Crystalline forms of 6'-([(1s, 3s)-3-([difluoromethoxy)- 2-pyrimidinyl]amino)cyclopentyl]amino)-2h-1,3'-bipyridin]-2-one and methods of synthesis

Abstract

Crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H- [1,3'-bipyridin]-2-one (AZD0780) in form B, a crystalline form comprising AZD0780 and fumaric acid as a co-crystal, a crystalline form comprising AZD0780 and succinic acid as a co-crystal, and a method of making AZD0780 with key intermediates.

Description

[0001] CRYSTALLINE FORMS AND METHODS OF SYNTHESIS Cross-reference to Related applications

[0002] This application claims the priority benefit of US Provisional Application No. 63 / 734676, filed December 16, 2024, and US Provisional Application No. 63 / 896231 , filed October 09, 2025, both of which are incorporated herein by reference in their entireties.

[0003] Field

[0004] The present disclosure relates to crystalline forms of the compound known as “AZD0780”, and the use of such forms, as well as to methods of synthesis of this compound, and intermediates in the synthesis.

[0005] Background

[0006] PCSK9, also referred to as “proprotein convertase subtilisin / kexin 9”, is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol (LDL-C) via the enhanced degradation of the LDLRs independently of its catalytic activity. Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9 / LDLR complex is internalized into endosomal / lysosomal compartments. The enhanced binding affinity of PCSK9 to the LDLR at the acidic pH of late endosomes / lysosomes reduces LDLR recycling and instead targets LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events.

[0007] For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins have failed to achieve proportional LDL-C lowering effects.

[0008] Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDLR, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab showed an about 50% decrease in LDL levels compared to placebo (Elbitar 2016). Patients taking evolocumab showed an about 60-75% decrease in LDL levels. The potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body. Cardiovascular diseases often require management over a person’s lifetime, unlike an infection that could be episodic. Thus, ease of dosing and administration become important factors for patient compliance with maintenance drug treatments.

[0009] “AZD0780” refers to a compound with the chemical name 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one, the structure of which is shown below:

[0010] AZD0780 is an effective binder to PCSK9 and is currently in early-stage clinical trials as laroprovstat. The synthesis of AZD0780 is described in W02020 / 150473 (see scheme 1 , below), the contents of which are hereby incorporated by reference in their entirety.

[0011] Scheme 1: AZD0780 synthesis in WO 2020 / 150473 Step (i) Cs2CO3(1.2 eq), DMF, Sodium 2-chloro-2,2-difluoroacetate (3 eq), RT to 100°C, 5 hours. Step (ii) tert-butyl ((1S, 3S)-3-aminocyclopentyl) carbamate (1.05 eq), DIPEA (3.13 eq), DMSO, 110°C, 12 hours. Step (Hi) HCI in dioxane, MeOH, RT, 2.5 hours. Step (iv) Cu(l)l (0.1 eq), N, N'-Dimethyl-1 ,2-cyclohexanediamine (0.2 eq), K3PO4 (2 eq), DMSO, 120°C, overnight. Step (v) tBuXphos Pd G3 (0.1 eq), tBuOK (0.2 eq), dioxane, 110°C, overnight, N2.

[0012] The synthetic route used in WO 2020 / 150473 is an early-stage synthesis and involves steps with low yields as well as conditions unsuited to scale up, such as chromatographic purification, high temperatures and toxic solvents.

[0013] For development of AZD0780 as a pharmaceutical, and for use in an oral dosage form, a stable form needs to be developed. There is also a need to develop new methods for synthesising AZD0780 in an efficient manner.

[0014] Summary

[0015] In some embodiments, disclosed is crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) in Form B.

[0016] In some embodiments, disclosed is solid 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) having improved stability compared to crystalline AZD0780 in Form A. In some embodiments, the improved stability is improved thermodynamic stability. In some embodiments, the solid is substantially free of crystalline AZD0780 in Form A.

[0017] In some embodiments, disclosed is a pharmaceutical composition comprising crystalline 6'- ([(1S,3S)-3-([5-(difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]- 2-one (“AZD0780”) in Form B, and a pharmaceutically acceptable excipient, carrier or diluent.

[0018] In some embodiments, disclosed is a method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease, comprising administering to a subject in need thereof crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) in Form B.

[0019] In some embodiments, disclosed is crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) in Form B for use in a method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease.

[0020] In some embodiments, disclosed is the use of crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)- 2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) in Form B in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease

[0021] In some embodiments, disclosed is a method of obtaining 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) in crystalline Form B. In some of these embodiments, this method comprises the step of converting the AZD0780 succinic acid form or AZD0780 fumaric acid form to crystalline AZD0780 in Form B. In some embodiments, this conversion is carried out in 2- butanone and water, with sodium chloride and aqueous ammonium hydroxide. In some embodiments, this conversion is carried out in ethyl acetate, with a solution of potassium carbonate in water.

