FAK inhibitors

Abstract

The present invention is directed to compounds of formula: (Formula(I)) that inhibit Focal Adhesion Kinase (FAK), also known as protein tyrosine kinase 2 (PTK2) and to pharmaceutical compositions containing such compounds. Methods of using said compounds for the treatment of proliferative and fibrotic diseases are also disclosed.

Description

FAK InhibitorsCross-reference to related applications

[0001] This application claims the benefit of priority from Australian provisional application no. 2024903680, filed on 11 November 2024, the contents of which is incorporated herein by reference in its entirety.Field of the invention

[0002] The present invention is directed to compounds that inhibit Focal Adhesion Kinase (FAK), also known as protein tyrosine kinase 2 (PTK2) and to pharmaceutical compositions containing such compounds. The invention also relates to methods of making said compounds, intermediates, and using said compounds for the treatment of proliferative and fibrotic diseases.Background of the invention

[0003] Directional cell migration is important in many physiological and pathological processes including embryonic development, wound healing, angiogenesis, tumour invasion and metastasis. Transduction of extracellular signals, that stimulate cells to move directionally, may be induced by a number of processes including transmembrane integrins binding to extra cellular matrix proteins and the action of growth factors (for example EGF, IGF and VEGF) on the extracellular domains of their cognate receptors.

[0004] Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase that is known to mediate signals from both transmembrane integrins and growth factor receptors. FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. FAK also plays a role in the development of fibrotic disorders. Excessive fibrous tissue can impair the normal functioning of various organs in the body, such as the lungs, liver, heart and kidneys, resulting in major health issues.

[0005] For these reasons, small molecule FAK inhibitors have been a promising area of research, with many groups trying to develop new therapies and treatment regimens for proliferative and fibrotic diseases utilising FAK inhibitors. Selective FAK inhibitors are thought to be able to target specific biological pathways, without the issues caused by the inhibition of other protein kinases.

[0006] There have been many different FAK inhibitors developed with varying structural motifs. One class of FAK inhibitors are substituted pyrimidines, such as those disclosed in WO2012 / 110774.

[0007] Many cancers, particularly fibrous cancers like pancreatic cancer (specifically pancreatic ductal adenocarcinoma (PDAC)) have shown little improvement in the 5-year survival rate over the last four decades. Furthermore, there are currently very few effective treatments for fibrosis available. Given the continued poor prognosis of cancer and fibrotic diseases, there remains a need for new drugs and treatments to improve patient outcomes.

[0008] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.Summary of the invention

[0009] In a first aspect of the invention there is provided a compound or pharmaceutically acceptable salt thereof according to Formula (I)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups; each of R2a, R2b, R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi-Cealkyl, or either (i) taken together, R2aand R2bor R3aand R3bform a carbonylgroup; or (ii) two of R2a, R2b, R3aor R3btogether form a Cs-Cs cycloalkyl ring or a Cs-Cs heterocyclic ring;R4is selected from H, -CDs or Ci-Cealkyl;R5aand R5bare independently selected from H, D, F, OH, -Ci-Cealkyl or -OCi-Cealkyl; and wherein at least one of R2a, R2b, R3a, R3b, R5aor R5bis not H.

[0010] In an alternative aspect of the invention, there is provided a compound or pharmaceutically acceptable salt thereof according to Formula (la)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups;R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi-Cealkyl, or taken together, form a carbonyl group, a Cs-Cs cycloalkyl ring or a Cs-Cs heterocyclic ring; R4is selected from H, -CDs or Ci-Cealkyl; and at least one of R3aand R3bis not H.

[0011] In an alternative aspect of the invention, there is provided a compound or pharmaceutically acceptable salt thereof according to Formula (II)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups;R3is selected from OH, or -OCi-Cealkyl; andR4is selected from H or Ci-Cealkyl.

[0012] In an alternative embodiment of this aspect, the carbon attached to R3is of absolute configuration:

[0013] In an alternative embodiment of this aspect, the carbon attached to R3is of absolute configuration:

[0014] In a preferred embodiment of each of these aspects and embodiments of the invention, said compound is greater than 90% enantiomerically pure, greater than 95% enantiomerically pure and greater than 99% enantiomerically pure.

[0015] In another aspect of the invention, there is provided a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, according to any one of the disclosed embodiments.

[0016] In one embodiment, the composition is used with one or more additional therapeutic agents; preferably the one or more additional therapeutic agents are selected from anti-cancer agents and anti-fibrotic agents.

[0017] In another aspect of the invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt thereof, having the structure:including contacting a compound having the structure:with a reducing agent capable of reducing the carbonyl to an alcohol to provide a compound having the structure:

[0018] In one embodiment the process further includes the step of converting a compound having the structure:with formaldehyde and a hydride source to provide a compound having the structure:

[0019] In an alternative aspect of the invention, there is provided a method of inhibiting Focal Adhesion Kinase (FAK) in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of the herein disclosed embodiments.

[0020] In one embodiment there is provided a method of treating a proliferative disease in a subject in need thereof, comprising administering to said subject a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments.

[0021] In an alternative embodiment there is provided a method of treating a fibrotic disease in a subject in need thereof, comprising administering to said subject a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments.

[0022] In another aspect of the invention, there is provided the use of a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments in the manufacture of a medicament for treating a proliferative disease.

[0023] In another aspect of the invention, there is provided the use of a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments in the manufacture of a medicament for treating a fibrotic disease.

[0024] In an alternative aspect of the invention, there is provided a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments for use in the treatment of a proliferative disease.

[0025] In an alternative aspect of the invention, there is provided a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments for use in the treatment of a fibrotic disease.

[0026] In one preferred embodiment of the invention, the proliferative disease is cancer.

[0027] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Brief description of the drawings

[0028] Figure 1 : pFAK Inhibition in (A) OVCAR3 and (B) OVCAR5 cells by AMP962 and AMP963. pY397-FAK levels in ovarian cancer cells treated with AMP962 or AMP963 at a range of concentrations for 6 hours in vitro were determined using the MSD immunoassay (anti-FAK (total) capture antibody and anti-pFAK detection antibody). Data shown is mean ± SD of technical duplicates, with ICso values calculated using GraphPad Prism v10.2.2 using a nonlinear regression dose response inhibition equation (variable slope).

[0029] Figure 2: Dose-dependent inhibition of tumour growth with AMP962 but not AMP963 treatment in the TOV-21G xenograft model. (A) Tumour volume for each treatment group over the 18-day treatment period. (B) The percentage tumour growth change at day 18 ((tumour volume at day 18 / tumour volume at baseline) x 100) is shown for each treatment group. Comparison between test compounds and vehicle control groups was performed using one-way ANOVA followed by Dunnett’s multiple comparisons test; significance levels: *p<0.05, **p<0.01 , ***p<0.001 , ****p<0.0001 , ns = not significant. N = 8 mice for vehicle group; n = 5 mice for treatment groups.

[0030] Figure 3: Inhibition of tumour growth by AMP962 in combination with PLD treatment in the TOV-21G xenograft model (A) Tumour volume for each treatment group over the 21-day treatment period. (B) The percentage tumour growth change at day 21 ((tumour volume at day 21 / tumour volume at baseline) x 100) for PLD only and combination treatment groups. Comparison performed using an unpaired t test; significance level: **p<0.01.

[0031] Figure 4: AMP962 treatment in primary human kidney fibroblasts results in inhibition of FAK activity and reduced expression of fibrotic markers. Protein expression in primary human kidney fibroblasts for (A) pFAK / FAK, (B) pERK / ERK, (C) a-SMA and (D) fibronectin. Protein expression was determined by Western blot relative to vinculin levels (densitytarget / density control), in the case of phospho-proteins (A & B) this ratio was then compared to the ratio for total protein. All results are calculated as a percentage compared to TFG-p stimulated vehicle-treated fibroblasts. Data was analyzed by the t test method compared to TFG-p stimulated vehicle-treated fibroblasts; *p <0.05, **p<0.01.

[0032] Figure 5: X-ray Powder Diffraction (XRPD) analysis of AMP962.

[0033] Figure 6: The molecular structure of one of the two unique molecules of AMP962 in the asymmetric unit. Displacement ellipsoids are at the 50% probability level.

[0034] Figure 7: Comparison of the simulated XRPD. Based on the single crystal data (bottom) with the experimental powder diffraction data from the sample of AMP962 (top).Definitions

[0035] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0036] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a salt” may include a plurality of salts anda reference to “at least one heteroatom” may include one or more heteroatoms, and so forth.

[0037] The term “and / or” means “and” or “or”.

[0038] "About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in some instances ±5%, in some instances ±1%, and in some instances ±0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods.

[0039] Ranges: throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0040] Unless otherwise herein defined, the following terms will be understood to have the general meanings which follow.

[0041] The term “Ci-Ce alkyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms and refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl and the like.

[0042] The term “Cs-Cs cycloalkyl” refers to non-aromatic cyclic groups having from 5 to 8 carbon atoms, including cyclopentyl, cyclohexyl and the like. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl.

[0043] The terms “Cs-Cs heterocycle” or “Cs-Cs heterocyclyl” refer to a saturated or unsaturated cyclic alkyl group having from 3 to 8 ring atoms, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of heterocyclyl groups include oxirane (or ethylene oxide), pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, morpholinyl and the like.

[0044] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0045] The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1- 19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, gentisic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0046] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material which is included in the composition for a purpose other than pharmaceutical efficacy (this is not intended to exclude materials which may have some biological effect).

[0047] As used herein, "preventing" or "prevention" is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or condition (i.e., causing at least one of the clinical symptoms of the disease not to develop in an individual that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians. The skilled artisan will appreciate that "prevention" is not an absolute term. In particularly preferred embodiments, the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimize progression, of a symptom of a disease or condition as described herein. As such, the methods of the present invention have utility as treatments as well as prophylaxes.

[0048] The terms "treatment" or "treating" of a subject includes delaying, slowing, stabilising, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition. The term "treating" refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating. Treatment may not necessarily result in the complete clearance of a disease or disorder but may reduce or minimise complications and side effects of infection and the progression of a disease or disorder. The success or otherwise of treatment may be monitored by, amongst other things, physical examination of the individual, CT scan, MRI, or blood biomarkers.

[0049] The term “therapeutically-effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, or a treatment regime and the components thereof, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen.

[0050] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are a modified version of the denotations taken from Maehr J. Chem. Ed. 62, 114-120 (1985): simple lines provide no information about stereochemistry and convey only connectivity; if simple lines are used, both enantiomerically pure compounds are contemplated. Solid and broken wedges are used to denote the absolute configuration of a chiral element; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not necessarily denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of the indicated relative stereochemistry of indeterminate absolute configuration.

[0051] In the priority application 2024903670, AMP961 is referred to as Compound 3 and 3-rac; the names are used interchangeably for the same racemic compound. AMP962 is referred to as Compound 3a and is used interchangeably for the same enantiomer. AMP963 is referred to as Compound 3b and is used interchangeably for the same enantiomer.

