and concentrated. Chromatography on SiO₂ (0-50% EtOAc/DCM, 80 g silica) gave the desired Boc-protected intermediate, tert-butyl (3S,4R)-4-((2-(3-((4-(dimethylphosphoryl)-2- methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7- yl)amino)-3-fluoropiperidine-1-carboxylate. MS (EI) (m/z): 670.1 [M+H]⁺. Step 2 A mixture containing tert-butyl (3S,4R)-4-((2-(3-((4-(dimethylphosphoryl)-2- methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7- yl)amino)-3-fluoropiperidine-1-carboxylate (180 mg, 0.270 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was aged for 1 h, then concentrated. The residue was dissolved in DMSO (2 mL) and purified by reverse phase chromatography (26-55% MeCN/water with 0.1% NH₄OH) to provide the desired product, (4-((3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide. ¹H NMR (499 MHz, DMSO) δ 7.51 (t, J = 8.2 Hz, 1H), 7.21 (dd, J = 11.1, 8.6 Hz, 1H), 7.14 (d, J = 11.8 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.86 (dd, J = 8.0, 2.8 Hz, 1H), 6.56 – 6.46 (m, 2H), 6.07 (t, J = 6.3 Hz, 1H), 4.76 (m, 1H), 4.36 (m, ‐ 164 ‐ Agent Ref: 12617.0003-00304 2H), 4.04 – 3.91 (m, 1H), 3.86 (s, 3H), 3.16 (t, J = 12.1 Hz, 1H), 2.96 (d, J = 13.5 Hz, 1H), 2.81 (dd, J = 39.8, 14.4 Hz, 1H), 2.67 – 2.59 (m, 1H), 1.76 (d, J = 9.4 Hz, 2H), 1.57 (d, J = 13.2 Hz, 6H). MS (EI) (m/z): 570.2 [M+H]⁺. Example 49: (4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide prop- yn- - methoxyphenyl)dimethylphosphine oxide (30 mg, 0.053 mmol) in DMF (0.50 mL) was treated with cesium carbonate (35 mg, 0.107 mmol) and iodomethane-d3 (10 mg, 0.069 mmol) and stirred for 1 h at RT. The reaction mixture was purified by reverse phase chromatography 29- 59% MeCN/water with 0.1% NH₄OH to provide the desired product, (4-((3-(7-(((3S,4R)-3- fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. ¹H NMR (499 MHz, DMSO) δ 7.51 (t, J = 8.2 Hz, 1H), 7.21 (dd, J = 11.1, 8.5 Hz, 1H), 7.14 (d, J = 11.8 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.85 (dd, J = 8.1, 2.8 Hz, 1H), 6.49 (m, 2H), 6.07 (t, J = 6.4 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.35 (m, 2H), 3.86 (s, 3H), 3.05 (t, J = 11.0 Hz, 1H), 2.78 (d, J = 10.9 Hz, 1H), 2.28 (dd, J = 38.1, 12.8 Hz, 1H), 2.12 (t, J = 10.9 Hz, 1H), 2.04 – 1.92 (m, 1H), 1.81 (d, J = 9.5 Hz, 1H), 1.57 (d, J = 13.2 Hz, 6H). MS (EI) (m/z): 621.2 [M+H]⁺. Example 50: (4-((3-(7-(((Trans)-4-(dimethylamino)cyclohexyl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide. ‐ 165 ‐ Agent Ref: 12617.0003-00304 SCF₃ SCF NH ₃ ^I O Step 1. A (400 mg, 1.06 mmol) and (trans)-N1,N1-dimethylcyclohexane-1,4-diamine (300 mg, 2.11 mmol) in DMA (4.0 mL) was treated with Hunig's base (300 mg, 2.30 mmol) and stirred overnight at 130 °C. The reaction mixture was diluted with DCM/MeOH, washed with water, dried (Na₂SO₄), and concentrated. The crude material was dissolved in DMSO (4 mL), and water was added to precipitate the desired product, which was removed by filtration. MS (EI) (m/z): 485.0 [M+H]⁺. Step 2 A mixture containing (trans)-N1-(2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)- N4,N4-dimethylcyclohexane-1,4-diamine (30 mg, 0.062 mmol) and (3-methoxy-4-(prop-2-yn- 1-ylamino)phenyl)dimethylphosphine oxide (30 mg, 0.126 mmol) in DMSO (2.0 mL) was deoxygenated by bubbling Argon gas for 10 min. Hunig's base (40 mg, 0.31 mmol), copper(I) iodide (5.0 mg, 0.026 mmol), and palladiumtetrakis (7.0 mg, 0.006 mmol) were added, and the reaction mixture was stirred at 50 °C for 18 h, then filtered before purification by reverse phase chromatography (19-49% MeCN/water with 0.1% TFA) gave the desired product. ¹H NMR (499 MHz, DMSO) δ 9.56 (s, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.21 (dd, J = 11.0, 8.5 Hz, 1H), 7.15 (d, J = 11.6 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.0, 2.6 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.58 (s, 2H), 3.16 (s, 1H), 2.76 (d, J = 4.9 Hz, 6H), 2.06 (s, 4H), 1.64 – 1.53 (m, 9H). MS (EI) (m/z): 594.2 [M+H]⁺. Example 51: 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide. ‐ 166 ‐ Agent Ref: 12617.0003-00304 mg, mg, 4.49 mmol) in DMF (2.0 mL) was treated with an 80% solution of 3-bromoprop-1-yne in toluene (400 mg, 2.69 mmol). The reaction mixture was warmed to 60 °C and stirred for 2 hours, before being filtered, diluted with EtOAc and washed with water. Organic layer was dried (Na₂SO₄) and concentrated. Chromatography on SiO₂ (0-30% EtOAc/DCM) gave desired product, tert-butyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate. MS (EI) (m/z): 262.1 [M+H]⁺. Step 2 A mixture of tert-butyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate (70 mg, 0.268 mmol) and N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine (60 mg, 0.127 mmol) in DMSO (2.0 mL) was deoxygenated by bubbling Argon gas for 5 min. Tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol), copper(I) iodide (10 mg, 0.053 mmol) and Hunig's base (74 mg, 0.57 mmol) were added, and the mixture was stirred overnight before being filtered and purified by reverse phase chromatography (34- 64% MeCN/water with 0.1% TFA) gave the desired product as a TFA salt. MS (EI) (m/z): 608.2 [M+H]⁺. containing tert-butyl 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate ‐ 167 ‐ Agent Ref: 12617.0003-00304 (57 mg, 0.094 mmol) in DCM (0.50 mL) and TFA (0.50 mL) was aged for 1 h, then concentrated. MS (EI) (m/z): 552.1 [M+H]⁺. Step 4 A mixture containing 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (15 mg, 0.027 mmol), ammonium chloride (30 mg, 0.56 mmol), HATU (30 mg, 0.079 mmol) in DMF (1.0 mL) was treated with Hunig's base (30 mg, 0.23 mmol) and stirred for 18 h. The reaction mixture was filtered and purified by reverse phase chromatography (17-47% MeCN/water with 0.1% TFA) to give the desired product, 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzamide.¹H NMR (499 MHz, DMSO) δ 9.80 (s, 1H), 7.69 (s, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.46 (dd, J = 8.3, 1.8 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.13 – 7.01 (m, 2H), 6.98 (s, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 6.06 (s, 1H), 5.21 (d, J = 47.2 Hz, 1H), 4.36 (s, 2H), 4.10 (d, J = 29.5 Hz, 1H), 3.85 (s, 3H), 3.16 (s, 1H), 2.83 (s, 3H), 2.41 – 2.27 (m, 1H), 2.06 (d, J = 12.7 Hz, 1H). MS (EI) (m/z): 551.1 [M+H]⁺. Example 52: (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(morpholino)methanone. O O H₂N Step 1 HN O A mixture containing (4-amino-3-methoxyphenyl)(morpholino)methanone (1.00 g, 4.23 mmol) in DMF (10 mL) was treated with potassium carbonate (1.60 g, 11.6 mmol) and then 3- bromoprop-1-yne, 80 wt% in toluene (800 mg, 5.38 mmol). The mixture was stirred for 1 h at 50 °C, then filtered, concentrated, and purified by chromatography on SiO₂ (50% EtOAc/DCM) gave the desired product. MS (EI) (m/z): 275.1 [M+H]⁺. ‐ 168 ‐ Agent Ref: 12617.0003-00304 Step 2. A mixture containing N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (20 mg, 0.042 mmol), (3-methoxy-4- (prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (25 mg, 0.091 mmol) in DMSO (1.0 mL) was deoxygenated by bubbling Argon gas for 2 min. Palladiumtetrakis (5.0 mg, 0.043 mmol), copper iodide (4.0 mg, 0.21 mmol) was added, and the mixture was deoxygenated for 2 min. Hunig's base (27 mg, 0.21 mmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with sat. NH₄Cl. The organic layer was dried (Na2SO4) and concentrated. The residue was then repurified by reverse phase chromatography (36-66% MeCN/water with 0.1% NH₄OH) to provide the desired product, (4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone. ¹H NMR (500 MHz, DMSO) δ 7.51 (t, J = 8.2 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.97 – 6.88 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.50 (m, 2H), 5.97 (t, J = 6.3 Hz, 1H), 4.88 (d, J = 49.1 Hz, 1H), 4.34 (m, 2H), 4.01 – 3.84 (m, 2H), 3.83 (s, 3H), 3.55 (dd, J = 31.2, 4.2 Hz, 8H), 3.08 (s, 1H), 2.80 (s, 1H), 2.37 (s, 1H), 2.22 (s, 2H), 2.16 (s, 1H), 1.99 (d, J = 9.8 Hz, 1H), 1.83 (d, J = 9.8 Hz, 1H), 1.24 (s, 1H). MS (EI) (m/z): 621.1 [M+H]⁺. The following example was prepared in an analogous fashion to Examples 14 to 52, using the appropriate intermediates. Example Intermediate; Structure & Name; characterising data N 45 H, m) ‐ 169 ‐ Agent Ref: 12617.0003-00304 03 = ), 94 ), 50 ), S Synthesis of 56: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-6- (methylsulfonyl)pyridin-3-yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine Step 1: Intermediate X2 (AG): 3-methoxy-5-(methylsulfonyl)-N-(prop-2-yn-1-yl)pyridin-2- amine ‐ 170 ‐ Agent Ref: 12617.0003-00304 A mixture of 3-methoxy-5-(methylsulfonyl)pyridin-2-amine (100 mg, 494 μmol) and potassium carbonate (137 mg, 989 μmol) was taken up in DMF (2.47 mL).3-bromoprop-1-yne (176 mg, 1.48 mmol) was added dropwise and the reaction mixture was stirred at 50 °C for 8 hours. The reaction mixture was cooled to rt, filtered, and concentrated under reduced pressure. The crude product was diluted to 4 mL in 1:1 MeOH DMSO and was submitted for mass directed reverse phase purification by HPLC, using acetonitrile/water gradient with base modifier linear gradient to afford 3-methoxy-5-(methylsulfonyl)-N-(prop-2-yn-1-yl)pyridin-2-amine (46.2 mg, 0.192 mmol). MS (m/z) 241.0 [M+H]⁺. Step 2: 56: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-6- (methylsulfonyl)pyridin-3-yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine , - - ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (20.0 mg, 0.422 mmol), Tetrakis(triphenylphosphine)palladium(0) (7.31 mg, 6.33 μmol), Hunig's base (43.6 mg, 58.8 μL, 337 μmol), CuI (3.21 mg, 16.9 μmol), and DMSO (843 μL) were taken up in a vial. Reaction vessel was stirred at 50 °C for 2 hours. The reaction mixture was quenched by adding saturated ammonium chloride and desired product was extracted with DCM. Organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to afford the crude reaction mixture. The crude product was diluted to 4 mL in 1:1 MeOH DMSO and was submitted for singleton purification, for mass directed reverse phase purification by HPLC, using acetonitrile/water gradient with base modifier using a linear gradient to afford N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-6-(methylsulfonyl)pyridin-3- yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (21.8 mg, 37.2 μmol). MS (m/z) 587 [M+H]⁺.¹H NMR (499 MHz, DMSO-d6) δ 7.56 – 7.47 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 6.2 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 4.88 (d, J = 50.1 Hz, 1H), 4.41 (d, J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.93 – 3.79 (m, 1H), 3.12 (s, 3H), 2.80 (d, J = 10.8 Hz, 1H), 2.55 (s, 1H), 2.34 (d, J = 12.6 Hz, 1H), 2.21 (s, 3H), 2.15 (t, J = 11.4 Hz, 1H), 1.98 (dd, J = 12.1, 3.2 Hz, 1H), 1.84 (s, 1H). ‐ 171 ‐ Agent Ref: 12617.0003-00304 Synthesis of 57: (4-((3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide methoxyphenyl)dimethylphosphine oxide (6e) (15.0 mg, 30.7 μmol), cesium carbonate (40.1 mg, 123 μmol), rac BINAP Pd-G4 (4.64 mg, 4.61 μmol), and 1,4-Dioxane (615 μL), were taken up in a reaction vial. Vial was purged with nitrogen 3 times, and reaction mixture was stirred at 80 °C for 6 hours. LC-MS indicated product formation. Palladium scavenger was added, and reaction mixture was stirred at rt for 15 min. The crude product was diluted to 4 mL in 1:1 MeOH DMSO and was submitted for singleton purification, for mass directed reverse phase purification by HPLC, using acetonitrile/water gradient with base modifier linear gradient to afford (4-((3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide (10.6 mg, 17.9 μmol). MS (m/z) 485.0 [M+H]⁺, ¹H NMR (499 