[0022] In some embodiments, disclosed is a crystalline form comprising 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) and fumaric acid as a co-crystal, herein referred to as AZD0780 fumaric acid form.

[0023] In some embodiments, disclosed is a solid form comprising 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) and fumaric acid. In some embodiments, disclosed is a solid form obtained from a solid form comprising 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) and fumaric acid by removal of the fumaric acid.

[0024] In some embodiments, disclosed is a crystalline form comprising 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) and succinic acid as a co-crystal, herein referred to as AZD0780 succinic acid form.

[0025] In some embodiments, disclosed is a solid form comprising 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) and succinic acid. In some embodiments, disclosed is a solid form obtained from a solid form comprising 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) and succinic acid by removal of the succinic acid.

[0026] In some embodiments, disclosed is a method of making crystalline 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) fumaric acid form.

[0027] In some embodiments, disclosed is a method of making crystalline 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (“AZD0780”) succinic acid form.

[0028] Also, provided herein are processes and intermediates useful for the synthesis of laroprovstat also known as AZD0780 (6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one) and referred to herein as compound 8.

[0029] An aspect provides a process for preparing 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or cocrystal thereof:

[0030] Compound 8 comprising one or more of steps (i) to (iv):

[0031] (i) contacting compound 1 and amine 1 to form compound 2: compound 1 amine 1 compound 2

[0032] (ii) contacting compound 2 and 2-pyridone to form compound 3:

[0033] (iii) deprotecting compound 3 with an acid and forming a fumaric acid or camphorsulfonic acid salt of compound 4: compound 3 compound 4

[0034] (iv) contacting compound 6 and the fumaric acid or camphorsulfonic acid salt of compound 4 in the presence of an inorganic base to form 6'-([(1S,3S)-3-([5- (difluoromethoxy)-2-pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8) or a salt or co-crystal thereof: compound 6 compound 4

[0035] Compound 8 wherein compounds 1 to 3 and 6, and amine 1 may be provided as a salt.

[0036] In some embodiments, a process for preparing compound 8, or a salt or co-crystal thereof comprises two or more of steps (i) to (iv).

[0037] In some embodiments, a process for preparing compound 8, or a salt or co-crystal thereof comprises three or more of steps (i) to (iv).

[0038] In some embodiments, a process for preparing compound 8, or a salt or co-crystal thereof comprises one of steps (i) to (iv).

[0039] In some embodiments, a process for preparing compound 8, or a salt or co-crystal thereof comprises two of steps (i) to (iv).

[0040] In some embodiments, a process for preparing compound 8, or a salt or co-crystal thereof comprises three of steps (i) to (iv).

[0041] In some embodiments, a process for preparing compound 8, or a salt or co-crystal thereof comprises all of steps (i) to (iv).

[0042] A further aspect provides an intermediate compound selected from: a) compound 2 (tert-butyl ((1S,3S)-3-((5-bromopyridin-2-yl)amino)cyclopentyl)carbamate), or a salt thereof: compound 2 b) compound 4a (6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2-one.CSA(+)): compound 4a

[0043] A further aspect provides a method for preparing compound 6, or a salt thereof, by contacting compound 5, or a salt thereof, and compound 7: compound 5 compound 7 compound 6 Further aspects provide the methods of any one of step (i) to (iv).

[0044] Brief Description of the Figures

[0045] Figure 1 illustrates the powder X-ray diffraction diagram of AZD0780 in form A.

[0046] Figure 2 illustrates the powder X-ray diffraction diagram of AZD0780 in form B.

[0047] Figure 3 illustrates the powder X-ray diffraction diagram of AZD0780 fumaric acid form. Figure 4 illustrates the powder X-ray diffraction diagram of AZD0780 succinic acid form. Figure 5 shows the rate of formation of compound 2 for five different sets of reaction conditions.

[0048] Figure 6 shows the rate of formation of Imp 1 for five different sets of reaction conditions.

[0049] Figure 7A and 7B show the prediction of the amount of Imp 1 resulting from combinations of temperature and amount of compound 1 for different reaction durations.

[0050] Figure 8 shows the experimental validation of the conditions predicted in Figure 7A and 7B. Figure 9 shows the rate of formation of compound 3 for 3 different ligand loadings.

[0051] Detailed Description

[0052] Crystalline Forms

[0053] Currently 11 polymorphic forms of AZD0780 have been found, some of which are solvates and would not be suitable for further pharmaceutical development.

[0054] Form A is a meta-stable form of AZD0780. Form B is the most thermodynamically stable anhydrous form of AZD0780 and shows good crystallinity, thermal properties and hygroscopicity.