[0052] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.Detailed description of the embodiments

[0053] The present inventors have surprisingly found that the modification of selected FAK inhibitors based on the class of substituted pyrimidines described in WO 2012 / 110774 show excellent activity for the inhibition of FAK. Deuteration or substitution of the ethylene bridge linking the pyrimidine and phenyl ring, or substitution at the acetamide group provides a FAK inhibitor with comparable activity to the highlyselective and potent FAK inhibitor, narmafotinib (one of the compounds described in WO 2012 / 110774).Compounds

[0054] In a first aspect of the invention there is provided a compound or pharmaceutically acceptable salt thereof according to Formula (I)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups; each of R2a, R2b, R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi-Cealkyl, or (i) taken together, R2aand R2bor R3aand R3bform a carbonyl group; or (ii) two of R2a, R2b, R3aor R3btogether form a Cs-Cs cycloalkyl ring or Cs-Cs heterocyclic ring;R4is selected from H, -CDs or Ci-Cealkyl;R5aand R5bare independently selected from H, D, F, OH, -Ci-Cealkyl or -OCi-Cealkyl; and wherein at least one of R2a, R2b, R3a, R3b, R5aor R5bis not H.

[0055] In a preferred embodiment of this aspect of the invention, R1may be -Me.

[0056] In a preferred embodiment of this aspect of the invention, R2aand R2bmay be independently selected from H, D, OH, or taken together, form a carbonyl group.

[0057] In a preferred embodiment of this aspect of the invention, R3aand R3bmay be independently selected from H, D, OH, or taken together, form a carbonyl group.

[0058] In a preferred embodiment of this aspect of the invention, R2aand R2bmay both be H.

[0059] In an alternative embodiment of this aspect of the invention, R2aand R2bmay both be D.

[0060] In a preferred embodiment of this aspect of the invention, one of R3aor R3bis OH and the other is H.

[0061] In an alternative embodiment of this aspect of the invention, each of R2a, R2b, R3aand R3bare D.

[0062] In an alternative embodiment of this aspect of the invention, one of R2aor R2band one of R3aor R3btogether form a Cs-Cs cycloalkyl ring; preferably one of R2aor R2band one of R3aor R3btogether form a cyclopropane ring.

[0063] In an alternative embodiment of this aspect of the invention, R3aand R3btaken together form a Cs-Cs cycloalkyl or a Cs-Cs heterocyclic ring; preferably, R3aand R3btaken together form a heterocyclic ring; more preferably R3aand R3btaken together from an oxirane ring.

[0064] In a preferred embodiment, R4may be selected from H or -CHs.

[0065] In a preferred embodiment, R5aor R5bmay be OH.

[0066] In an alternative aspect of the invention, there is provided a compound or pharmaceutically acceptable salt thereof according to Formula (la)wherein R1is selected from H, -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups;R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi-Cealkyl, or taken together, form a carbonyl group, a Cs-Cs cycloalkyl or a Cs-Cs heterocyclic ring; andR4is selected from H, -CDs or Ci-Cealkyl; and at least one of R3aand R3bis not H.

[0067] In a preferred embodiment of this aspect of the invention, R1may be -Me.

[0068] In a preferred embodiment of this aspect of the invention, at least one of R3aand R3bmay be OH.

[0069] In a preferred embodiment of this aspect of the invention, one of R3aor R3bis OH, and the other is H or D.

[0070] In a preferred embodiment, R4may be selected from H or -CHs.

[0071] In an alternative embodiment of this aspect of the invention, R3aand R3btaken together form a heterocyclic ring; more preferably R3aand R3btaken together from an oxirane ring.

[0072] In an alternative aspect of the invention, there is provided a compound or pharmaceutically acceptable salt thereof according to Formula (II)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups; andR3is selected from OH, or -OCi-Cealkyl; andR4is selected from H or Ci-Cealkyl.

[0073] In an alternative embodiment of this aspect, the carbon attached to R3may be of absolute configuration:

[0074] In an alternative embodiment of this aspect, the carbon attached to R3may be of absolute configuration:

[0075] In one embodiment of each of these aspects and embodiments of the invention, said compound may be greater than 90% enantiomerically pure.

[0076] In another embodiment of each of these aspects and embodiments of the invention, said compound may be greater than 95% enantiomerically pure.

[0077] In yet another embodiment of each of these aspects and embodiments of the invention, said compound may be greater than 99% enantiomerically pure.

[0078] The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below. In the example shown below, a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, e.g., the R enantiomer. ee=(90-10) / 100=80%.

[0079] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. Some compositions described herein contain an enantiomeric excess of at least about 50%, 75%, 90%, 95%, or 99% of one enantiomer. For example, compositions may contain an enantiomeric excess of the S enantiomer over the R enantiomer, or alternatively, compositions may contain an enantiomeric excess of the R enantiomer over the Senantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of at least about 50%, 75%, 90%, 95%, or 99% of one enantiomer.

[0080] For instance, an isomer / enantiomer can, in some embodiments, be provided substantially free of the corresponding enantiomer, and can also be referred to as "optically enriched," "enantiomerically enriched," "enantiomerically pure" and "non- racemic," as used interchangeably herein. These terms refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1 :1 by weight). For example, an enantiomerically enriched preparation of the S enantiomer, means a preparation of the compound having greater than about 50% by weight of the S enantiomer relative to the R enantiomer, such as at least about 75% by weight, further such as at least about 80% by weight. In some embodiments, the enrichment can be much greater than about 80% by weight, providing a "substantially enantiomerically enriched," "substantially enantiomerically pure" or a "substantially non- racemic" preparation, which refers to preparations of compositions which have at least about 85% by weight of one enantiomer relative to other enantiomer, such as at least about 90% by weight, and further such as at least 95% by weight. In certain embodiments, the compound provided herein is made up of at least about 90% by weight of one enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of one enantiomer.

[0081] In a preferred embodiment of this aspect of the invention, R1may be -Me.

[0082] In a preferred embodiment of this aspect of the invention, R3is OH.

[0083] In a preferred embodiment of this aspect of the invention, R4may be H or -CH3.

[0084] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:

[0086] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:

[0087] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:

[0088] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:

[0089] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:

[0090] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:

[0091] In an alternative aspect, and in preferred embodiments of previous aspects, the invention provides a compound selected from:Formulations

[0092] While it is possible for the compounds of the present invention to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one compound or a pharmaceutically acceptable salt thereof, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.

[0093] Thus, in an alternative aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.

[0094] Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0095] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0096] General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts suchas “Handbook of Pharmaceutical salts” P. H. Stahl, C. G. Wermuth, 1st edition, 2002, Wiley-VCH and S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0097] Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

[0098] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product.

[0099] Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges (or lozenges), granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.

[0100] Formulations suitable for oral administration (e.g. by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the compound or pharmaceutically acceptable salt; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

[0101] A tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxy methyl cellulose); surface-active or dispersing or wetting agents (e.g. sodium lauryl sulfate); and preservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid).Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the FAK inhibitor therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0102] Formulations suitable for parenteral administration (e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound or pharmaceutically acceptable salt in the solution is from about 1 ng / ml to about 10 pg / ml, for example from about 10 ng / ml to about 1 pg / ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, 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. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.Combination products and therapies

[0103] In an alternative aspect, the composition may be used with, or formulated with, one or more additional therapeutic agents to create a combination therapeutic. The combination may also be a combination therapy involving, in addition to the administration of the compounds of the invention, combining that treatment with complementary therapies such as conventional surgery or radiotherapy or chemotherapy.

[0104] In one embodiment, the at least one additional therapeutic agent may comprise an anti-cancer agent. Preferably the anti-cancer agent is be selected from one or more of gemcitabine, paclitaxel, docetaxel, cisplatin, oxaliplatin, irinotecan, fluorouracil or leucovorin, or a combination thereof such as FOLFIRINOX. But the skilled person would appreciate that the at least one anti-cancer agent may include one or more of the following categories of anti-tumour / anti-cancer agents and complimentary therapies:(i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil, capecitabine and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and docetaxel (Taxotere) and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); cytotoxic agents may further be delivered to tumour tissue though attachment to cancer targeting species (for example antibody-drug conjugates such as Trastuzumab emtansine (Kadcyla®), Enfortumab vedotin (Padcev®), Fam-trastuzumab deruxtecan (Enhertu®), Sacituzumab govitecan (Trodelvy®), Mirvetuximab soravtansine (Elahere®));(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-alpha reductase such as finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitors such as dasatinib, bosutinib and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparinase);(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab or the anti erbB1 antibody cetuximab [Erbitux]); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family for example gefitinib, erlotinib and Osimertinib, erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and / or AKT kinases, such as trametinib, binimetinib and avutometinib, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, MET inhibitors, JAK inhibitors (for example ruxolitinib and momelotinib), IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors, mutant KRAS inhibitors (for example adagrasib, sotorasib, MRTX1133, BI-2493 and RMC-6236) and cyclin dependent kinase inhibitors such as CDK2 inhibitors, CDK4 inhibitors, CDK4 / 6 inhibitors, CDK7 and / or CDK9 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as sunitinib and pazopanib, and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin)];(vi) vascular damaging agents such as Combretastatin A4;(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene or cell therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and(ix) immunotherapy approaches, include a range of strategies designed to enhance the immune system's ability to recognise and attack tumour cells such as immune checkpoint inhibitors (for example anti-PD-1 , anti-PD-L1 , and anti-CTLA-4 antibodies), adoptive cell therapies (including CAR T cells, CAR-NK cells, and CAR-NKT cells), and cytokine-based therapies (such as interleukin 2, interleukin 4, and granulocyte macrophage colony stimulating factor); methods to increase tumour immunogenicity, that involve for example the use of STING agonists, transfected dendritic cells, cytokine- transfected tumour cell lines, and anti-idiotypic antibodies, including antibody-drug conjugates;(x) inhibitors of epigenetic processes such as HDAC inhibitors (for example Vorinostat (SAHA), romidepsin, belinostat and Panobinostat); DNMT inhibitors such as Azacitidine and Decitabine; EZH2 inhibitors such as tazemetostat; BRD4 inhibitors such as molibresib (GSK525762), birabresib (OTX015 / MK-8628), INCB054329, AZD5153, and ABBV-744; and xi) Anti-fibrosis combinations.

[0105] In some embodiments, any one of the above-mentioned inhibitors may be a protein degrader. For example, the inhibitor may be a protein degrader such as a proteolysis-targeting chimera (ProTACs) or molecular glue. Other examples of protein degraders are contemplated.

[0106] In one embodiment, the at least one additional therapeutic agent may comprise an additional anti-fibrosis agent. Preferably the anti-fibrosis agent may be selected from nintedanib (Ofev®), Pirfenidone (Esbriet®), lysyl oxidase inhibitors, ROCK inhibitors or obeticholic acid.

[0107] Preferably, the formulation of the compound is suitable for oral administration that can be administered sequentially with an additional therapeutic agent or at the same time (i.e. concurrent administration) as the additional therapeutic agent but as its own formulation.

[0108] In one embodiment involving combination therapy, the composition of the invention and an additional therapeutic agent can be administered in each of the embodiments of the invention in the following ways:the compound or composition may be administered in a pulsed-dosing regimen that is ceased prior to commencing treatment with the additional therapeutic agent.• the compound or composition may be administered in a pulsed-dosing regimen prior to commencing treatment with the additional therapeutic agent, and continued once the treatment with the additional therapeutic agent commences.• the compound or composition may be administered concurrently with the additional therapeutic agent and may or may not be continuously administered throughout the treatment cycle.• the compound or composition may continue to be administered once administration of the additional therapeutic agent has ceased (ie maintenance setting).Methods of use

[0109] The FAK inhibitors of the invention are useful for treating proliferative and fibrotic diseases. In some instances, the proliferative disease and fibrotic disease is one in the same. For example, pancreatic cancer is a fibrous cancer.