MHz, DMSO-d6) δ 7.47 (t, J = 8.2 Hz, 1H), 7.21 (ddd, J = 11.6, 8.0, 1.3 Hz, 1H), 7.15 (dd, J = 11.9, 1.4 Hz, 1H), 6.94 – 6.87 (m, 2H), 6.83 (dd, J = 8.1, 3.0 Hz, 1H), 6.34 (d, J = 7.7 Hz, 1H), 6.07 (t, J = 6.3 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.86 (s, 3H), 3.52 – 3.42 (m, 1H), 2.18 (s, 7H), 1.99 (d, J = 11.3 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H), 1.68 (d, J = 13.3 Hz, 1H), 1.58 (d, J = 13.2 Hz, 5H), 1.50 (q, J = 10.3 Hz, 2H), 1.40 – 1.28 (m, 2H). The following examples were made in an analogous fashion to 57, using the appropriate intermediates. Example No. Intermediate; Structure & Name; characterising data ‐ 172 ‐ Agent Ref: 12617.0003-00304 (4-((3-(7-(((3R,4R)-3-(hydroxymethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- ), z, z, z, 58 l)- Synthesis of 61: (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6- methoxypyridin-2-yl)dimethylphosphine oxide ‐ 173 ‐ Agent Ref: 12617.0003-00304 a vial, dimethylphosphine oxide (365.2 mg, 2.5 Eq, 4.6789 mmol) and xantphos (54.147 mg, 0.05 Eq, 93.578 μmol) and palladium(II) acetate (21.009 mg, 0.05 Eq, 93.578 μmol) and potassium phosphate, dibasic (374.86 mg, 1.15 Eq, 2.1523 mmol) and DMF (1.60 mL) were added and the vial was thoroughly purged with N₂. The vial was subjected to microwave irradiation at 130 °C for two hours. The reaction was monitored using LC. Excess solvent was removed under reduced pressure and the residue was directly purified on a silica gel column using gradient elution with 0-20% DCM-MeOH. Appropriate fractions were pooled, excess solvent was removed under reduced pressure. The product obtained was vacuum dried to give (5- amino-6-methoxypyridin-2-yl)dimethylphosphine oxide. MS ESI calcd. C₈H₁₄N₂O₂P [M+H]⁺ 201, found 201.1 STEP 2: (6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)dimethylphosphine oxide To (5-amino-6-methoxypyridin-2-yl)dimethylphosphine oxide (195.00 mg, 1 Eq, 974.12 μmol) and 3-bromoprop-1-yne (121.68 mg, 1.05 Eq, 1.02 mmol) in DMF (0.60 mL), potassium carbonate (262.52 mg, 1.95 Eq, 1.90 mmol) was added and the reaction was stirred at 50 °C for three hours. LC showed the desired mass. The reaction mixture was purified on a silica gel column using gradient elution with 0-15% DCM-MeOH. Appropriate fractions were pooled, excess solvent was removed under reduced pressure, and the product obtained was vacuum dried and used for the next step directly. (6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2- yl)dimethylphosphine oxide was obtained. MS ESI calcd. C₁₁H₁₆N₂O₂P [M+H]⁺ 239, found 239.1 STEP 3: 5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6- methoxypyridin-2-yl)dimethylphosphine oxide To N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine (50.00 mg, 1 Eq, 105.4 μmol) and (6-methoxy-5-(prop-2-yn-1- ylamino)pyridin-2-yl)dimethylphosphine oxide (45.21 mg, 1.8 Eq, 189.8 μmol) in a vial, copper(I) iodide (10.04 mg, 0.5 Eq, 52.71 μmol) and tetrakis(triphenylphosphine)palladium(0) (12.18 mg, 0.10 Eq, 10.54 μmol) and DIEA (122.6 mg, 165 μL, 9.00 Eq, 948.8 μmol) and ‐ 174 ‐ Agent Ref: 12617.0003-00304 DMSO (0.70 mL) were added and the vial was thoroughly purged with N₂ and stirred at room temperature overnight. The reaction was monitored using LC. The reaction was quenched with water and extracted with ethyl acetate. The aq. layer was extracted twice, the organic layers were combined, washed with brine, dried over anhy. MgSO₄, filtered and excess solvent was removed under reduced pressure, and the product obtained was purified on a silica gel column using gradient elution with 0-15% DCM-MeOH. Appropriate fractions were pooled, excess solvent was removed under reduced pressure and the product obtained was vacuum dried to give the title compound. MS ESI calcd. C₂₅H₃₀F₄N₆O₂PS [M+H]⁺ 585, found 585.1. ¹H NMR (499 MHz, DMSO) δ 7.49 (s, 1H), 7.42 (s, 1H), 7.08 (s, 1H), 6.97 (s, 1H), 6.48 – 6.41 (m, 3H), 4.86 (d, J = 49.7 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.93 (s, 3H), 3.46 (s, 3H), 3.03 (s, 1H), 2.76 (s, 1H), 2.29 (d, J = 12.8 Hz, 1H), 2.23 (s, 1H), 2.17 (s, 3H), 2.09 (d, J = 22.2 Hz, 1H), 1.97 (d, J = 21.2 Hz, 1H), 1.81 (d, J = 10.4 Hz, 1H), 1.58 (d, J = 13.3 Hz, 6H). Synthesis of 62: 3-fluoro-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide trifluoroacetate salt oxide To (4-amino-3-fluorophenyl)dimethylphosphine oxide (1.00g, 1equv, 5.34 mmol) and 3- bromoprop-1-yne (648 mg, 1.02 Eq, 5.45 mmol) in a vial, 1 mL DMF and potassium carbonate (1.44 g, 1.95 Eq, 10.4 mmol) were added, and the vial was purged with N₂ and then stirred at 50⁰C for an hour. The reaction was filtered, excess solvent was removed under pressure, and the product was purified on a silica gel column using gradient elution with 0-15% DCM- MEOH. Appropriate fractions were pooled, excess solvent was removed under pressure, and the product obtained was vacuum dried to (3-fluoro-4-(prop-2-yn-1- ylamino)phenyl)dimethylphosphine oxide. MS ESI calcd. C₁₁H₁₄FNOP [M+H]⁺ 226, found 226.0. STEP 2: 3-fluoro-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino) phenyl) dimethylphosphine oxide trifluoroacetate salt To a vial N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-7-amine (40.0 mg, 1eq, 37.9 µmol) and CuI (16.06 mg, 1eq, 84.34 ‐ 175 ‐ Agent Ref: 12617.0003-00304 µmol) and tetrakistriphenylphosphine)palladium (0) (97.46 mg, 1eq, 84.34 µmol) and DIEA (98.11 mg, 132 µL, 9.00 Eq, 759.1 µmol) and DMSO (0.70 mL) were added, and the vial was purged with N₂ and then stirred at room temperature overnight. The reaction was monitored using LC. The reaction was filtered and diluted with additional 1 mL DMSO and purified on a reverse phase HPLC using gradient elution with 0-100% ACN-water using 0.1% TFA as a modifier. Appropriate fractions were pooled, and excess solvent was