[0055] A number of initial crystallisation approaches to AZD0780 produced either Form A or a mixture of Form A and amorphous AZD0780. For example, sonication experiments on amorphous AZD0780 in iPrOAc, IPA, MTBE, ACN:toluene (1 :4), methylcyclohexane, DMF:MTBE (1 :4), DMSO:MTBE (1 :4), 2-Me-THF, BuOAc, acetone / water (1 :1) all yielded either Form A or a mixture of Form A and amorphous form. Slurry experiments a 5°C on amorphous AZD0780 in EtOAc, toluene, THF:MTBE (1 :4), DCM:heptane (1 :4), Acetone:heptane (1 :4), IPA, DMF:water (1 :9), MEK, DMAc and MIBK:heptane (1 :4) all yielded either Form A or a mixture of Form A and amorphous form.

[0056] As described below, methods of reliably producing Form B were developed. One of these approaches proceeds via AZD0780 succinic acid form as an intermediate. Another one of these approaches proceeds via AZD0780 fumaric acid form as an intermediate. Form A

[0057] In some embodiments, AZD0780 form A has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 19.7°.

[0058] In some embodiments, AZD0780 form A has a XRPD pattern comprising at least one peak expressed as 26±0.2° at 6.7°.

[0059] In some embodiments, AZD0780 form A has a XRPD pattern comprising at least two peaks expressed as 28±0.2° at 19.7° and 6.7°.

[0060] In some embodiments, AZD0780 form A has a XRPD pattern comprising the following ten peaks expressed as 26±0.2°:

[0061] In some embodiments, AZD0780 form A has a XRPD pattern substantially similar to Figure 1.

[0062] The above XRPD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu Karadiation. In some embodiments, the measurements take place at room temperature, such as 20°C.

[0063] When it is stated that the present disclosure relates to AZD0780 form A, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%. In some embodiments, AZD0780 form B has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 21 .9°.

[0064] In some embodiments, AZD0780 form B has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 19.1 °.

[0065] In some embodiments, AZD0780 form B has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 11 .6°.

[0066] In some embodiments, AZD0780 form B has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 21.9° and 19.1 °.

[0067] In some embodiments, AZD0780 form B has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 21 .9° and 11 .6°.

[0068] In some embodiments, AZD0780 form B has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 19.1 ° and 11.6°.

[0069] In some embodiments, AZD0780 form B has a XRPD pattern comprising at least three peaks expressed as 29±0.2° at 21.9°, 19.1 ° and 11.6°.

[0070] In some embodiments, AZD0780 form B has a XRPD pattern comprising the following six peaks expressed as 29±0.2°:

[0071] In some embodiments, AZD0780 form B has a XRPD pattern comprising the following ten peaks expressed as 29±0.2°:

[0072] In some embodiments, AZD0780 form B has a XRPD pattern substantially similar to Figure 2.

[0073] The above XRPD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu Karadiation. In some embodiments, the measurements take place at room temperature, such as 20°C.

[0074] When it is stated that the present disclosure relates to a AZD0780 form B, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.

[0075] In some embodiments, disclosed is AZD0780 form B substantially in the absence of AZD0780 form A.

[0076] When it is stated that the present disclosure relates to AZD0780 form B substantially in the absence of AZD0780 form A, this means that at least 80% of crystalline AZD0780 is in Form B and less than 20% of crystalline AZD0780 is in Form A. In some embodiments at least 90%, at least 95%, at least 98%, or at least 99% of crystalline AZD0780 is in Form B.

[0077] AZD0780 fumaric acid form

[0078] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 25.7°.

[0079] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 15.9°.

[0080] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 20.6°.

[0081] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 25.7° and 15.9°.

[0082] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 25.7° and 20.6°. In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 20.6° and 15.9°.

[0083] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising at least three peaks expressed as 29±0.2° at 25.7°, 15.9° and 20.6°.

[0084] In some embodiments, AZD0780 fumaric acid has a XRPD pattern comprising the following five peaks expressed as 29±0.2°: In some embodiments, AZD0780 fumaric acid form has a XRPD pattern comprising the following ten peaks expressed as 29±0.2°:

[0085] In some embodiments, AZD0780 fumaric acid form has a XRPD pattern substantially similar to Figure 3.

[0086] The above XPRD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu Karadiation. In some embodiments, the measurements take place at room temperature, such as 20°C. When it is stated that the present disclosure relates to a AZD0780 fumaric acid form, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.

[0087] AZD0780 succinic acid form

[0088] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 7.6°.

[0089] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 19.2°.

[0090] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least one peak expressed as 29±0.2° at 7.9°.

[0091] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 7.6° and 19.2°.

[0092] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 7.6° and 7.9°.

[0093] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least two peaks expressed as 29±0.2° at 7.9° and 19.2°.

[0094] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising at least three peaks expressed as 29±0.2° at 7.6°, 7.9° and 19.2°.

[0095] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising the following five peaks expressed as 29±0.2°:

[0096] In some embodiments, AZD0780 succinic acid form has a XRPD pattern comprising the following ten peaks expressed as 29±0.2°:

[0097] In some embodiments, AZD0780 succinic acid form has a XRPD pattern substantially similar to Figure 4.