[0110] In one aspect of the invention, there is provided a method of inhibiting Focal Adhesion Kinase (FAK) in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of the herein disclosed embodiments.

[0111] In an alternative embodiment of the invention, there is provided a method of treating a proliferative and / or a fibrotic disease in a subject in need thereof, comprising administering to said subject the compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments.

[0112] In an alternative embodiment of the invention, there is provided the use of a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments in the manufacture of a medicament for treating a proliferative and / or a fibrotic disease.

[0113] In an alternative aspect of the invention, there is provided a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments for use in the treatment of a proliferative and / or a fibrotic disease.

[0114] In some embodiments, where the proliferative disease is a fibrotic cancer, the proliferative disease and fibrotic disease the same.

[0115] The subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutan, gibbon), or a human.Cancer

[0116] In a preferred embodiment of the invention, the proliferative disease may be cancer. The cancer may be selected from a solid cancer, including but not limited to bone cancer, brain stem glioma, breast cancer, cancer of the adrenal gland, cancer of the anal region, cancer of the bladder, cancer of the endocrine system, cancer of the oesophagus, cancer of the head or neck, cancer of the kidney or ureter, cancer of the liver, cancer of the parathyroid gland, cancer of the penis, cancer of the small intestine, cancer of the thyroid gland, cancer of the urethra, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, carcinoma of the vagina, carcinoma of the vulva, colon cancer, cutaneous or intraocular melanoma, fibrosarcoma, lung cancer, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, primary CNS lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, sarcoma of soft tissue, skin cancer, spinal axis tumours, solitary fibrous tumour, stomach cancer and uterine cancer. More preferably, the cancer is selected from pancreatic cancer, ovarian cancer, colon cancer, rectal cancer, fibrosarcoma or solitary fibrous tumours.

[0117] The compounds or compositions of the present invention can be used as in the treatment of proliferative diseases, in particular as an anticancer agent. One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.

[0118] Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin. In each of the above treatment options, the subject may be treatment naive, or may have had previous treatments, such as chemotherapy treatments.Fibrotic diseases and conditions

[0119] Deposition of collagen, fibrin and other components of the extracellular matrix is an integral part of wound healing and normal tissue repair. However, in the setting of chronic inflammatory diseases, the persistent activity of myofibroblast cells recruited to the site of inflammation or differentiated from mesenchymal precursors can lead to excessive and sustained fibrous connective tissue deposition resulting in organ scarring, malfunction and death.

[0120] FAK has been shown to contribute to multiple mechanisms underlying fibrosis and taken together, this evidence provides a strong biological rationale for targeting FAK for the treatment and prevention of fibrotic diseases of the lung and other tissues.

[0121] In a preferred embodiment of the invention, the proliferative disease may be a fibrotic cancer. Preferably, the cancer may be selected from a solid cancer including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, endometrial, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, skin and bile duct.

[0122] In an alternative preferred embodiment of the invention the fibrotic disease may be selected from pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH), chronic viral infection especially HCV infection, Crohn’s disease, endometriosis and chronic kidney disease.

[0123] Idiopathic pulmonary fibrosis (IPF) is a rare progressive disease, mainly in older adults and is characterized by chronic and progressive fibrosing of the lung interstitium leading to exertion-related breathlessness, cough, dyspnea and worsening lung function.

[0124] Furthermore the compounds, compositions and combinations of the invention may be useful in managing coronavirus infections as data from previous coronavirusinfections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing and / or treating fibrosis after SARS-CoV-2 infection.

[0125] Kidney or renal fibrosis, characterised by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in chronic kidney disease (CKD). However, at present no antifibrotic therapies against CKD exist. Accordingly, in one preferred embodiment of the invention, there is provided a method of treating chronic kidney disease (CKD) in a subject comprising administering to said subject a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the herein disclosed embodiments, or a combination therapy according to any one of the herein disclosed embodiments.Dosing and dosage of the compounds

[0126] It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

[0127] Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment.

[0128] Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used fortherapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.

[0129] In general, a suitable dose of a compound of the present invention is in the range of about 100 pg to about 250 mg per kilogram body weight of the subject per day.Process for preparing compounds of the invention

[0130] In an alternative aspect of the invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt thereof, having the structure:including contacting a compound having the structure:with a reducing agent capable of reducing the carbonyl to an alcohol to provide a compound having the structure:

[0131] In a preferred embodiment of the process, the reducing agent may be selected from one or more hydride sources. Preferably, the hydride source may be an alkalimetal borohydride, more preferably, sodium borohydride. Other reducing agents known in the art are contemplated.

[0132] In an alternative embodiment of the process, the reducing agent may be selected from a chiral hydride source. Preferably the chiral hydride source is a chiral borohydride, chiral alkylborohydride, or hydrogen with a chiral transition metal catalyst. Other chiral hydride sources known in the art are contemplated. Use of a chiral hydride may provide enantiopure alcohols which do not need chiral separation.

[0133] As used herein “chiral hydride source” refers to a reagent or combination of reagents in which a hydride ion (H“) is delivered to a compound such that one enantiomeric form is formed in preference to the other.

[0134] In a preferred embodiment of the process, the process may further include the step of converting a compound having the structure:with formaldehyde and a hydride source to provide a compound having the structure:

[0135] In some embodiments of the process, the process may further include the step of chiral separation to separately provide two enantiomers of the compound having the structure:

[0136] In an alternative aspect of the invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt thereof, having the structure:including contacting a compound having the structure:with a sulphur ylide to provide a compound having the structure:

[0137] One example of a reaction between an alkene and a sulphur ylide is theJohnson-Corey-Chaykovsky reaction. The person skilled in the art would be aware of the various conditions that may be used in this reaction. For example, the deprotonation of a sulfonium halide or trimethylsulfoxonium iodide in the presence of a base (egsodium hydride) to form a suitable sulphur ylide which is contacted with the desired alkene.

[0138] In a preferred embodiment of the above aspects, the process may further include the step of converting a compound having the structure:with formaldehyde and a hydride source to provide a compound having the structure:

[0139] In an alternative aspect of the invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt thereof, having the structure:including contacting a compound having the structure:with a sulphur ylide to provide a compound having the structure:

[0140] One example of a reaction between a carbonyl and a sulphur ylide is the Corey- Chaykovsky reaction. The person skilled in the art would be aware of the various conditions that may be used in this reaction. For example, the deprotonation of a sulfonium halide or trimethylsulfoxonium iodide in the presence of a base (eg sodium hydride) to form a suitable sulphur ylide which is contacted with the desired carbonyl.

[0141] In a preferred embodiment of the above aspects, the process may further include the step of converting a compound having the structure:with formaldehyde and a hydride source to provide a compound having the structure:

[0142] Several hydride sources are known in the art and the person skilled in the art would know of suitable hydride sources to form the above compounds described in each of the above aspects using this method.

[0143] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Examples

[0144] The invention will now be described by reference to the following non-limiting examples.

[0145] In the priority application 2024903670 and in some sections of this application, AMP961 is referred to as Compound 3 and 3-rac; the names are used interchangeably for the same racemic compound. AMP962 is referred to as Compound 3a and is used interchangeably for the same enantiomer. AMP963 is referred to as Compound 3b and is used interchangeably for the same enantiomer.Example 1 - materials and methods

[0146] Deionised water, methanol, ethanol, isopropyl alcohol, n-hexane, diethylamine, formic acid, acetonitrile, dichloromethane (DCM), 1 ,4-dioxane, ethyl acetate, DL-malic acid, diisopropylethylamine, ammonium acetate, ammonium hydroxide, sodium carbonate (Na2COs), trifluoroacetic acid (TFA), PdCl2(PPh3)2, Pd / C, NaBFU, NaBD4, formaldehyde, d2-paraformaldehyde, NaBHsCN, B2(Cat)2, DMSO-de, CD3OD, and D2O were obtained from commercial sources.Chemical characterisation

[0147] Chiral HPLC was performed using an Agilent 1100 chiral HPLC equipped with a CHIRALCEL®OZ-H column of column size of 0.46 cm I.D. x 25 cm L x 5 pm. 5 pL of a 1.3 mg / mL sample in 50% methanol and 50% ethanol was injected into the column and a mobile phase of n-hexane / ethanol / diethylamine (75 / 25 / 0.1 v / v / v) was used. The flow rate was set at 1.0 mL / min and the temperature was 35°C.

[0148] Analytical thin-layer chromatography was performed on Merck silica gel 60F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or acidic anisaldehyde or a basic potassium permanganate dip.

[0149] Flash chromatography was performed using either a Teledyne Isco CombiFlash Rf purification system using standard RediSep® cartridges or a Biotage Isolera purification system using either Grace or Biotage silica cartridges.

[0150] Where necessary, anhydrous solvents were prepared using a Braun purification system or purchased from Sigma-Aldrich.

[0151] 1H NMR spectra were recorded on either a Bruker Avance DRX300 (300 MHz), a Bruker Ultrasheild plus (400 MHz), QOne AS400 (400 MHz) spectrometer or a Varian Unity Inova 600 (600 MHz) spectrometer in either DMSO-de or CD3OD at 25°C. The multiplicity of a signal is designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz.

[0152] 13C NMR were recorded on a Bruker Avance DRX300 (75 MHz), a Bruker Ultrasheild plus (100 MHz) or a Varian Unity Inova 600 (150 MHz) spectrometer in a broad band decoupled mode in either DMSO-de or CD3OD at 25°C.