lyophilized.3-fluoro-4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide trifluoroacetate salt was obtained. MS ESI calcd. C₂₇H₂₇F₈N₅O₃PS [M+H]⁺ 572, found 572.2. ¹H NMR (499 MHz, DMSO) δ 9.83 (s, 1H), 7.55 (d, J = 16.5 Hz, 1H), 7.51 – 7.36 (m, 2H), 7.16 – 6.99 (m, 3H), 6.67 (s, 1H), 6.50 (d, J = 7.9 Hz, 1H), 5.21 (d, J = 47.1 Hz, 1H), 4.39 (s, 2H), 4.21 – 4.02 (m, 1H), 3.96 – 3.81 (m, 1H), 3.50 (s, 1H), 3.24 – 3.13 (m, 1H), 2.83 (s, 3H), 2.40 – 2.28 (m, 1H), 2.11 – 2.03 (m, 1H), 1.60 (s, 6H). Synthesis of 63: (4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino) phenyl) dimethylphosphine oxide, 2,2,2-trifluoroacetate salt STEP 1: A mixture containing (4-aminophenyl)dimethylphosphine oxide (1.00 g, 1 Eq, 5.91 mmol) DMF (10.0 mL) was treated with potassium carbonate (1.60 g, 1.96 Eq, 11.6 mmol) and then with 3-bromoprop-1-yne, 80 wt% in toluene (900 mg, 80% Wt, 1.02 Eq, 6.05 mmol). The mixture was stirred for 1 h at 50 °C. The reaction was filtered and concentrated and purified on a silica gel column using gradient elution with 0-15% DCM-MeOH to give the title compound. MS ESI calcd. C₁₁H₁₅NOP [M+H]⁺ 208 found 208.1. STEP 2: 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide, 2,2,2-trifluoroacetate salt To N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine (25.00 mg, 1 Eq, 52.71 μmol) and dimethyl(4-(prop-2-yn-1- ‐ 176 ‐ Agent Ref: 12617.0003-00304 ylamino)phenyl)phosphine oxide (21.85 mg, 2.00 Eq, 105.4 μmol) in DMSO (0.50 mL), CuI (5.020 mg, 0.5 Eq, 26.36 μmol) and tetrakis(triphenylphosphine)palladium(0) (6.092 mg, 0.10 Eq, 5.271 μmol) and DIEA (61.32 mg, 82.6 μL, 9.0 Eq, 474.4 μmol) were added and the reaction stirred for two hours. The reaction was monitored using LC. The reaction was diluted with EtOAc and washed with sat NH₄Cl. Organic layer was dried over anhydrous MgSO₄, filtered and concentrated. The product was purified by chromatography on a silica gel column 0-10% MeOH/DCM to provide the desired product. This was repurified on a reverse phase HPLC using gradient elution with 0-100% ACN-water using 0.1% TFA as a modifier. Appropriate fractions were pooled and lyophilized to give (4-((3-(7-(((3R,4S)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide, 2,2,2-trifluoroacetate salt. MS ESI calcd. C27H29F7N5O3PS- [M+H]⁺ 554, found 554.2. ¹H NMR (499 MHz, DMSO) δ 9.81 (s, 1H), 7.60 – 7.46 (m, 3H), 7.07 (t, J = 8.9 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.50 (d, J = 7.9 Hz, 1H), 5.21 (d, J = 47.4 Hz, 1H), 4.34 (s, 2H), 4.22 – 4.04 (m, 1H), 3.98 – 3.68 (m, 2H), 3.30 – 3.10 (m, 2H), 2.83 (s, 3H), 2.40 – 2.27 (m, 1H), 2.19 – 2.00 (m, 1H), 1.54 (d, J = 20.0 Hz, 6H). Example 64: N-((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine A mixture of example 2 (28 mg, 0.049 mmol) and DIEA (0.026 mL, 0.147 mmol), Iodomethane-d3 (2.142 µL, 0.034 mmol) in MeCM (1 mL) was stirred at 25 °C for 1 h. LCMS showed the desired product was found. The reaction was diluted with water (3 mL), extracted with EtOAc (3 mL*3). The combined organic layers were washed with brine (5 mL*2), and dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by Prep- HPLC (Column Phenomenex Gemini-NX 150*30mm*5um Condition water (7 mM HCOONH₄)- ACN Begin B 35 End B 65 Gradient Time(min) 15100%B Hold Time 3 Flow Rate(ml/min) 25) to give N-((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine (2.68 mg, 4.45 µmol,). MS (ESI) m/z: [M+H]⁺: 589.3.¹H NMR (400 MHz,CDCl₃) δ 7.73 ‐ 177 ‐ Agent Ref: 12617.0003-00304 - 7.82 (m, 1 H), 7.52 (dd, J=8.34, 1.91 Hz, 1 H), 7.26 - 7.26 (m, 1 H), 6.83 - 6.93 (m, 2 H), 6.23 - 6.37 (m, 1 H), 5.40 - 5.51 (m, 1 H), 5.11 - 5.23 (m, 1 H), 4.80 - 5.04 (m, 1 H), 4.37 (d, J=6.08 Hz, 2 H), 3.93 (s, 3 H), 3.51 - 3.71 (m, 1 H), 3.19 - 3.34 (m, 1 H), 3.02 (s, 3 H), 2.95 - 3.01 (m, 1 H), 2.17 - 2.53 (m, 2 H), 1.99 - 2.10 (m, 2 H). The following example was prepared in an analogous fashion to Example 64, using the appropriate intermediates. Example Intermediate; Structure & Name; characterising data No. Example 66: 4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide ‐ 178 ‐ Agent Ref: 12617.0003-00304 A mixture of intermediate 5e (200 mg, 0.435 mmol) and DIEA (0.228 mL, 1.304 mmol), Iodomethane-d3 (70.6 mg, 0.487 mmol) in MeCN (2 mL) was stirred at 25 ^oC for 1 h. LCMS showed desired Ms. The reaction was diluted with water (3 mL), extracted with EtOAc (3 mL*3). The combined organic layers were washed with brine (10 mL*2) and dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by Prep-HPLC (condition: Preparative HPLC on instrument fitted with henomenex Gemini-NX C18150*40 mm*5 µm using the mobile phase A-B: water(10 mM-NH₄HCO₃)-ACN, Gradient: 50-80% B, 0-11 min; 100% B, 11-13.5 min; 10% B,13.5-15.5 min. FlowRate: 25 mL/min ) to give N- ((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine (80 mg, 0.151 mmol). MS (ESI) m/z: 477.8 [M+H]⁺. Step 2 To a solution of intermediate 5h (40 mg, 0.084 mmol) in DMSO (0.4 mL) was added diisopropylamine (0.106 mL, 0.754 mmol), Pd(PPh₃)₄ (11.62 mg, 10.06 µmol), Copper(I) iodide (6.38 mg, 0.034 mmol) and the mixture was stirred at 25 °C under N₂ atmosphere. After stirring for 3 min, a solution of 3b (21.95 mg, 0.101 mmol) in DMSO (0.2 mL) was added. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was finished. The reaction was diluted with water (5 mL), extracted with EtOAc (4 mL*3). The combined organic layers were washed with brine (10 mL*2), and dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by Prep-HPLC (condition: Preparative HPLC on EE instrument fitted with YMC-Actus Triart C18150*30 mm*5 µm using the mobile phase A-B: water(0.1%TFA)-ACN, Gradient: 28-48% B, 0-11.5 min; 100% B, 11.5-12.5 min; 10% B,12.5- 14.5 min. FlowRate: 40 mL/min) to give 4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide (17.15 mg, 0.028 mmol). MS (ESI) m/z: 568.1 [M+H]⁺.