[0098] The above XRPD measurements are carried out using X-rays with a wavelength of 1 .5418 A. These X-rays may be Cu Karadiation. In some embodiments, the measurements take place at room temperature, such as 20°C.

[0099] When it is stated that the present disclosure relates to a AZD0780 succinic acid form, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.

[0100] Medical and Pharmaceutical Use

[0101] In some embodiment is disclosed a method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease, comprising administering to a subject in need thereof crystalline AZD0780 in Form B.

[0102] In some embodiments, disclosed is crystalline AZD0780 in Form B, for use in a method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease.

[0103] In some embodiments, disclosed is the use of crystalline AZD0780 in Form B in the manufacture of a medicament for use in lowering LDL-C levels, reducing cardiovascular risk and / or a method of treating a cardiovascular disease.

[0104] The language “pharmaceutical composition” includes compositions comprising an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent, wherein the active ingredient is crystalline AZD0780 in Form B. The language “pharmaceutically acceptable excipient, carrier or diluent” includes compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as ascertained by one of skill in the art. In some embodiments, the pharmaceutical compositions are in solid dosage forms, such as capsules, tablets, granules, powders or sachets.

[0105] In some embodiments, crystalline AZD0780 in Form B is administered orally. In some embodiments, crystalline AZD0780 in Form B is in tablet dosage form.

[0106] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a paediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. Preferred subjects are humans.

[0107] The reduction of cardiovascular events through the lowering of LDL-C by inhibition of PCSK9 has been described, e.g., in Robinson 2015. The term “LDL-C level” is used herein to mean the amount of LDL-C in the circulating serum of a patient.

[0108] Lowering LDL-C levels leads to significant reduction in major vascular events including myocardial infarction, coronary deaths, stroke, and coronary revascularizations (Collins 2016). Current clinical guidelines for LDL-C reduction and the consequent reduction of CVD (cardiovascular disease) risk are summarised in Atar 2021 . Additional evidence demonstrates that aggressively lowering LDL-C levels to < 40 mg / dL lowers CVD risk in a wider range of patients (Marston 2021).

[0109] In some embodiments, reduction of LDL-C to less than 100 mg / dL, less than 70 mg / dL, less than 55 mg / dL or less than 40 mg / dL may be achieved by the treatment disclosed herein.

[0110] In some embodiments, in patients with elevated LDL-C (such as greater than 100 mg / dL), reduction of the untreated level of LDL-C by greater than or equal to 30%, 40%, 50%, 60%, 65%, 70% or 75% may be achieved by the treatment disclosed herein. The term untreated as used herein refers to the level as measured before any LDL-C lowering treatment has been administered, i.e. the LDL-C baseline level.

[0111] In some embodiments, the treatment disclosed herein reduces cardiovascular risk (i.e., the incidence of myocardial infarction, ischemic stroke and urgent coronary revascularization, cardiovascular death) in adults with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event (such as myocardial infarction, resuscitated cardiac arrest, fatal coronary heart disease (CHD), fatal and non-fatal stroke, and other atherosclerotic or cardiovascular death). The risk for a first ASCVD event for a patient within 10 years can be categorized into those at low (<5%), borderline (5 to <7.5%), intermediate (7.5 to <20%), and high (>20%) risk (Wong 2022).

[0112] In some embodiments, the treatment disclosed herein reduces LDL-C, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).

[0113] Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure or congestive heart failure. In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.

[0114] In some cases, exemplary cardiovascular diseases and conditions include dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure or congestive heart failure. In some cases, exemplary cardiovascular diseases and conditions include hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, and coronary artery disease. In some embodiments, the treatment of a cardiovascular disease includes reducing the LDL- C level to less than 100 mg / dL, less than 70 mg / dL, less than 55 mg / dL or less than 40 mg / dL. In some embodiments, the treatment of a cardiovascular disease in patients with elevated LDL-C (such as greater than 100 mg / dL), includes reduction of the untreated level of LDL-C by greater than or equal to 30%, 40%, 50%, 60%, 65%, 70% or 75%.

[0115] In certain embodiments, the disclosed methods of treatment can decrease high levels of circulating serum cholesterol, such as LDL-C and VLDL-Cholesterol (very low-density lipoprotein-cholesterol). In addition, the disclosed methods are useful for decreasing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C and atherogenic lipoproteins. In certain embodiments, the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation. Subjects having a gain-of-function mutation in the PCSK9 gene also benefit with treatment with the disclosed compounds and compositions counteracting the mutation through their inhibition of PCSK9.

[0116] In some embodiments, crystalline AZD0780 in Form B is administered continuously.

[0117] The term “continuous” or “continuously” refers to administration of a therapeutic agent, e.g. crystalline AZD0780 in Form B, at regular intervals without stopping or interruption.