[0153] LC / MS data was generated using either a Finnigan LCQ Advantage Max (LCMS-A), a Waters ZQ 3100 system (LCMS-B) or an Agilent 6100 Series Single Quad LC / MS (LCMS-C) according to the following methods:LCMS Method A (LCMS-A)Instrument: Finnigan LCQ Advantage Max Pump: Finnigan Surveyor LC Pump Finnigan Surveyor Autosampler Finnigan Surveyor PDA DetectorLC conditions:Reverse Phase HPLC analysisColumn: Gemini 3p C18 20x4.0mm 110AInjection Volume 10pLSolvent A: Water 0.1 % Formic AcidSolvent B: Acetonitrile 0.1 % Formic AcidGradient: 10-100% B over 10min Detection. 00-600nmMS conditions:Ion Source: Ion trapIon Mode: ES positiveTemp: 300°CCapillary V- 25Detection: Ion countingScan Range: 80-1000A muScan Time: 0.2 secAcquisition time: 10minLCMS Method B (LCMS-B)Instrument: Waters ZQ 3100 - Mass DetectorWaters 2545-PumpWaters SFO System Fluidics OrganizerWaters 2996 Diode Array DetectorWaters 2767 Sample ManagerLC conditions:Reverse Phase HPLC analysisColumn: XBridge TM C18 5pm 4.6x100mmInjection Volume 10pLSolvent A: Water 0.1 % Formic AcidSolvent B: Acetonitrile 0.1 % Formic AcidGradient: 10-100% B over 10minFlow rate: 1.5 mL / minDetection: 100-600nmMS conditions:Ion Source: Single-quadrupoleIon Mode: ES positiveSource Temp: 150°CDesolvation Temp: 350°CDetection: Ion countingCapillary (KV)-3.00Cone (V): 30Extractor (V): 3RF Lens (V): 0.1Scan Range: 100-1000 AmuScan Time: 0.5 secAcquisition time: 10minGas FlowDesolvation L / hr-650LCMS Method C (LCMS-C)Instrument: Agilent 6100 Series Single Quad LC / MSAgilent 1200 Series HPLCPump: 1200 Series G1311A Quaternary pumpAutosampler: 1200 Series G 329A Thermostatted AutosamplerDetector: 1200 Series G1314B Variable Wavelength DetectorLC conditions:Reverse Phase HPLC analysisColumn: Luna C8(2) 5p 50x4.6mm 100AColumn temperature: 30°CInjection Volume: 5pLSolvent A: Water 0.1 % Formic AcidSolvent B: Acetonitrile 0.1 % Formic AcidGradient: 5-100% B over 10minDetection: 254 nm or 214 nmMS conditions:Ion Source: QuadrupoleIon Mode: Multimode-ESDrying gas temp: 300°CVaporizer temperature: 200°CCapillary voltage (V): 2000 (positive)Capillary voltage (V): 4000 (negative)Scan Range: 100-1000Step size: 0.1 secAcquisition time: 10minLCMS - Chiral AssayLC MS Parameters:Strong wash 50% I PAMP-A: Amm. acetate 10mM, 0.1% Ammonium hydroxideMP-B: MeOHColumn: LUX Cellulose-1, 150 x 4.6 mm, 3 pm (Part number: 00F-4458-B0) LCC-726Starting conditions: 65% BFlow rate 0.35 mL / minLC-MS (Agilent-S12-3min):LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Agilent EclipsePlus RRHD C18, 1.8pm, 3.0x50 mm. Mobile phase: A: 0.05% Formate in water (v / v), B: 0.05% Formate in MeCN(v / v). Flow Rate: 0.8 mL / min at 25 °C. Detector: 214 nm, 254 nm. Gradient stop time, 3 min. Timetable:HPLC (Agilent-1260- A2):LC: Agilent Technologies 1200 series, Binary Pump, Diode Array Detector. Column Temperature: 35°C; Acquisition wavelength: 214 nm, 254 nm; Mobile Phase A: 0.1% TFA in water (v / v);Mobile Phase B: CAN; Run time: 18.01 min; Post time: 2 min; Flow rate: 1.0 ml / min, timetable:X-ray powder diffraction (XRPD)

[0154] X-ray powder diffraction analysis was carried out on a PANalytical Xpert Pro diffractometer equipped with a X’Celerator detector. The sample was prepared on a zero background holder and run in reflectance mode between 3 and 45 °20 employing Cu K radiation. The analysis was carried out using a step size of 0.008°29 and scan step time of 29.8s, with generator settings of 40 kV and 40mA.Single crystal X-ray diffraction (SCXRD)

[0155] For SCXRD analysis, crystals were mounted on a mylar loop in Paratone oil.Data were collected using a XtaLAB Synergy R, HyPix-Arc 100 diffractometer equipped with an Oxford Cryosystems Cryostream 1000 low temperature device operating at T = 100.00(10) K. Data were measured using co scans with Cu Ka radiation. The diffraction pattern was indexed and the total number of runs and images was based on the strategy calculation from the program CrysAlisPro 1.171.43.143a (Rigaku OD, 2024). The maximum resolution that was achieved was 0 = 77.575° (0.79 A).

[0156] The unit cell was refined using CrysAlisPro 1.171.43.143a (Rigaku OD, 2024). Data reduction, scaling and absorption corrections were performed using CrysAlisPro 1.171.43.143a (Rigaku OD, 2024). A multi-scan absorption correction was performed using CrysAlisPro 1.171.43.143a (Rigaku Oxford Diffraction, 2024) Empirical absorption correction using spherical harmonics, implemented in SCALES ABSPACK scaling algorithm.

[0157] The structure was solved and the space group determined by the SheIXS (Sheldrick, 2008) structure solution program using direct methods and refined by full matrix least squares minimisation on F2 using version 2018 / 3 of ShelXL 2018 / 3 (Sheldrick, 2015). All non-hydrogen atoms were refined anisotropically. Most hydrogen atom positions were calculated geometrically and refined using the riding model, but some hydrogen atoms were refined freely.

[0158] O- and N-bound H atoms were refined using geometric restraints.

[0159] Experimental absorption process details: CrysAlisPro 1.171.43.143a (RigakuOxford Diffraction, 2024) using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.

[0160] Determination of absolute structure (Hooft parameter) was using Bayesian statistics on Bijvoet differences using Olex2.Example 2 - general schemes

[0161] Schemes below provide exemplary synthetic methods for the preparation of compounds provided herein. A person of ordinary skill in the art will understand that similar methods may be employed to prepare the compounds provided herein. In other words, a person of ordinary skill in the art will recognise that suitable adjustments to reagents, reaction conditions, reaction sequences, purification methods and chiral separation conditions may be employed to prepare a desired embodiment. The reactions may be scaled upwards or downwards to suit the amount of material to be prepared.

[0162] In one embodiment, a compound of formula 1-1 may be prepared according to scheme 1 .Scheme 1

[0163] In one embodiment, a suitable precursor compound is reacted with trifluoroacetic acid (TFA) in dichloromethane (DCM) at room temperature to render a compound of formula 1-1.

[0164] The precursor compound described in Scheme 1 may be formed according to the reaction described below in Scheme 2.Scheme 2

[0165] In one embodiment to produce the compound provided in Scheme 2, a precursor compound (which can be synthesised as described in WO 2012110774) is contacted with 2-(2-ethynylphenyl)acetamide in a Sonogashira palladium cross-coupling reaction to produce the product. The person of ordinary skill in the art would appreciate the numerous methods for palladium cross-coupling reactions that could be employed to prepare such compounds.Scheme 3

[0166] In another embodiment, the compound of formula 1-1 is reacted with a suitable hydride source (for example NaBH4) to render compound I-2 (Scheme 3). Compound I- 2 is formed as a racemic mixture, which may be separated using chiral HPLC to provide single enantiomers. In some cases, a chiral hydride source may be used to selectively provide one enantiomer of compound I-2. Other methods of separating enantiomers of a compound (such as the use of resolving agents to alter the physical properties of the enantiomers so that they can be separated) are envisaged.Scheme 4

[0167] In another embodiment, the compound of formula I-2 is reacted with formaldehyde and a suitable hydride source (for example NaBHsCN) to render compound I-3 (Scheme 4). In an alternative embodiment, compound I-3 may be generated from the compound of formula I-2 using a suitable transition metal catalyst and molecular hydrogen as the hydride source (for example 37% CH2O, Pd / C, H2, 1 atm, MeOH). Compound I-3, if compound I-2 was not purified by chiral HPLC, is formed as a racemic mixture. The racemic mixture of Compound I-3 may be separated using chiral HPLC to provide single enantiomers. Other methods of separating enantiomers of a compound (such as the use of resolving agents to alter the physical properties of the enantiomers so that they can be separated) are envisaged.Scheme 5

[0168] In another embodiment, a suitable precursor compound is reacted with deuterium oxide in the presence of bis(catecholato)diboron and palladium on carbon to render a reduced deuterated compound I-4 (Scheme 5). Other methods to reduce alkynes are contemplated to perform this transformation, but with the hydrogen source that would be typically used replaced with its deuterated counterpart.

[0169] In a further embodiment, the compound of I-4 is reacted with a suitable acid source to deprotect the piperidine nitrogen and remove the Boc (-C(O)OtBu) group, thereby forming a compound of formula I-5. The person skilled in the art would be ableto easily determine suitable acid groups for deprotecting an amine in this manner. For example, trifluoroacetic acid may be suitable.

[0170] In another embodiment, the compound of formula I-5 can be reacted with d2- paraformladhyde and a suitable deuteride source (such as NaBD4) to produce a compound of formula I-6 (Scheme 6). Compound I-6 as shown in Scheme 6 is isotopically enhanced so that all 7 of the shown deuterium atoms can be present (dyl- 6). Compounds with 3 or 4 deuterium atoms respectively (ie compounds where only one of Scheme 5 or Scheme 6 are performed with deuterated reagents) can also be formed, thereby forming ds-l-6 (with only the piperidine methyl being deuterated) and d4-l-6 (with only the ethylene linker being deuterated). Isotopically enriched compounds where incomplete incorporation of deuterium are also envisaged, for example, where only 1 , 2 or 3 deuterium atoms are incorporated on the ethylene bridge. In addition, compounds that are further isotopically enriched are contemplated, for example where R1= -CDs. Such compounds, including those envisaged where R1= -CDs can be made from an isotopically enriched starting material.Scheme 7

[0171] In a further embodiment, compound 1-1 may be reacted with a sulphur ylide such as (CH3)2S=CH2to form an epoxide in a Corey-Chaykovsky reaction (Scheme 7). Ylides may be formed in situ from the reaction of sulfonium halides with strong bases, for example sodium hydride. The person skilled in the art would be able to determine alternative conditions for this reaction, such as using alternative ylides, or using alternative bases to form said ylides in situ. Following formation of the epoxide, the compound may be reacted to methylate the piperidine nitrogen under similar conditions to those described by Scheme 4.Scheme 8

[0172] In another embodiment, the group linking the phenyl ring and pyrimidine ring may be a cycloalkyl ring. The synthetic route to an example compound containing a cyclopropane ring is shown in Scheme 8. In a first step, the alkyne group of a precursor compound as described above is reduced to the alkene. Several synthetic methods are known for this transformation, for example alkali metal in ammonia (sodium shown in scheme 8), or Lindlar’s catalyst with hydrogen gas. The alkene may then be reacted with a sulphur ylide to form the cyclopropane ring in a Johnson-Corey-Chaykovsky reaction. The person skilled in the art would be able to determine alternative conditions for this reaction, such as using alternative ylides, or using alternative bases to form saidylides in situ. Following formation of the cyclopropane ring, the piperidine NH is deprotected by removing the Boc group. Suitable conditions for deprotecting the NH would be known to the person skilled in the art, for example, TFA in DCM. Following deprotection, the final compound is formed through methylation of the piperidine nitrogen in a similar fashion to that described by Scheme 4.Scheme 9

[0173] In another embodiment, substitution of the CH2 portion of the acetamide moiety on the phenyl ring is contemplated. To synthesise compounds with this substitution, precursor alkynes may be synthesised according to scheme 9. Starting from commercially available starting materials like 2-(2-iodophenyl)propanoic acid (as shown) or 2-hydroxy-2-(2-iodophenyl)acetic acid, these compounds may be reacted in a Sonogashira coupling reaction with a silyl acetylene (preferably TMS acetylene), followed by deprotection of the terminal alkyne by removing the silyl group with TBAF. Other suitable starting materials are contemplated. The compounds formed from this reaction may then be used in subsequent steps.