¹H NMR (400 MHz, MeOH-d₄) δ ppm 7.41 - 7.50 (m, 2 H), 7.36 (d, J=1.55 Hz, 1 H), 7.09 (d, J=8.58 Hz, 1 H), 6.87 (d, J=8.34 Hz, 1 H), 6.39 (d, J=7.75 Hz, 1 H), 5.13 - 5.29 (m, 1 H), 4.38 (s, 2 H), 4.07 - 4.24 (m, 1 H), 3.89 - 4.00 (m, 4 H), 3.42 - 3.68 (m, 2 H), 3.21 - 3.30 (m, 1 H), 2.90 (s, 3 H), 2.24 - 2.33 (m, 2 H). The following example was prepared in an analogous fashion to Example 66, using the appropriate intermediates. Example Intermediate; Structure & Name; characterising data ‐ 179 ‐ Agent Ref: 12617.0003-00304 Intermediate 5h & 3f , 1 8 , appropriate intermediates. Example Intermediate; Structure & Name; characterising data N z, 1 .53 H), H), ‐ 180 ‐ Agent Ref: 12617.0003-00304 Intermediate 6e 31, , z: BIOLOGICAL EXAMPLES Expression and purification of protein constructs The recombinant DBD of p53 (residues 94-312) containing the Y220C mutation was overexpressed in Escherichia coli grown in 2xYT media (SEQ ID NO: 1). Recombinant protein was isolated from lysates using Ni-NTA affinity chromatography, heparin chromatography and finally size-exclusion chromatography. For the SPR construct (SEQ ID NO: 2), the expression tags were removed by application of TEV protease followed by in vitro biotinylation of the Avi- tag before application to the heparin column. Purified proteins were concentrated to approximately 5 mg/ml and stored in 25 mM sodium phosphate, 150 mM NaCl, 1 mM TCEP, pH 7.2 at -80 °C. Surface plasmon resonance Surface plasmon resonance (SPR) experiments were performed on a Biacore S200 at 25 °C. Biotinylated Y220C protein was captured on a series S SA sensor chip (Cytiva) in a running buffer comprising 10 mM HEPES, 150 mM NaCl, 2 mM TCEP and 0.05% Tween 20 at pH 7.5. Compounds were analysed in multi-cycle mode, typically with an 8-point halving dilution series in the immobilisation buffer plus 5% DMSO. A flow rate of 100 μl/min was used with a contact time of 140 s and a dissociation time ranging from 300-1200 s, dependent upon ‐ 181 ‐ Agent Ref: 12617.0003-00304 the compound off rate. All SPR data analyses were performed with Biacore S200 evaluation software. BIOLOGICAL EXAMPLE 1: p53Y220C in vitro competition HTRF assay Process 1: Compounds were tested to determine their ability to displace a fluorescent tracer binding in a pocket close to amino acid residue Cys220. Recombinantly expressed and purified DNA binding domain of p53Y220C with a C-Terminus 6xHis tag (SEQ ID NO: 3) (0.5 nM in assay buffer) was incubated with test compounds in the presence of 40 nM fluorescent tracer (COc1cc(ccc1NCC#Cc2cc3c(NC4CCN(CCOCCOCCNC(=O)c5ccc6C(=O)OC7(c6c5)c8ccc( O)cc8Oc9cc(O)ccc97)CC4)cccc3n2CC(F)(F)F)S(=O)(=O)N) and 0.34 nM Terbium labelled anti-His antibody (#PV5895, ThermoFisher, Massachusetts, USA) for 1 hour at room temperature in assay buffer (25 mM Na+ phosphate, pH 7.2, 30 mM NaCl, 0.01 % TritonX- 100, 0.01 % Bovine Serum Albumin, 1 mM TCEP, prior to being read in the BMG Pherastar FSX in HTRF mode (Excitation 337 nm, Emission A 520 nm, Emission B 490 nm). Positive controls consisted of p53Y220C protein and tracer (no inhibition), and negative controls contained tracer only (100% inhibition). Raw data were normalised to the controls as % inhibition and analysis was performed using GraphPad Prism (GraphPad Software, version 9, La Jolla, USA) to determine IC50 values using a 4-parameters non-linear least-squares analysis. Process 2: Compounds were tested to determine their ability to displace a fluorescent tracer binding in a pocket close to amino acid residue Cys220. Recombinantly expressed and purified DNA binding domain of p53Y220C with a C-Terminus 6xHis tag (SEQ ID NO: 3) (0.1 nM in assay buffer) was incubated with test compounds in the presence of 125 nM fluorescent tracer (COc1cc(ccc1NCC#Cc2cc3c(NC4CCN(CCOCCOCCNC(=O)c5ccc6C(=O)OC7(c6c5)c8ccc( O)cc8Oc9cc(O)ccc97)CC4)cccc3n2CC(F)(F)F)S(=O)(=O)N) [WMD2] and 0.2 nM Terbium labelled anti-His antibody (#PV5895, ThermoFisher, Massachusetts, USA) for 1 hour at room temperature in assay buffer (25 mM Na+ phosphate, pH 7.2, 30 mM NaCl, 0.01 % TritonX- 100, 0.1 % Bovine Serum Albumin, 1 mM TCEP, prior to being read in the BMG Pherastar FSX in HTRF mode (Excitation 337 nm, Emission A 520 nm, Emission B 490 nm). Positive controls consisted of p53Y220C protein and tracer (no inhibition), and negative controls contained p53Y220C, tracer and 1.25 µM N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- ‐ 182 ‐ Agent Ref: 12617.0003-00304 amine (100% inhibition). Raw data were normalized to the controls as % inhibition and analysis was performed using Spotfire Tool to determine IC₅₀ values using a 4-parameters non-linear least-squares analysis. A number of example compounds of formula (I) were tested in these assays and the results are shown in Table 1 below. Table 1: IC₅₀ or % inhibition assay results from p53^Y220C in vitro competition HTRF assay p53^Y220C in vitro competition Example No. HTRF assay (IC₅₀ or % ‐ 183 ‐ Agent Ref: 12617.0003-00304 p53^Y220C in vitro competition Example No. HTRF assay (IC₅₀ or % ‐ 184 ‐ Agent Ref: 12617.0003-00304 p53^Y220C in vitro competition Example No. HTRF assay (IC₅₀ or % The resu o bind to the Y220C p53 mutant which could potentially stabilise the protein and restore the ability of the p53 mutant to bind DNA. Therefore, the compounds of formula (I) are expected to have utility in the treatment of disease or disorder affected by p53 mutation such as a proliferative disease e.g., cancer, since such activity of the p53 mutant can lead to inhibition of cancer progression as described in the “Background of the Invention”. BIOLOGICAL EXAMPLE 2: p21 MSD assay Compounds were tested to determine their ability to induce p21 levels in NUGC-3 cells (p53^Y220C) in vitro. NUGC-3 cells (#JCRB0822, JCRB / tebu-bio, Peterborough, UK) were seeded into 