[0118] In some embodiments, crystalline AZD0780 in Form B is administered once a day (QD).

[0119] Methods of synthesis

[0120] Creating robust and safe synthetic routes for commercial drugs is a complex challenge. In addition to strict regulatory requirements for purity and impurities, there is an economic and environmentally driven desire to have efficient and high-yielding synthetic routes, ideally using readily available materials and ambient conditions. As such, there are many hurdles to overcome.

[0121] For all of steps (i) to (iv) and the preparation of compound 6 described below it is to be appreciated that the time taken for a reaction to go to completion is a function of many variables, and so the optimal reaction time may vary between different combinations of parameters and depending on the scale of a reaction. An appropriate reaction time for a particular set of conditions and for a particular scale can be determined by a practitioner of ordinary skill in the art using readily available analytical techniques, such as TLC, HPLC, NMR and MS.

[0122] Step (i): SNAr reaction

[0123] In WO 2020 / 150473, reaction of elaborated amine 1 with 2-fluoro-5-iodopyridine proceeds under high temperatures (140°C), with 3 equivalents of base and a yield of about 44% (see Reference Example 1 Step (i) WO 2020 / 150473). Similarly, in WO 2024 / 062090, reaction of amine 1 with 2-fluoro-5-iodopyridine proceeds at high temperatures (125°C) and 2 equivalents of base and only affords 67% yield (see Reference Example 2 Step (i)

[0124] WO 2024 / 062090). In contrast, the reaction of 5-bromo-2-fluoropyridine (compound 1) with tert-butyl ((1S, 3S)-3-aminocyclopentyl)carbamate (amine 1) can proceed at lower temperatures (<110°C), with fewer equivalents of base (<1.5 eq) and with a higher yield of 93% of tert-butyl ((1S,3S)-3-((5-bromopyridin-2-yl)amino)cyclopentyl)carbamate (compound 2). Compound 2 may subsequently be converted into compound 8.

[0125] It is further found that controlling reaction conditions such as temperature, reagent stoichiometries and reaction duration can help to control the formation of impurity tert-butyl ((1 R,3S)-3-(3-((1 S,3S)-3-((5-bromopyridin-2- yl)amino)cyclopentyl)ureido)cyclopentyl)carbamate (imp 1), which is otherwise difficult to purge during work up and isolation:

[0126] Imp 1

[0127] In some cases, when compound 2 is prepared according to a method of step (i), compound 2 comprises less than 0.5 % of Imp 1 relative to the total weight of the compound 2. Thus, in some embodiments there is provided compound 2 in the presence of less than 0.5 wt% of Imp1 (where the wt% relates to the total amount of compound 2 and Imp1).

[0128] In some cases, when compound 8 is prepared according to a method comprising step (i), the final material comprises less than 0.5 % of Imp 1 relative to the total weight of the final product. Thus, in some embodiments there is provided compound 8 in the presence of less than 0.5 wt%, less than 0.2 wt%, less than 0.1 wt%, or less than 0.01 wt% of Imp1 (where the wt% relates to the total amount of compound 8 and Imp1). In some embodiments, when compound 8 is prepared according to a method comprising step (i), compound 8 is provided in the absence of more than 0.5 wt%, more than 0.2 wt%, more than 0.1 wt%, or more than 0.01 wt% of Imp 1 relative to the total weight of the final material.

[0129] In the following description of step (i), amine 1 is the limiting reagent against which molar equivalents (eq) are calculated. Molar equivalents refer to the amount of reagent at the start of the reaction.

[0130] The amount of compound 1 in step (i) may be at least 1 eq, at least 1 .05 eq, at least 1.1 eq, or at least 1.15 eq. The amount of compound 1 in step (i) may be up to 1.5 eq, up to 1.4 eq, up to 1 .3 eq, or up to 1.25 eq. The amount of compound 1 in step (i) may be from 1 to 1 .5 eq, from 1.05 to 1.4 eq, from 1.1 to 1.3 eq, or from 1.15 to 1.25 eq. The amount of compound 1 may be from 1.1 to 1.3 eq. The amount of compound 1 may be 1 .2 eq.

[0131] The SNAr reaction of step (i) may be a base-mediated SNAr reaction. That is, the reaction of step (i) may proceed in the presence of a base. The base may be an organic or inorganic base. The base for use in step (i) may be an inorganic base. The inorganic base may be selected from a metal carbonate, metal bicarbonate or combinations thereof. The base for use in step (i) may be a group(l) or (II) metal carbonate or bicarbonate. The base for use in step (i) may be an inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, or potassium bicarbonate. The base for use in step (i) may be sodium carbonate or potassium carbonate. The base for use in step (i) may be sodium carbonate.