[0174] In further embodiments, the subsequent steps may include palladium crosscoupling as described in Scheme 2 (Scheme 10).Scheme 10

[0175] In further embodiments, the subsequent steps may further include reduction of an alkyne (formed as per Scheme 10) to a carbonyl or alkane as described above in Scheme 1 and 5 respectively. Although Scheme 5 uses deuterated reagents, hydrogen alternatives may be used and are contemplated. Deprotection and methylation of the piperidine nitrogen is also contemplated and may be achieved with similar conditions to those already described in Scheme 4 and Scheme 5.Example 3 - compounds of the invention

[0176] Representative compounds of the invention were prepared in the following examples utilizing the general schemes above and procedures below. 2-(2-((2-methoxy-4-(piperidin-4-vl)phenyl)amino)-5-idin-4-

[0177] 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)acetyl)phenyl)acetamide was prepared according to Scheme 1.

[0178] To a solution of tert-butyl 4-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (5 g, 8.21 mmol) in DCM (15 mL) was added TFA (9.5 mL) at 0°C. The solution was stirred at room temperature overnight. The solution was concentrated to give a crude. The crude was diluted with H2O (60 mL), adjusted to pH=8 with a saturated sodium bicarbonate solution and extracted with DCM (100 mL x 3). The organic layers were combined and washed with brine (150 mL), dried over Na2SC>4 and concentrated to give a crude (4.77g, 100% yield) which was used without purification. LCMS (Waters-QDA-P2): Rt = 1.027 min; m / z calculated for [M+H]+ = 528.57, find [M+H]+= 528.57.1H NMR (400 MHz, CD3OD) 5 ppm: 8.34 (s, 1 H), 7.52-7.33 (m, 5H), 7.01-6.91 (m, 2H), 3.90-3.89 (m, 3H), 3.69 (s, 2H), 3.52-3.48 (m, 3H), 3.17-3.11 (m, 3H), 2.99-2.93 (m, 1H), 2.15 (d, J = 12 Hz, 2H), 1.96-1.87 (m, 2H).Preparation of 2-(2-(1-hvdroxy-2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2a and 2b)

[0179] 2-(2-(1-hydroxy-2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide was prepared according to Scheme 3.

[0180] To a solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)acetyl)phenyl)acetamide (4.32 g, 8.2 mmol) in MeOH (50.7 mL) at 0°C was added NaBH4 (929 mg, 24.6 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with H2O (60 mL) and extracted with DCM (100 mL x 3). The organic layers were combined and washed with brine (150 mL), dried over Na2SC>4 and concentrated to give a crude (4.2 g, 100%) which was used without further purification. LCMS (Waters-QDA-P2): Rt = 1.08 min; m / z calculated for [M+H]+ = 530.2, find [M+H]+= 530.2.1H NMR (400 MHz, CD3OD) 5 ppm: 8.55 (s, 1 H), 8.07 (d, J = 8 Hz, 1 H), 7.57 (d, J = 4 Hz, 1 H), 7.34-7.25 (m, 3H), 6.94 (d, J = 4Hz, 1 H), 6.91 (dd, J = 4Hz, 8 Hz, 1 H), 5.75 (dd, J = 4 Hz, 8Hz, 1 H), 3.93 (s, 3H), 3.76-3.70 (m, 2H), 3.35-3.54 (m, 1 H), 3.28 (d, J = 8Hz, 1 H), 3.16-3.11 (m, 1 H), 2.97-2.90 (td, J = 4 Hz, 8Hz, 2H), 2.82-2.76 (m, 1 H), 2.00 -1.96 (m, 2H), 1 .86- 1.75 (m, 2H).Preparation of 2-(2-(1-hydroxy-2-(2-((2-methoxy-4-(1-methylpiperidin-4- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (3a and 3b; herein also referred to as AMP962 and AMP963 respectively)

[0181] 2-(2-(1-hydroxy-2-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide was prepared according to Scheme 4.

[0182] To a solution of 2-(2-(1-hydroxy-2-(2-((2-methoxy-4-(piperidin-4- yl)phenyl)amino) -5-(trifluoro methyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (4.2 g, 8 mmol) in MeOH (100 mL) was added a solution of 37% HCHO in H2O (3.25 g, 0.04 mol) at room temperature. The reaction was stirred for 30 minutes then NaBHsCN (997 mg, 16 mmol) was added to the solution. Stirring was continued for 2 hours then the reaction was quenched with H2O (150 mL), extracted with DCM (200 mL x 3). The organic layers were combined and washed with brine (300 mL), dried over Na2SC>4 and concentrated. The residue obtained was purified by silica gel column (DCM / MeOH / NH3.H2O=100 / 5 / 1 , v / v / v) to give the desired product (720 mg, 17% yield over three steps) as a white solid. The desired product (700 mg) was purified by chiral prep-HPLC to give 210.9 mg Compound 3a (also referred to as AMP962) and 209 mg Compound 3b (also referred to as AMP963).

[0183] Compound 3 (also referred to as AMP961) is present as a racemic mixture, due to the chiral center on the carbon bearing the hydroxyl group on the ethylene bridge. HPLC chiral separation was used to separate the racemate into its two individual enantiomers, compound of formula (3a / AMP962) and compound of formula (3b / AMP963), where the compound of formula (3a) is the enantiomer that eluted first on a HPLC chromatogram, and the compound of formula (3b) is the enantiomer that eluted second on a HPLC chromatogram. The purity of the compound of formula (3a) and the compound of formula (3b) were each measured to be greater than 99%.

[0184] NMR data for compound 3 (Racemate):1H NMR (400 MHz, CD3OD) 5 ppm: 8.54 (s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.33-7.25 (m, 3H), 6.93 (s, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 5.76 (d, J = 9.2 Hz, 1 H), 3.92 (s, 3H), 3.75-3.67 (m, 2H), 3.28 (d, J = 8Hz, 1 H), 3.16-3.11 (m, 1 H), 3.03-3.00 (d, J = 11.6 Hz, 2H), 2.59-2.53 (m, 1 H), 2.34 (s, 1 H), 2.21-2.14 (m, 2H), 1.90-1.80 (m, 4H).

[0185] Data for compound 3a / AMP962: LCMS (Agilent-S12): Rt = 1.066 min; m / z calculated for [M+H]+ =544.2, find [M+H]+= 544.2. HPLC (Agilent-1260-A2): Rt: 7.35 min, 100% purity.1H NMR (400 MHz, CD3OD) 5 ppm: 8.54 (s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.33-7.25 (m, 3H), 6.93 (s, 1 H), 6.90 (d, J = 8.4 Hz, 1 H),5.76 (d, J = 9.2 Hz, 1 H), 3.92 (s, 3H), 3.75-3.67 (m, 2H), 3.28 (d, J = 8Hz, 1 H), 3.16-3.11 (m, 1 H), 3.03 (d, J = 11.6 Hz, 2H), 2.59-2.53 (m, 1 H), 2.34 (s, 1 H), 2.21-2.16 (m, 2H), 1.90-1.79 (m, 4H).

[0186] Data for compound 3b / AMP963: LCMS (Agilent-S12): Rt = 1.07 min; m / z calculated for [M+H]+ =544.2, find [M+H]+= 544.2. HPLC (Agilent-1260-A2): Rt: 7.37 min, 100% purity.1H NMR (400 MHz, CD3OD) 5 ppm: 8.54 (s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8 Hz, 1 H), 7.32-7.25 (m, 3H), 6.93 (s, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 5.76 (d, J = 9.2 Hz, 1 H), 3.92 (s, 3H), 3.76-3.67 (m, 2H), 3.28 (d, J = 8.8 Hz, 1 H), 3.16- 3.11 (m, 1 H), 3.04 (d, J = 11.2 Hz, 2H), 2.60-2.54 (m, 1 H), 2.35 (s, 1 H), 2.23-2.16 (m, 2H), 1.90-1.80 (m, 4H).

[0187] Chiral HPLC Ret time = 11.409 and 14.715 minutes. Enantiopurity of both enantiomers was >99%.

[0188] tert-butyl 4-(4-((4-(2-(2-(2-amino-2-oxoethyl)phenyl)ethyl- 1 ,1 ,2, 2-d4)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate was prepared according to Scheme 5.

[0189] A solution of tert-butyl 4-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5- (trifluoro methyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1 -carboxylate (500 mg) in a mixture of DCM (1 mL), methanol-d4 (5 mL) and D2O (1 mL) was stirred at RT for 2 mins and the solvent removed three times to deuterate the exchangeable hydrogens. Pd / C (50 mg) was wetted with D2O (2 mL) and the D2O removed twice. A solution of the starting materials (500 mg, 0.82 mmol) and B2(cat)2 (605 mg, 2.55 mmol) in a mixture of DCM (1 mL), methanol-d4 (5 mL) and D2O (1.25 mL) was added to the wetted Pd / C (50 mg) at RT under N2 atmosphere. The solution was stirred at RT for 24h. The suspension was filtered and concentrated, and the residue obtained purified by prep-HPLC to give the desired product (150 mg, 30% yield) as a white solid. LCMS (Agilent-1290-S12): Rt = 2.32 min; m / z calculated for [M+H]+ =618.2, find [M+H]+= 618.2.1HNMR (400 MHz, DMSO-d6) 5 ppm: 8.87 (s, 1 H), 8.58 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 7.23-7.15 (m, 4H), 6.95 (s, 1 H), 6.89 (s, 1 H), 6.83 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1 H), 4.10-4.07 (m, 2H), 3.82 (s, 3H), 3.48 (s, 2H), 2.80 (s, 2H), 2.67 (t, J = 12 Hz, 1 H), 1.77 (d, J = 12.8 Hz, 2H), 1.59-1.48 (m, 2H), 1.42 (s, 9H).Preparation of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl-1 , 1 ,2,2-d4)phenyl)acetamide 7)

[0190] To a solution of tert-butyl 4-(4-((4-(2-(2-(2-amino-2-oxoethyl)phenyl)ethyl- 1 , 1 ,2,2-d4) -5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1- carboxylate (100 mg, 0.16 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) and the reaction stirred at RT for 2h. The mixture was concentrated to give the title compound (100 mg, TFA salt) which was used for next step without further purification. LCMS (Agilent-1290-S12): Rt = 0.46 min; m / z calculated for [M+H]+ =518.1 , find [M+H]+= 518.1.Preparation of 2-(2-(2-(2-((2-methoxy-4-(1-(methyl-d3)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl-1 , 1 ,2,2-d4)phenyl)acetamide (d?-9)

[0191] 2-(2-(2-(2-((2-methoxy-4-(1-(methyl-d3)piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl-1 , 1 ,2,2-d4)phenyl)acetamide was prepared according to Scheme 6.

[0192] To a solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)ethyl-1 ,1 ,2,2-d4)phenyl)acetamide (100 mg, 0.19 mmol) in methanol-d4 (2 mL) was added paraformaldehyde^ (30 mg, 0.95 mmol). The reaction was stirred for 1h then the reaction was cooled to -40 °C and NaBD4 (16 mg, 0.38 mmol) was added. The mixture was stirred at -40 °C for 40 mins, then allowed to warm to RT and stirred for 1h. The reaction was quenched with water (2 mL), extracted with DCM (20 mL x 3) and the organic layers washed with brine (60 mL), dried over Na2SC>4, filtered and concentrated. The residue obtained was purified with prep-TLC (DCM / MeOH =10 / 1 , v / v) to give the desired product (53.3 mg, 53% yield) as a white solid.