96-well plates at a density of 7 x 10⁴ cells/well in RPMI medium supplemented with 10% FBS and incubated for 24 hours. Compounds were diluted first in DMSO and then into water (#AM9939, ThermoFisher, Massachusetts, USA) acidified with a 1:500 dilution of 1N HCl (#H9892, Merck, Gillingham, UK), before being added to cells in triplicate to give a final concentration of 0.1% DMSO. Plates were incubated at 37°C for 6 hours in a humidified atmosphere of 5% CO₂ in air. Following compound treatment, medium was removed, and cells were lysed by adding 50 µL of MSD Tris lysis buffer (#R60TX-2, MesoScale Discovery, Maryland, USA) supplemented with cOmplete™ Mini Protease Inhibitor Cocktail (#11836153001, Merck) and PhosSTOP™ (#4906837001, Merck) to each well. Plates were ‐ 185 ‐ Agent Ref: 12617.0003-00304 then incubated for 20 minutes at room temperature with shaking and placed in the -80 °C freezer overnight. p21 protein levels were measured in cell lysates using MSD assay. MSD gold small spot streptavidin plate (#L45SA-1, MSD) were coated with capture biotinylated anti-p21 antibody (#60480SF, Cell Signaling Technology, Danvers, US) biotinylated with EZ-link biotinylation kit (#21925, Pierce, Paisley, UK} https://www.thermofisher.com/order/catalog/product/21925). The capture antibody (2 µg/mL diluted in PBS) was added at 25 µl/well and left for 1 hour shaking at room temperature. The plates were then washed 3 times with 1X MSD Tris Wash Buffer (#R61TX-1, MesoScale Discovery). Cell lysates (25 µl) were added to MSD plate and incubated at room temperature for 1 hour with shaking. After washing 3 times with 1x MSD Tris Wash Buffer, anti-p21-sulfo tag detection antibody sulfo-tagged in house (#AF1047, R&D Systems, Minneapolis, US) diluted to 1 µg/mL in Assay Diluent 100 (#R50AA-2, MesoScale Discovery) was added per well. The plates were incubated for 1 hour at room temperature with shaking. After 3 washes with MSD Tris Wash Buffer, 150 µl/well of 1 x MSD read buffer T (#R92TC-2, MesoScale Discovery) was added before reading each plate on MSD SECTOR Imager. EC50 values were determined from dose-response curves generated using GraphPad Prism (GraphPad Software, La Jolla, USA) and fitted using the four-parameter logistic curve fit. A number of example compounds of formula (I) were tested in this assay and the results are shown in Table 2 below. Table 2: EC₅₀ or % inhibition assay results from p21 MSD assay No. p21 MSD µM) ‐ 186 ‐ Agent Ref: 12617.0003-00304 Example No. p21 MSD assay (EC₅₀ µM) 13 0.18 ‐ 187 ‐ Agent Ref: 12617.0003-00304 Example No. p21 MSD assay (EC₅₀ µM) 47 - The results shown in Table 2 indicate that the compounds of formula (I) are able to induce p21 levels in NUGC-3 cells (p53^Y220C) in vitro. Therefore, the compounds of formula (I) are expected to have utility in the treatment of disease or disorder affected by p53 mutation such as a proliferative disease e.g., cancer, since such activity of the p53 mutant can lead to inhibition of cancer progression as described in the “Background of the Invention”. BIOLOGICAL EXAMPLE 3: Proliferation assay Compounds were tested to determine their ability to inhibit cell growth of NUGC-3 p53Y220C and NUGC3 p53null cells in vitro. NUGC-3 cells were purchased from JCRB (#JCRB0822) and NUGC-3 p53 knock-out isogenic line was engineered with CRISPR ‐ 188 ‐ Agent Ref: 12617.0003-00304 technology. Both cell lines were plated out into 96-well plates (200 µl/well) at 1 x 10³ cells/well in complete culture media (RPMI + 10% FBS) and incubated overnight at 37°C in a humidified atmosphere of 5% CO₂ in air. Following day, compounds were diluted first in DMSO and then into water (#AM9939, ThermoFisher, Massachusetts, USA) acidified with a 1:500 dilution of 1N HCl (#H9892, Merck, Gillingham, UK), before being added to cells in triplicate to give a final concentration of 0.1% DMSO. The compounds were incubated with the cells for 5 days before CellTiter-Glo reagent (20 µl/well, #G7570, Promega, Southampton, UK) was added to each well and incubated for 10 minutes with shaking. The luminescence signal was read on BMG PheraStar and EC50 values were determined from dose-response curves generated using GraphPad Prism (GraphPad Software, La Jolla, USA) and fitted using the four- parameter logistic curve fit. A number of example compounds of formula (I) were tested in this assay and the results are shown in Table 3 below. Table 3: Proliferation assay results Example NUGC-3 p53^Y220C NUGC3 p53^null No (EC or % inhibition) (µM) (EC or % inhibition) (µM) ‐ 189 ‐ Agent Ref: 12617.0003-00304 Example NUGC-3 p53^Y220C NUGC3 p53^null No. (EC₅₀ or % inhibition) (µM) (EC₅₀ or % inhibition) (µM) ‐ 190 ‐ Agent Ref: 12617.0003-00304 Example NUGC-3 p53^Y220C NUGC3 p53^null No. (EC₅₀ or % inhibition) (µM) (EC₅₀ or % inhibition) (µM) *not a The results shown in Table 3 indicate that the compounds of formula (I) are able to inhibit cell growth of NUGC-3 p53Y220C and show selectivity over NUGC3 p53null cells in vitro. In particular, the compounds of formula (I) bind to the p53 Y220C mutant (see NUGC-3 p53Y220C (EC50 or % inhibition) values compared with the corresponding NUGC3 p53null (EC50 or % inhibition) values). Thus, the compounds of formula (I) are expected to slow the proliferation of cancer cell lines or kill cancer cells with a Y220C mutation but have no effect on healthy cells. ‐ 191 ‐

Claims