[0132] The base for use in step (i) may be present in at least 0.6 eq, at least 0.8 eq, at least 0.9 eq, or at least 1 eq. Undercharging the base (<0.6 eq) may lead to formation of HF and potentially result in etching of a glass vessel, which is a safety concern. The base for use in step (i) may be present in up to 1 .5 eq, up to 1 .4 eq, up to 1 .3 eq, or up to 1 .2 eq. The base for use in step (i) may be present in from 0.6 to 1 .5 eq., from 0.8 to 1 .4 eq, from 0.9 to 1 .3 eq, or from 1 to 1 .2 eq. The base for use in step (i) may be present in about 1.1 eq.

[0133] The SNAr reaction of step (i) may be carried out in a variety of organic solvents. Step (i) may be carried out in dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N- dimethylacetamide (DMAc), sulfolane, 2-methyltetrahydrofuran (2-MeTHF), a mixture of tetrahydrofuran (THF) and water, isopropylacetate (IPAc), acetonitrile (MeCN), toluene (PhMe), anisole, cyclopentyl methyl ether (CPME), diglyme, 3-pentanone, N,N- dimethylformamide (DMF) or combinations thereof. Step (i) may be carried out in dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, or combinations thereof. Step (i) may be carried out in DMSO.

[0134] Step (i) may be heated. The reaction of step (i) may be heated to at least 100°C, at least 102°C or at least 104°C. Reaction temperatures of less than 100°C may result in incomplete reaction and reduced yield. Step (i) may be heated up to 110°C, up to 108°C, or up to 106°C. Reaction temperatures of more than 110°C may result in increased impurity formation and reduced purity and yield. In the interest of maximizing product formation and minimizing byproducts, the reaction of step (i) may be heated at from 100 to 110°C, from 102 to 108°C, or from 104 to 106°C. The reaction of step (i) may be heated to about 105°C.

[0135] Step (i) may take place under the conditions comprising: an inorganic base; a temperature of from 100 to 110°C; a solvent selected from dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, 2-methyltetrahydrofuran (2-MeTHF), a mixture of tetrahydrofuran (THF) and water, isopropyl acetate (IPAc), acetonitrile (MeCN), toluene (PhMe), anisole, cyclopentyl methyl ether (CPME), diglyme, 3-pentanone, N,N- dimethylformamide (DMF) or combinations thereof.

[0136] Step (i) may take place under the conditions comprising:

[0137] 1 to 1 .5 eq of compound 1 ;

[0138] 0.6 to 1 .5 eq of an inorganic base; and a temperature of from 100 to 110°C.

[0139] In some of these cases, further conditions may be that the base is selected from a metal carbonate, metal bicarbonate or combinations thereof. The solvent in such cases may be DMSO. In some of these cases, compound 1 may be present in 1.1 to 1.3 eq, the base may be present in 1 to 1.2 eq, and the temperature may be from 104 to 106°C. Step (i) may take place under conditions comprising:

[0140] 1 to 1 .5 eq of compound 1 ;

[0141] 0.6 to 1 .5 eq of a base selected from sodium carbonate or potassium carbonate; a temperature of from 100 to 110°C; and a solvent selected from dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, 2-methyltetrahydrofuran (2-MeTHF), a mixture of tetrahydrofuran (THF) and water, isopropylacetate (IPAc), acetonitrile (MeCN), toluene (PhMe), anisole, cyclopentyl methyl ether (CPME), diglyme, 3-pentanone, N,N- dimethylformamide (DMF) or combinations thereof.

[0142] In some of these conditions, compound 1 may be present in 1.1 to 1.3 eq. The base may be present in 1 to 1.2 eq.

[0143] Step (i) may take place under conditions including at least one of:

[0144] 1 to 1 .5 eq of compound 1 ;

[0145] 0.6 to 1 .5 eq of sodium carbonate; and a temperature from 100 to 110°C.

[0146] In some cases, step (i) takes place under conditions including all three of these parameters.

[0147] Step (i) may take place under the conditions including at least one of:

[0148] 1.2 eq of compound 1 ;

[0149] 1.1 eq of an inorganic base; a temperature of about 105°C; a solvent selected from dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, 2-methyltetrahydrofuran (2-MeTHF), a mixture of tetrahydrofuran (THF) and water, isopropylacetate (IPAc), acetonitrile (MeCN), toluene (PhMe), anisole, cyclopentyl methyl ether (CPME), diglyme, 3-pentanone, N,N- dimethylformamide (DMF) or combinations thereof.