[0193] Data for compound 9: LCMS (Agilent-S12-3min): Rt = 1.33 min; m / z calculated for [M+H]+ =535.2, find [M+H]+= 535.2. HPLC (Agilent-1260-A2): Rt: 10.90 min, 100% purity.1HNMR (400 MHz, DMSO-d6) 5 ppm: 8.87 (s, 1 H), 8.57 (s, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.40 (s, 1 H), 7.23-7.15 (m, 4H), 6.94-6.82 (m, 3H), 3.82 (s, 3H), 3.47 (s, 2H), 2.90 (d, J = 11.2 Hz, 2H), 2.44(s, 1 H), 2.02 (t, J = 11.2 Hz, 2H), 1.75-1.65 (m, 4H). 5-

[0194] 2-(2-(2-(2-((2-methoxy-4-(1-(methyl)piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl-1 , 1 ,2,2-d4)phenyl)acetamide was prepared according to Scheme 6. Minor impurities of the ds-analogue, where one deuterium on the ethylene bridge is replaced by hydrogen, also formed (Compound da-12a and da- 12b).

[0195] To a solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)ethyl-1 ,1 ,2,2-d4)phenyl)acetamide (100 mg, 0.16 mmol, TFA salt) in MeOH (2 mL) was added NaHCOa (27 mg, 0.32 mmol) and formaldehyde (37% aqueous, 65 mg, 0.80 mmol). The reaction was stirred for 30 mins then NaBHsCN (20 mg, 0.32 mmol) was added and stirring continued for 2h. The reaction wasquenched with water (2 mL), and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SC>4, filtered and concentrated. The residue obtained was purified by prep-TLC (DCM / MeOH =10 / 1, v / v) to give the desired product (50 mg, 60% yield) as a white solid.

[0196] Data for compound 11: LCMS (Agilent-S12): Rt = 1.33 min; m / z calculated for [M+H]+ =532.2, find [M+H]+= 532.2. HPLC (Agilent-1260-A2): Rt: 10.12 min, 100% purity.1H NMR (400 MHz, DMSO-d6) 5 ppm: 8.88 (s, 1 H), 8.57 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.40 (s, 1 H), 7.23-7.14 (m, 4H), 6.94 (s, 1 H), 6.89 (s, 1 H), 6.83 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1 H), 3.82 (s, 3H), 3.46 (s, 2H), 2.93 (d, J = 10.0 Hz, 2H), 2.46 (s, 1H), 2.26 (s, 3H), 2.08-2.00 (m, 2H), 1.79-1.67 (m, 4H).Example 4 - Clearance rate for deuterated analogues

[0197] To determine intrinsic clearance values for deuterated analogues, the below compounds were examined and compared with the intrinsic clearance values for their non-deuterated counterparts.Microsomal incubations

[0198] Human (Lot # 1910096), rat (Lot # 1910100), mouse (Lot # 2210246) and dog (Lot # 1410114) liver microsomes used were sourced from XenoTech (USA) and stored in a -80°C freezer until use. For use in stability assessment, liver microsomes were suspended in 0.1 M potassium phosphate buffer (pH 7.4). A cocktail containing dextromethorphan, diclofenac, omeprazole, phenacetin and verapamil was included to serve as positive controls. All control values for this experiment fell within the historical range.

[0199] Aliquots of microsomal suspension were spiked with compounds (test or control cocktail) and pre-equilibrated (for 10 minutes) at 37°C. The metabolic reaction was initiated by the addition of preformed NADPH (cofactor required for CYP450 enzyme activity) and quenched at various time points over 60 min by addition of acetonitrile containing an internal standard. Control samples with no cofactor were included to confirm the absence of NADPH-independent degradation. Quenched samples were left on ice for approximately 15 minutes, centrifuged and the supernatant removed and analysed by tandem quadrupole-Time of Flight MS (Waters G2 QToF) with a mass range scan of 50-1200 Da.

[0200] The in vitro intrinsic clearance (pL / min / mg) was calculated from the first order degradation rate constant (min-1) obtained from the linear regression slope of the natural log of the peak area ratio (relative to internal standard) versus time profile.

[0201] A statistical analysis was performed to confirm that the degradation slopes were statistically different to zero. The standard error of the estimated slopes was <20% unless stated otherwise. Degradation slopes for deuterated and non-deuterated compounds were compared using the extra sum of squares F test (Prism, Ver. 9.3.1) testing for significance at a=0.05. 95% confidence intervals for the degradation slopes (determined using GraphPad Prism 9.3.1) were also calculated and compared.

[0202] The control compound 11 is a compound from WO2012 / 110774 and is also known as narmafotinib. In the case of ds-12a and ds-12b, these were examined as a mixture of both isomers:

[0203] Metabolic stability parameters following incubation, and CLint are shown inTable 1 , with the deuterated compounds being denoted as d4 or ds. There were nosignificant differences in the intrinsic clearance values for the non-deuterated narmafotinib and the deuterated analogues within each species for compounds d4-11 and the mixture of ds-12a and ds-12b.Table 1 Metabolic stability parameters following incubation of compounds (corrected) with human, rat, mouse and dog liver microsomes. Units of T1 / 2 are minutes, units of CLint are (pL / min / mg)Biology examples

[0204] The binding kinetics, enzymatic inhibitory activity, pFAK inhibition and 3- dimensional growth inhibition in several cell lines was assessed for Compound 3 of the invention compared to the FAK inhibitor narmafotinib (control compound 11) described in WO 2012 / 110774. Compound 3 is chiral, therefore some of the examples have been conducted with the racemate (3-rac) and others with the enantiomers (3a and 3b).Compound 3a and 3b were shown to have different binding profiles and activity towards FAK. Compound 3a selectivity binding profiles and ICsos (safety screen, hERG and kinase profile) were similar to narmafotinib and did not present any additional safety flags.

[0205] As noted above, in the priority application 2024903670 and in some sections of this application, AMP961 is referred to as Compound 3 and 3-rac; the names are used interchangeably for the same racemic compound. AMP962 is referred to as Compound3a and is used interchangeably for the same enantiomer. AMP963 is referred to as Compound 3b and is used interchangeably for the same enantiomer.Example 5 - FAK inhibition by AMP961, AMP962 and AMP963

[0206] ICso assays were conducted with radiometric protein kinase assay (33PanQinase™ Activity Assay) for for AMP961 , AMP962 and AMP963, as well as for clinical comparator FAK inhibitor defactinib. These assays were run with ATP concentration at Km. ICso values were measured by testing 10 concentrations (3pM to 0.09nM) of each compound in singlicate. Results indicated AMP962 has comparable activity to defactinib, while AMP961 was 1.9-fold and AMP963 was ~24-fold less active than the clinical comparator (Table 2).Table 2 ICso Results (FAK) using Radiometric [Km ATP]33PanQinase™ Activity AssayExample 6 - Binding Kinetics

[0207] The binding kinetics of AMP962 and AMP963 were measured by KINETICfinder®, a TR-FRET Binding Kinetic Assay based on the binding and displacement of an active-site directed fluorescent probe. Kinetic parameters such as the kon, koff, residence time values and the equilibrium dissociation constant were determined and Table 3 summarizes the results obtained; notably the results demonstrate the high affinity of AMP962, while AMP963 had lower Kd = 4.3E-09 M, and short residence time of 1.3 min (compared with 32.5 mins for narmafotinib). Staurosporin, defactinib and narmafotinib were included as a clinical comparator.Table 3 Binding Kinetic CharacterizationExample 7 - Inhibition of Recombinant Human Y397-FAK Phosphorylation in Cells

[0208] The cellular phosphorylation assay for FAK determines the autophosphorylation on Tyr397 of the FAK protein. Inhibition of phosphorylation of Y397 FAK, the FAK autophosphorylation site, was measured in murine embryonic fibroblast cells deficient of the endogenous FAK but expressing a human full-length FAK which is phosphorylated in adherent cells. ICso assays were conducted for AMP961, AMP962 and AMP963, as well as defactinib. Results indicated AMP962 had the strongest inhibitory activity, while AMP961 and defactinib were less active, and AMP963 showed the lowest pFAK inhibitory activity of the compounds tested (Table 4). This was consistent with biochemical data.Table 4 ICso Y397 FAK Phosphorylation in CellsExample 8 - AMP962 and AMP963 Inhibit endogenous pY397-FAK in Ovarian Cancer Cell Lines

[0209] Inhibition of pY397-FAK was investigated in two ovarian cancer cell lines, OVCAR3 and OVCAR5, grown in vitro.

[0210] Methods for pFAK MSP assay on lysates from ovarian cancer cell lines treated with narmafotinib, 3a and 3b. i. OVCAR 5 was seeded at 1x106cells per well and OVCAR 3 at 1x105cells per well (6 well plate). ii. Cells were incubated with various concentrations of drug (3000 nM diluted 1 :3 down to 0.01 nM, as well as DMSO only control cells) for 6 h r at 37°C using a total FAK capture antibody (610088, BD Biosciences) and phospho-FAK Tyr397 detection antibody (3283, Cell Signalling Technology). pFAK (Y397) was detected in cell lysates using a Meso Scale Discovery (MSD) immunoassay according to manufacturer’s instructions, which utilizes ELISA based technology coupled to electrochemiluminescent detection and quantitation.

[0211] ICso values for pFAK inhibition for AMP962 were comparable the two different ovarian cancer cell lines (Figure 1), whereas AMP963 showed a lower pFAK inhibitory capacity with IC50 values unable to be accurately determined using the concentration range.Example 9 - AMP961, AMP962 and AMP963 Inhibit Cell Proliferation in a Number of Cancer Types

[0212] The ability of AMP961 , AMP962 and AMP963 to inhibit 3-dimensional (3D) cell growth on Matrigel over 14 days was tested in a variety of different cancer cell lines from five different cancer types compared to clinical comparator FAK inhibitor defactinib.

[0213] Human cancer line cells were plated into 96-well ultra-low cluster plate on 2% Matrigel in complete media defined for that cell type and allowed to settle overnight prior to treatment with compounds at the following concentrations: 20 mM, 6.67 mM, 2.22 mM, 0.74 mM, 0.25 mM, 0.08 mM, 0.03 mM, 0.01 mM using DMSO as the diluent.

[0214] On days 4, 7 and 11 , media was slowly and carefully removed and replaced with fresh media and diluted compounds. On day 14, media was removed and CellTiter Gio reagents were added to each well before being transferred to a flat-bottom 96-well white / black plate and read with PerkinElmer luminance 700 nm. The inhibition activity was calculated using the following formula: % Inhibition = [1-(LumTest-LumBlank) / (LumDMSO-LumBlank)]*100, and the IC50 was calculated by fitting the Curve using Graphpad 8 with the following equation: Y=100 / (1+10A((LoglC50- X)*HillSlope)).