Agent Ref: 12617.0003-00304 CLAIMS 1. A compound of formula (I): (I) or a wherein: ring A is a cyclohexyl, piperidinyl, oxanyl or thianyl-1,1-dioxide wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; R¹ is chosen from H, fluoro, chloro, CH3, OCH3, C1haloalkyl and OC1haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached, join to form a cyclopropyl ring or oxetanyl ring; ‐ 192 ‐ Agent Ref: 12617.0003-00304 R³ is chosen from H, S(O)_1-2CH₃, S(O)₂N(R⁵)(R⁶), C(=O)N(R⁵)(R⁶), P(=O)(C_1-3alkyl)₂, CN and C(CH₃)₂CN; R⁴ is chosen from H, OC_1-2alkyl, O-cyclopropyl, C₁haloalkyl, halo, CN and OC_1- ₂haloalkyl; wherein when one of R³ or R⁴ is H, the other of R³ or R⁴ is not H; R⁵ is H or C_1-3alkyl; R⁶ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; Or R⁵ and R⁶, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms independently chosen from N, O, and S; R⁷ is chosen from C_1-4alkyl, C_3-6cycloalkyl, 4- to 7-membered heterocyclyl, and C(=O)CH₃, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH₃, and wherein the C_3-6cycloalkyl and 4- to 7-membered heterocyclyl are optionally substituted by one or two CH₃ groups; R⁸ is H or C_1-2alkyl; R⁹ is H or C1-2alkyl, wherein the C1-2alkyl is optionally substituted by one OCH3; or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms wherein the second heteroatom is independently chosen from N, O, and S; and n is 0, 1 or 2. 2. The pharmaceutically acceptable salt according to claim 1. 3. The compound of formula (I) according to claim 1. 4. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 3, wherein ring A is piperidinyl wherein the N atom of the piperidinyl ring is optionally substituted by R⁷. 5. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 3, wherein ring A is thianyl-1,1-dioxide. 6. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 5, wherein X¹ is C and X² is N. ‐ 193 ‐ Agent Ref: 12617.0003-00304 7. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 5, wherein X¹ is N and X² is C. 8. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 7, . 9. The compound of formula (I) or and/or solvate thereof according to any one of claims 1 to 8 wherein V¹, V² and V³ are each CH. 10. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 8, wherein V¹ and V² are each CH and V³ is N. 11. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 10, wherein R¹ is H. 12. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 11, wherein R² is fluoro. 13. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 12, wherein R³ is chosen from S(O)_1-2CH₃, C(=O)N(R⁵)(R⁶), and P(=O)(C_1-3alkyl)₂. 14. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 13, wherein R⁴ is OC_1-2alkyl. 15. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 14, wherein n is 0. 16. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 15, wherein n is 1. 17. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 3 which is chosen from: ‐ 194 ‐ Agent Ref: 12617.0003-00304 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; 4-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine; 3-methoxy-N-methyl-4-[(3-{7-[(oxan-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; 4-[(3-{7-[(1,1-dioxo-1λ⁶-thian-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)piperidin-4-amine; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)-1-methylpiperidin-4-amine; N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl)-1-methylpiperidin-4-amine; (3S,4R)-N-[2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-7-yl]-3-fluoro-1-methylpiperidin-4-amine; (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine; 4-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; N-(3-{7-[(piperidin-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2- yn-1-yl)acetamide; N-(3-{7-[(oxan-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1- yl)acetamide; N-[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl]acetamide; ‐ 195 ‐ Agent Ref: 12617.0003-00304 3-methoxy-N-methyl-4-[(3-{7-[(1-methylpiperidin-4-yl)amino]-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; and 5-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylpyridine-2-carboxamide; 3-methoxy-N-methyl-4-((3-(8-((1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)acetamide; 3-methoxy-N-methyl-4-((3-(8-(piperidin-4-ylamino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1- yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine; N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzonitrile; 3-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylpicolinamide; (3-cyclopropoxy-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (3-(difluoromethoxy)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; 3-chloro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; ‐ 196 ‐ Agent Ref: 12617.0003-00304 2-fluoro-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylbenzamide; (3-(difluoromethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; 3-cyano-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxypyridin-2-yl)dimethylphosphine oxide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxypyrimidin-2-yl)dimethylphosphine oxide; (5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)dimethylphosphine oxide; 4-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-methoxy-4-((3-(8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 4-((3-(8-((1-(2-hydroxyethyl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((2-(3-((4-methoxypyridin-3-yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-8-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide; (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; 4-((3-(8-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide; 4-((3-(8-(((3S,4R)-1,3-dimethylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-methoxy-N-methyl-4-((3-(8-((5-methyl-5-azaspiro[2.5]octan-8-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; ‐ 197 ‐ Agent Ref: 12617.0003-00304 (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyridin-2- yl)dimethylphosphine oxide; (4-((3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((Trans)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(morpholino)methanone; N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; N-(3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-6-(methylsulfonyl)pyridin-3- yl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine; (4-((3-(7-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (4-((3-(7-(((3R,4R)-3-(hydroxymethyl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; 