[0150] In some cases, step (i) takes place under conditions including all of these parameters. In some of these conditions, the solvent may be dimethyl sulfoxide (DMSO), N-methyl-2- pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, or mixtures thereof, and the base may be selected from a metal carbonate, a metal bicarbonate, or combinations thereof. The base may be sodium carbonate. Step (ii): Coupling

[0151] In WO 2020 / 150473, reaction of 5-methoxy-2-pyridone with 2-chloro-5-iodopyridine at the 5- position uses 0.1 equivalents of catalyst comprising 1 :2 Cu(l)l:CyDMEDA and a reaction temperature of 120°C to afford 32% yield (see Reference Example Step (ii) WO 2020 / 150473). The reaction of tert-butyl ((1S,3S)-3-((5-bromopyridin-2- yl)amino)cyclopentyl)carbamate (compound 2) with 2-pyridone can proceed under lower catalyst loadings, lower temperatures and afford higher yields. For example, using only 0.05 equivalents of catalyst comprising 1 :3 Cu(l)l:CyDMEDA and a reaction temperature of 110°C achieves a yield of around 83% of tert-butyl ((1S,3S)-3-((2-oxo-2H-[1 ,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate (compound 3). Compound 3 may subsequently be converted into compound 8.

[0152] Where step (ii) is mediated by a transition metal catalyst comprising a transition metal and a ligand, controlling the ratio of transition metal to ligand to be 1 :X where X is greater than 1 may increase the rate of reaction. In other words, increasing the amount of ligand relative to the amount of transition metal may increase the rate of reaction. A transition metal:ligand ratio of 1 :X where X is greater than 2, for example where X is 3, may exponentially increase the rate of reaction (see Figure 9).

[0153] In the following description of step (ii), compound 2 is the limiting reagent against which molar equivalents (eq) are calculated. Molar equivalents refer to the amount of reagent at the start of the reaction.

[0154] The reaction may take place in the presence of a catalyst. The catalyst may be a transition metal catalyst. The catalyst may be a pre-formed catalyst, or it may be generated in-situ, for example by the combination of a transition metal salt and an appropriate ligand. The catalyst may be a copper catalyst.

[0155] The catalyst may be present in an amount of from 0.005 eq, from 0.01 eq, from 0.02 eq, or from 0.03 eq. The catalyst may be present in an amount up to 0.2 eq, up to 0.19 eq, up to 0.15 eq, up to 0.10 eq, or up to 0.08 eq. The catalyst may be present in an amount of less than 0.2 eq, or less than 0.15 eq. The catalyst may be present in an amount of from 0.005 to 0.19 eq, from 0.01 to 0.15 eq, from 0.02 to 0.1 eq, or from 0.03 to 0.08 eq. The copper catalyst may be present in an amount of about 0.05 eq.

[0156] The copper catalyst may comprise copper metal or a copper salt. The copper catalyst may comprise a copper halide salt. The copper catalyst may comprise a copper(l) salt. The copper catalyst may comprise a copper(l) halide salt. The copper catalyst may comprise a copper(l) halide salt selected from copper(l) chloride, copper(l) bromide, copper(l) iodide, or combinations thereof. The copper catalyst may comprise a copper(l) halide salt, which is copper(l) iodide.

[0157] The copper catalyst may be generated in situ, for example by the coordination of a ligand with a copper ion from a copper salt. Thus, a ligand may be included in step (ii). The ligand may be selected from N,N'-dimethyl-1 ,2-cyclohexanediamine (CyDMEDA), N,N- dimethylethylenediamine (DMEDA), 4,7-dimethoxy-1 ,10-phenanthroline, 2-methylquinolin-8- ol, or combinations thereof. The ligand may be N,N'-dimethyl-1 ,2-cyclohexanediamine (CyDMEDA).

[0158] The copper catalyst may comprise a combination of a copper salt and a ligand. The copper catalyst may comprise a combination of copper(l) salt selected from copper(l) chloride, copper(l) bromide, copper(l) iodide, or combinations thereof, and a ligand. The ligand may be selected from N,N'-dimethyl-1 ,2-cyclohexanediamine (CyDMEDA), N,N- dimethylethylenediamine (DMEDA), 4,7-dimethoxy-1 ,10-phenanthroline, 2-methylquinolin-8- ol, or combinations thereof. The copper(l) salt may be copper(l) iodide and the ligand may be CyDMEDA.

[0159] The 2-pyridone may be present in an amount of from 0.9 eq, from 1 eq, from 1 .05 eq, or from 1 .075 eq. The 2-pyridone may be present in excess relative to the amount of compound 2. The 2-pyridone may be present in an amount of up to 1.5 eq, up to 1.2 eq, up to 1.175 eq, up to 1.15 eq, or up to 1.125 eq. The 2-pyridone may be present in an amount of from 1 eq to 1.2 eq, from 1.05 eq to 1.175 eq, or from 1.05 eq to 1.15 eq. 2-Pyridone may be present in an amount of about 1.1 eq.

[0160] Step (ii) may take place in the presence of a base. The base may be an inorganic base. The base for use in step (ii) may be an inorganic base selected from a metal carbonate, metal bicarbonate, metal phosphate or combinations thereof. The base for use in step (i) may be an inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, magnesium carbonate, calcium carbonate, sodium bicarbonate, or potassium bicarbonate. The base for use in step (i) may be sodium carbonate, potassium carbonate, or potassium phosphate. The base for use in step (ii) may be potassium carbonate.