[0215] Results show growth inhibition at AMP962 concentrations ranging from 19 nM to 3127 nM (ICso) (Table 5), with AMP962 more potent than the comparator FAKi defactinib in several different cancer cell lines. In contrast, AMP961 and AMP963 were generally less active than AMP962.Table 5 Inhibition of Growth in 3D CultureExample 10 - Kinase Selectivity of AMP961, AMP962 and AMP963

[0216] The kinase selectivity profile of AMP961, AMP962 and AMP963 was evaluated against the 468-kinase panel provided by the DiscoverX KI NOM Escan® assay. In this assay, the compounds AMP961, AMP962 and AMP963 were shown to be highly selective for FAK with a selectivity score (S(10)) of 0.005 to 0.02 (Table 6). Selectivity Score or S-score is a quantitative measure of compound selectivity. It is calculated by dividing the number of kinases that compounds bind to by the total number of distinctkinases tested, excluding mutant variants: S (10) = (number of non-mutant kinases with %Ctrl <10) / (number of non-mutant kinases tested).Table 6 Kinase Selectivity

[0217] Selectivity was further refined and ICso values established based on any kinase hits <10% in the KI NOM Escan® assay, for potential off target effects, and in particular, in order to identify any significant differences in activity between the racemate AMP961 and individual enantiomers AMP962 and AMP963.

[0218] The kinase selectivity profiles are compared in Table 7 with ICso values for selected kinases. Table 7 Kinase selectivityExample 11 - Assessment of binding to human biological receptors

[0219] The potential for inhibition of off-target pharmacologically important receptors and enzymes was examined by profiling AMP961, AMP962 and AMP963 against the CEREP Diversity Profile™ Panel, which is composed of 72 binding and 29 enzyme assays. The binding assay panel is broadly defined with a roughly equal number of central and peripheral therapeutically relevant targets. The enzyme assay panelincludes the most representative targets from diverse enzyme families with a focus on phosphatases and specific enzymes involved in cell cycle regulation. Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target, and compound enzyme inhibition effect was calculated as a % inhibition of control enzyme activity. Compounds were tested at 10pM. At 10 pM, AMP961 inhibited7 targets by greater than 50%, as listed in Table 8.Table 8 Compound AM P961 CEREP SafetyScreen44™

[0220] To enable identification of significant off-target interactions with the compound 3 enantiomers, 3a and 3b were screened in an in vitro safety panel, CEREP SafetyScreen44™, consisting of 44 targets. At 10 pM AMP962 inhibited 6 targets and AMP963 also inhibited 6 targets by greater than 50% Table 9A and Table 9B. These data indicate that there was no significant inhibition of recognized safety targets for any compound.Table 9A AMP962 CEREP SafetyScreen44™Table 9B AMP963 CEREP SafetyScreen44™Example 12 - AMP962, but not AMP963, inhibits tumour growth in an ovarian cancer xenograft model

[0221] The ability of AMP962 and AMP963 to inhibit tumour growth was tested using the TOV-21G clear cell ovarian cancer subcutaneous xenograft model.

[0222] NOD SCID female mice were inoculated subcutaneously with 1 x 107TOV-21G ovarian cancer cells in lOO I RPMI 1640:Matrigel (1 :1). Once tumours reached an average size of 176mm3at day 7 post-inoculation, mice were treated by oral gavage with vehicle (10% research grade Captisol (CyDex Pharmaceuticals, KS) in 50 mM citrate buffer pH 5.0), AMP962 or AMP963 at the dose and frequency stated in Table 10.

[0223] Mouse body weights and tumour volumes [TV = D x d2 / 2] were measured twice weekly. Tumour growth inhibition compared to vehicle controls was calculated after 18 days of treatment (Table 10). Results showed dose-dependent anti-tumour effects with AMP962 treatment, whereas AMP963 treatment had no inhibitory effect on tumour growth compared to vehicle controls (Figure 2).Table 10 Anti-tumour activity of test compounds in the TOV-21G subcutaneous xenograft model*Tumour growth inhibition = (1-AT / AC) * 100%, where AT / AC = (TV treated final-TV treated initial) / (TV vehicle final-TV vehicle initial). QD - once daily dosing; BID - twice daily dosing with an 8-hour interval. Example 13 - AMP962 can combine with pegylated liposomal doxorubicin to enhance tumour growth inhibition in an ovarian cancer xenograft model

[0224] The ability of AMP962 to inhibit tumour growth in combination with chemotherapy treatment, pegylated liposomal doxorubicin (PLD), was tested using the TOV-21G clear cell ovarian cancer subcutaneous xenograft model.

[0225] NOD SCID female mice were inoculated subcutaneously with 1 x 107TOV-21G ovarian cancer cells in 100pl RPMI 1640:Matrigel (1 :1). Once tumours reached an average size of 163mm3at day 6 post-inoculation, mice were treated with vehicle (10% research grade Captisol (CyDex Pharmaceuticals, KS) in 50 mM citrate buffer pH 5.0) or AMP962 by oral gavage, and pegylated liposomal doxorubicin (PLD), by intravenous injection, as single agents, or in combination. Treatment groups are described in Table 11. Mouse body weights and tumour volumes [TV = D x d2 / 2] were measured twice weekly. Tumour growth inhibition compared to vehicle controls was calculated after 21 days of treatment (Table 11).Table 11 Anti-tumour activity of test compounds and PLD in the TOV-21 G subcutaneous xenograft model*Tumour growth inhibition = (1-AT / AC) * 100%, where AT / AC = (TV treated final-TV treated initial) / (TV vehicle final-TV vehicle initial). QD - once daily dosing; PLD was administered once weekly a total of 4 times over 21 days on days 1 , 8, 15 and 21 . N = 12 mice for groups 1 , 6, 7 and 8; n = 8 mice for groups 2, 3, 4 and 5.

[0226] During the experimental period, several animals experienced >10% body weight loss, as is common in this model. Mice that required an extended dosing holiday due to weight loss (>7 days without AMP962 and / or 1 or more missed PLD dose) were excluded from the following evaluation comparing changes in tumour volume between treatment groups (Figure 3).

[0227] Results show that after 21 days, treatment with AMP962 at 50 mg / kg once daily did not significantly reduce tumour volume compared to vehicle controls (unpaired t test at day 21 , p = 0.066); however, the addition of AMP962 in combination with PLD further reduced tumour growth compared to treatment with PLD alone. This resulted in an overall reduction in final tumour volume compared to volume at baseline in 7 of 11 animals receiving combination treatment, compared to just 1 of 7 animals in the PLD only group (Figure 3).Example 14 - Anti-fibrotic activity of AMP962 in a 2D in vitro model of human kidney fibrosis

[0228] To investigate the anti-fibrotic potential of AMP962, primary human kidney fibroblasts cultured in 2D conditions were stimulated with 5 ng / mL transforming growth factor-beta 1 (TGF-P) to induce fibrosis. After treatment for 72 hours, cells were harvested and processed for Western blot analysis.

[0229] Unstimulated control fibroblasts were compared to TGF-p (5 ng / ml) stimulated fibroblasts co-treated with vehicle (DMSO), AMP962 (5pM or 10pM) or ALK5 inhibitor SB 525334 (2pM) for changes in FAK activity and fibrosis markers. All treatments were performed in technical triplicate.

[0230] Stimulation with TGF-p resulted in an increased ratio of phosphorylated Tyr397- FAK to total FAK (pFAK / FAK) protein levels compared to unstimulated (control) fibroblasts, indicative of increased FAK activity with cytokine stimulation. Treatment with AMP962 significantly inhibited FAK activity compared to vehicle treated fibroblasts (Figure 4A), and there was a trend towards reduced downstream ERK signaling (reduced pERK / ERK) in AMP962 treated cells (Figure 4B).

[0231] Fibrosis markers alpha-smooth muscle actin (a-SMA) and fibronectin were also assessed by Western blot analysis. A significant increase in a-SMA was observed with TGF-p stimulation compared to unstimulated controls; treatment with AMP962 at 10 pM significantly reduced a-SMA levels to that seen in unstimulated fibroblasts (Figure 4C). A similar trend was observed for fibronectin, with both AMP962 (10 pM) and ALK5i (2 pM) treatment resulting in a significant reduction in fibronectin levels compared to vehicle treatment (Figure 4D).Example 15 - XRD characterisation of AMP962

[0232] Initial Polarized Light Microscopy (PLM) and X-ray Powder Diffraction (XRPD) analysis was carried out on AMP962 in order to generate baseline data for comparison with further results.

[0233] The PLM analysis showed very small, aggregated particles with very slight birefringence under cross-polarized light. XRPD analysis showed the material to be crystalline (Figure 5).

[0234] Single crystals of AMP962 were grown via slow evaporation and vapour diffusion from acetone and methylethyl ketone. A single crystal from slow evaporation in acetone was used for single crystal X-ray diffraction analysis with dimensions of 0.18 x 0.11 x 0.04 mm3. The unit cell was refined based on 200975 reflections, 60% of the observed reflections. The final completeness was 100.00 % out to 77.575° in 0. The absorption coefficient p of this crystal was 0.855 mm-1at this wavelength (A = 1.54184A) and the minimum and maximum transmissions were 0.772 and 1.000. The structure was solved and the space group P21 (# 4) was returned.

[0235] The single crystal XRD analysis confirmed both the connectivity and the absolute configuration for AMP962 (Figure 6). The structure indicated two molecules in the asymmetric unit, with no solvent present in the structure, indicating an anhydrous form. O-H...N and N-H...0 hydrogen bonds link adjacent molecules into a thick sheet composed of two hydrogen bonded layers, each layer comprises symmetry equivalent molecules. The model was refined with a pseudomerohedral twin law applied.

[0236] The chiral atoms in the structure were confirmed as C9(S) and C59(S). The simulated XRPD pattern determined based on the single crystal XRD data showed a good match with the experimental powder diffraction data, showing that the crystal analysed was consistent. The Hooft parameter was -0.009(15) confirming the absolute stereochemistry. The Hooft parameter is used to determine chirality of the crystal studied, the value should be near to 0, a value of 1 means that the stereochemistry is wrong and that the model should be inverted. A value of 0.5 means that the crystal consists of a racemic mixture of the two enantiomers. The crystal structure parameters for this data set are provided in Table 12.Table 12 Crystal structure parameters for AMP962.

[0237] The simulated XRPD pattern based on the single crystal data showed a good match with the experimental powder diffraction data showing that the crystal analysed was consistent. Some shifts were observed due to the difference in temperature for the data collections (298K for experimental powder XRD and 100K for single crystal XRD). Figure 7 shows a comparison between the simulated XRPD data and experimental XRPD data.Embodiments of the invention

[0238] Embodiment 1. A compound or pharmaceutically acceptable salt thereof according to Formula (I)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups; each of R2a, R2b, R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi-Cealkyl, or (i) taken together, R2aand R2bor R3aand R3bform a carbonyl group; or (ii) two of R2a, R2b, R3aor R3btogether form a Cs-Cs cycloalkyl ring or a Cs-Cs heterocyclic ring;R4is selected from H, -CDs or Ci-Cealkyl;R5aand R5bare independently selected from H, D, F, OH, -Ci-Cealkyl or -OCi-Cealkyl; and wherein at least one of R2a, R2b, R3a, R3b, R5aor R5bis not H.

[0239] Embodiment 2. The compound according to embodiment 1 , wherein R1is - Me.

[0240] Embodiment 3. The compound according to embodiment 1 or 2, wherein R2aand R2bare independently selected from H, D, OH, or taken together, form a carbonyl group, a Cs-Cs cycloalkyl ring or a Cs-Cs heterocyclic ring.

[0241] Embodiment 4. The compound according to any one of embodiments 1-3, wherein R3aand R3bare independently selected from H, D, OH, or taken together, form a carbonyl group.