1-cyclopropyl-3-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-2-one; 4-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-1-methylpiperidin-2-one; (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2- yl)dimethylphosphine oxide; (3-fluoro-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; ‐ 198 ‐ Agent Ref: 12617.0003-00304 (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; N-((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- amine; 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d₃)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 5-((3-(7-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; 4-((3-(8-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (4-((3-(7-(((1r,4r)-4-aminocyclohexyl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. 18. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically salt and/or solvate thereof according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient. 19. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 for use as a medicament. 20. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof for use or the pharmaceutical composition for use according to claim 19 for use in the prophylaxis or treatment of a disease or disorder associated with a p53 mutation. 21. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof for use or the pharmaceutical composition for use according to claim 20, wherein the disease or disorder associated with the p53 mutation is cancer. ‐ 199 ‐ Agent Ref: 12617.0003-00304 22. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof for use or the pharmaceutical composition for use according to claim 20 or claim 21, wherein the p53 mutation comprises a Y220C mutation. 23. The compound of formula (I) or pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 17 for use in combination with one or more other anticancer agents or therapies. 24. A compound chosen from: (a) a compound of formula (II): or a salt and/or solvate wherein: X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; and Q² is a leaving group; ‐ 200 ‐ Agent Ref: 12617.0003-00304 (b) a compound of formula (V): or a salt and/or solvate thereof; wherein: X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B 1 Q is a leaving group; and Q² is a leaving group; and (c) a compound of formula (VI): or a salt and/or solvate thereof; wherein: ring A is a cyclohexyl, piperidinyl, oxanyl, or thianyl-1,1-dioxide, wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; X¹ is C and X² is N such that ring B or ‐ 201 ‐ Agent Ref: 12617.0003-00304 X¹ is N and X² is C such that ring B ; R¹ is chosen from H, fluoro, chloro, CH₃, and OC₁haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached join to form a cyclopropyl ring or oxetanyl ring; R⁸ is H or C_1-2alkyl; R⁹ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; n is 0, 1, or 2; and Q¹ is a leaving group. 25. A process for the preparation of a compound of formula (I): or salt and/or solvate (a) reacting compound of formula (II): ; or salt and/or solvate (III): ‐ 202 ‐ Agent Ref: 12617.0003-00304 or salt and/or solvate thereof; in a base and a catalyst; wherein: ring A is a cyclohexyl, piperidinyl, oxanyl, or thianyl-1,1-dioxide, wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; R¹ is chosen from H, fluoro, chloro, CH₃, OCH₃, C₁haloalkyl, and OC₁haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same carbon and together with the carbon to which the two R² groups are attached join to form a cyclopropyl ring or oxetanyl ring; R⁸ is H or C_1-2alkyl; R⁹ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; n is 0, 1, or 2; and Q² is a leaving group; or ‐ 203 ‐ Agent Ref: 12617.0003-00304 (b) reacting a compound of formula (VI): A or salt and/or solvate (IV): or salt and/or solvate thereof; in the presence of an organic base, a catalyst, and Cu⁺; wherein: ring A is a cyclohexyl, piperidinyl, oxanyl, or thianyl-1,1-dioxide, wherein the N atom of the piperidinyl ring is optionally substituted by R⁷; X¹ is C and X² is N such that ring B or X¹ is N and X² is C such that ring B ; is not N; R¹ is chosen from H, fluoro, chloro, CH₃, OCH₃, C₁haloalkyl, and OC₁haloalkyl; each R² is independently chosen from fluoro, chloro, CH₃, C₁haloalkyl, CH₂OH, oxo, OH, OCH₃, OC₁haloalkyl, and N(R⁸)(R⁹), or two R² groups that are attached to the same ‐ 204 ‐ Agent Ref: 12617.0003-00304 carbon and together with the carbon to which the two R² groups are attached join to form a cyclopropyl ring or oxetanyl ring; R³ is chosen from H, S(O)_1-2CH₃, S(O)₂N(R⁵)(R⁶), C(=O)N(R⁵)(R⁶), P(=O)(C_1-3alkyl)₂, CN, and C(CH₃)₂CN; R⁴ is chosen from H, OC_1-2alkyl, O-cyclopropyl, C₁haloalkyl, halo, CN, and OC_1- ₂haloalkyl; wherein when one of R³ or R⁴ is H, the other of R³ or R⁴ is not H; R⁵ is H or C_1-3alkyl; R⁶ is H or C1-2alkyl, wherein the C1-2alkyl is optionally substituted by one OCH3; or R⁵ and R⁶, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; R⁷ is chosen from C_1-4alkyl, C_3-6cycloalkyl, 4- to 7-membered heterocyclyl, and C(=O)CH₃, wherein the C_1-4alkyl group is optionally substituted by one or more OH and/or one or more OCH₃, and wherein the C_3-6cycloalkyl and 4- to 7-membered heterocyclyl are optionally substituted by one or two CH3 groups; R⁸ is H or C_1-2alkyl; R⁹ is H or C_1-2alkyl, wherein the C_1-2alkyl is optionally substituted by one OCH₃; or R⁸ and R⁹, together with the nitrogen to which they are attached, can join to form a 6- membered heterocyclyl containing up to two heteroatoms, wherein the second heteroatom is independently chosen from N, O, and S; n is 0, 1, or 2; and Q¹ is a leaving group. ‐ 205 ‐