[0242] Embodiment 5. The compound according to any one of embodiments 1-4, wherein R2aand R2bare both H.

[0243] Embodiment 6. The compound according to any one of embodiments 1-4, wherein R2aand R2bare both D.

[0244] Embodiment 7. The compound according to any one of embodiments 1-6, wherein one of R3aor R3bis OH and the other is H.

[0245] Embodiment 8. The compound according to any one of embodiments 1-4, wherein each of R2a, R2b, R3aand R3bare D.

[0246] Embodiment 9. The compound according to any one of embodiments 1-8, wherein R4is selected from H or -CHs.

[0247] Embodiment 10. The compound according to any one of embodiments 1-9, wherein R5aor R5bis OH.

[0248] Embodiment 11. A compound or pharmaceutically acceptable salt thereof according to Formula (la)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups;R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi- Cealkyl, or taken together, form a carbonyl group, a C3-Cs cycloalkyl ring or a C3-Cs heterocyclic ring; andR4is selected from H, -CDs or Ci-Cealkyl; and at least one of R3aand R3bis not H.

[0249] Embodiment 12. The compound according to embodiment 11 , wherein R1is - CHs.

[0250] Embodiment 13. The compound according to embodiment 11 or 12, wherein at least one of R3aand R3bis OH.

[0251] Embodiment 14. The compound according to any one of embodiments 11-13, wherein one of R3aand R3bis OH, and the other is H or D.

[0252] Embodiment 15. The compound according to any one of embodiments 11-14, wherein R4is selected from H or -CH3.

[0253] Embodiment 16. A compound or pharmaceutically acceptable salt thereof according to Formula (II)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups, or one or more deuterium groups;R3is selected from OH, or -OCi-Cealkyl; and R4is selected from H or Ci-Cealkyl.

[0254] Embodiment 17. The compound according to embodiment 16, or pharmaceutically acceptable salt thereof, wherein the carbon attached to R3is of absolute configuration:

[0255] Embodiment 18. The compound according to embodiment 16, or pharmaceutically acceptable salt thereof, wherein the carbon attached to R3is of absolute configuration:

[0256] Embodiment 19. The compound according to any one of embodiments 16-18, wherein said compound is greater than 90% enantiomerically pure.

[0257] Embodiment 20. The compound according to any one of embodiments 16-19, wherein said compound is greater than 95% enantiomerically pure.

[0258] Embodiment 21. The compound according to any one of embodiments 16-20, wherein R1is -CH3.

[0259] Embodiment 22. The compound according to any one of embodiments 16-21, wherein R3is OH.

[0260] Embodiment 23. The compound according to any one of embodiments 16-22, wherein R4is selected from H or -CH3.

[0261] Embodiment 24. A compound selected from:5 Embodiment 25. A compound selected from:

[0262] Embodiment 26. A compound selected from:5

[0263] Embodiment 27. A compound selected from:

[0264] Embodiment 28. A compound selected from:

[0265] Embodiment 29. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-28.

[0266] Embodiment 30. The pharmaceutical composition according to embodiment 29, wherein said composition is suitable for oral administration.

[0267] Embodiment 31 . The pharmaceutical composition according to embodiment 29 or 30, wherein the composition is used with one or more additional therapeutic agents.

[0268] Embodiment 32. The pharmaceutical composition according to embodiment31 , wherein at least one additional therapeutic agent comprises an anti-cancer agent.

[0269] Embodiment 33. The pharmaceutical composition according to embodiment32, wherein the anti-cancer agent is selected from one or more of gemcitabine, Nab paclitaxel, docetaxel, doxorubicin, cisplatin, oxaliplatin, irinotecan, fluorouracil or leucovorin.

[0270] Embodiment 34. A process for preparing a compound, or a pharmaceutically acceptable salt thereof, having the structure:including contacting a compound having the structure:with a reducing agent capable of reducing the carbonyl to an alcohol to provide a compound having the structure:

[0271] Embodiment 35. The process according to embodiment 34, wherein the reducing agent is selected from one or more of hydride sources.

[0272] Embodiment 36. The process according to embodiment 34 or 35, wherein the reducing agent is selected from a chiral hydride source.

[0273] Embodiment 37. The process according to any one of embodiments 34-36, further including the step of converting a compound having the structure:with formaldehyde and a hydride source to provide a compound having the structure:

[0274] Embodiment 38. A method of inhibiting FAK in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of embodiments 1-28.

[0275] Embodiment 39. A method of treating a proliferative disease in a subject in need thereof, comprising administering to said subject the compound according to any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of embodiments 29-33.

[0276] Embodiment 40. Use of a compound according to any one of embodiments 1- 28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of embodiments 29-33 in the manufacture of a medicament for treating a proliferative disease.

[0277] Embodiment 41. A compound according to any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of embodiments 29-33 for use in the treatment of a proliferative disease.

[0278] Embodiment 42. The method, use or compound according to any one of embodiments 39-41, wherein the proliferative disease is cancer.

[0279] Embodiment 43. The method, use or compound according to embodiment 42, wherein the cancer is selected from a solid cancer, including but not limited to bone cancer, brain stem glioma, breast cancer, cancer of the adrenal gland, cancer of the anal region, cancer of the bladder, cancer of the endocrine system, cancer of the oesophagus, cancer of the head or neck, cancer of the kidney or ureter, cancer of the liver, cancer of the parathyroid gland, cancer of the penis, cancer of the small intestine, cancer of the thyroid gland, cancer of the urethra, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, carcinoma of the vagina, carcinoma of the vulva, colon cancer, cutaneous or intraocular melanoma, fibrosarcoma, lung cancer, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, primary CNS lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, sarcoma of soft tissue, skin cancer, spinal axis tumours, solitary fibrous tumour, stomach cancer and uterine cancer.

[0280] Embodiment 44. The method, use, or compound according to embodiment 42 or 43, wherein the cancer is pancreatic cancer, ovarian cancer, colon cancer, rectal cancer, fibrosarcoma or solitary fibrous tumours.

[0281] Embodiment 45. A method of treating a fibrotic disease in a subject in need thereof, comprising administering to said subject the compound according to any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiments 29-31.

[0282] Embodiment 46. Use of a compound according to any one of embodiments 1- 28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 29-31 in the manufacture of a medicament for treating a fibrotic disease.

[0283] Embodiment 47. A compound according to any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 29-31 for use in the treatment of a fibrotic disease.

Claims

CLAIMS1. A compound or pharmaceutically acceptable salt thereof according to Formula (I)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups; each of R2a, R2b, R3aand R3bare independently selected from H, D, F, OH, -Ci- Cealkyl, -OCi-Cealkyl, or (i) taken together, R2aand R2bor R3aand R3bform a carbonyl group; or (ii) two of R2a, R2b, R3aor R3btogether form a Cs-Cs cycloalkyl ring or a Cs-Cs heterocyclic ring;R4is selected from H, -CDs or Ci-Cealkyl;R5aand R5bare independently selected from H, D, F, OH, -Ci-Cealkyl or -OCi- Cealkyl; and wherein at least one of R2a, R2b, R3a, R3b, R5aor R5bis not H.

2. The compound according to claim 1 , wherein R2aand R2bare independently selected from H, D, OH, or taken together, form a carbonyl group, a Cs-Cs cycloalkyl ring or a Cs-Cs heterocyclic ring.

3. The compound according to claim 1 or claim 2, wherein R2aand R2bare both H or D.

4. The compound according to any one of claims 1 to 3, wherein one of R3aor R3bis OH and the other is H.

5. The compound according to claim 1 or claim 2, wherein each of R2a, R2b, R3aand R3bare D.

6. The compound according to any one of claims 1 to 5, wherein R5aor R5bis OH.

7. A compound or pharmaceutically acceptable salt thereof according to Formula (la)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups or one or more deuterium groups;R3aand R3bare independently selected from H, D, F, OH, -Ci-Cealkyl, -OCi- Cealkyl, or taken together, form a carbonyl group, a Cs-Cs cycloalkyl ring or a C3- Cs heterocyclic ring; andR4is selected from H, -CD3 or Ci-Cealkyl; and at least one of R3aand R3bis not H.

8. The compound according to any one of claims 1 to 7, wherein R1is -CH3.

9. The compound according to any one of claims 1 , 2, 7 or 8, wherein R3aand R3bare independently selected from H, D, OH, or taken together, form a carbonyl group; or one of R3aand R3bis OH, and the other is H or D.

10. The compound according to any one of claims 1 to 9, wherein R4is selected from H or -CH3.

11. A compound or pharmaceutically acceptable salt thereof according to Formula(II)wherein R1is selected from -Ci-Cealkyl optionally substituted by one or more fluoro groups, or one or more deuterium groups;R3is selected from OH, or -OCi-Cealkyl; and R4is selected from H or Ci-Cealkyl.

12. The compound according to claim 11 , or pharmaceutically acceptable salt thereof, wherein the carbon attached to R3is of absolute configuration:

13. The compound according to claim 11 or claim 12, wherein said compound is greater than 90% enantiomerically pure, or greater than 95% enantiomerically pure.

14. The compound according to any one of claims 11-13, wherein R1is -CH3; and / orR3is OH; and / orR4is selected from H or -CH3.

15. A compound selected from:

16. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15.

17. The pharmaceutical composition according to claim 16, wherein the composition is used with one or more additional therapeutic agents and / or an anti-cancer agent.

18. The pharmaceutical composition according to claim 17, wherein the anti-cancer agent is selected from one or more of gemcitabine, Nab paclitaxel, docetaxel, doxorubicin, cisplatin, oxaliplatin, irinotecan, fluorouracil or leucovorin.

19. A process for preparing a compound, or a pharmaceutically acceptable salt thereof, having the structure:including contacting a compound having the structure:with a reducing agent capable of reducing the carbonyl to an alcohol to provide a compound having the structure:

20. The process according to claim 19, wherein the reducing agent is selected from one or more of hydride sources; or the reducing agent is selected from a chiral hydride source.

21. A method of inhibiting FAK in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 15.

22. A method of treating a proliferative disease in a subject in need thereof, comprising administering to said subject the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 16 to 18; or use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 16-18 in the manufacture of a medicament for treating a proliferative disease; or a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 16-18 for use in the treatment of a proliferative disease.

23. The method, use or compound according to claim 22, wherein the proliferative disease is cancer.

24. The method, use or compound according to claim 23, wherein the cancer is selected from a solid cancer, including but not limited to bone cancer, brain stem glioma, breast cancer, cancer of the adrenal gland, cancer of the anal region, cancer of the bladder, cancer of the endocrine system, cancer of the oesophagus, cancer of the head or neck, cancer of the kidney or ureter, cancer of the liver, cancer of the parathyroid gland, cancer of the penis, cancer of the small intestine, cancer of the thyroid gland, cancer of the urethra, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, carcinoma of the vagina, carcinoma of the vulva, colon cancer, cutaneous or intraocular melanoma, fibrosarcoma, lung cancer, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, primary CNS lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, sarcoma of soft tissue, skin cancer, spinal axis tumours, solitary fibrous tumour, stomach cancer and uterine cancer.

25. A method of treating a fibrotic disease in a subject in need thereof, comprising administering to said subject the compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 to 17; or use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 16 to 17 in the manufacture of a medicament for treating a fibrotic disease; or a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 16 to 17 for use in the treatment of a fibrotic disease.

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