[0161] The base may be present in an amount of from 1 eq, from 2 eq, from 2.5 eq, or from 2.8 eq. The base may be present in excess relative to the amount of compound 2. The base may be present in an amount of up to 5 eq, up to 4 eq, up to 3.5 eq, or up to 3.2 eq. The base may be present in an amount of from 1 eq to 5 eq, from 2 eq to 4 eq, from 2.5 eq to 3.5 eq, or from 2.8 eq to 3.2 eq. The base may be present in an amount of about 3 eq.

[0162] A group (I) or (II) metal iodide salt may be present to activate the bromo-pyridine moiety. The metal iodide salt may be selected from sodium iodide, potassium iodide, magnesium iodide, and calcium iodide. The metal iodide may be a group (I) metal iodide salt. The metal iodide salt may be selected from sodium iodide and potassium iodide. The metal iodide may be sodium iodide.

[0163] The metal iodide may be present in an amount of from 0.5 eq, from 1.0 eq, from 1.5 eq, or from 1 .9 eq. The metal iodide may be present in an amount of up to 3.5 eq, up to 3.0 eq, up to 2.5 eq, or up to 2.1 eq. The metal iodide may be present in an amount of from 0.5 eq to 3.5 eq, from 1 eq to 3 eq, from 1 .5 eq to 2.5 eq, or from 1 .9 eq to 2.1 eq. The metal iodide may be present in an amount of about 2 eq.

[0164] The reaction of step (ii) may be carried out in a variety of suitable solvents. Step (ii) may be carried out in a polar solvent. Step (ii) may be carried out in a solvent selected from anisole, dimethyl sulfoxide (DMSO), butyronitrile, n-butanol (nBuOH), cyclopentyl methyl ether (CPME), tert-amyl alcohol (tAmOH), 2-methyltetrahydrofuran (2-MeTHF), isopropyl acetate (IPAc), isopropyl alcohol (IPA), acetonitrile (MeCN), benzonitrile (PhCN), dimethylformamide (DMF), EtOH, or combinations thereof. Step (ii) may be carried out in benzonitrile (PhCN).

[0165] Step (ii) may be heated. The reaction of step (ii) may be heated to at least 90°C, at least 95°C, at least 100°C, at least 105°C, or at least 108°C. The reaction may be heated up to 130°C, up to 125°C, up to 120°C, up to 115°C, or up to 112°C. The reaction may be heated at from 90°C to 130°C, from 100°C to 120°C, or from 105°C to 115°C. The reaction may be heated at from 108°C to 112°C. The reaction may be heated at about 110°C. The ratio of transition metal to ligand comprising the catalyst in step (ii) may be 1 :X where X is greater than 1 , greater than 1.5, greater than 2, greater than 2.5, or greater than 3. The ratio of transition metal to ligand comprising the catalyst in step (ii) may be 1 :X where X is greater than 1. A ratio of transition metal to ligand comprising the catalyst of 1 :X where X is greater than 1 may increase the rate of reaction.

[0166] The ratio of transition metal to ligand comprising the catalyst may be 1 :X where X is greater than 2. Having a ratio of transition metal to ligand comprising the catalyst of 1 :X where X is greater than 2 may exponentially increase the rate of reaction. The ratio of transition metal to ligand comprising the catalyst may be 1 :X where X is equal to or greater than 2.5. The ratio of transition metal to ligand comprising the catalyst may be 1 :X where X is equal to or greater than 3. The ratio of transition metal to ligand comprising the catalyst in step (ii) may be 1 :X where X is equal to or smaller than 10, equal to or smaller than 8, equal to or smaller than 7, equal to or smaller than 6, equal to or smaller than 5 or equal to or smaller than 4.

[0167] The ratio of transition metal to ligand comprising the catalyst in step (ii) may be from 1 :1 to 1 :10, from 1 : 1 to 1 :8, or from 1 :1 to 1 :5. The ratio of transition metal to ligand comprising the catalyst in step (ii) may be from 1 :2 to 1 :10, from 1 :2 to 1 :8, from 1 :2 to 1 :7, from 1 :2 to 1 :5, or from 1 :2 to 1 :4. The ratio of transition metal to ligand comprising the catalyst may be from 1 :2 to 1 :4. The ratio of transition metal to ligand comprising the catalyst may be about 1 :3. The transition metal and ligand comprising the catalyst in step (ii) may be copper and CyDMEDA.

[0168] Step (ii) may take place under the conditions of: excess 2-pyridone; a copper catalyst in an amount of at least 0.01 eq; and a temperature from 90°C to 130°C.

[0169] In some of these conditions, the copper catalyst may be present in an amount of at least 0.05 eq. The copper catalyst may comprise a copper (I) salt. The ligand may be CyDMEDA. A solvent selected from anisole, dimethyl sulfoxide (DMSO), butyronitrile, n-butanol (nBuOH), cyclopentyl methyl ether (CPME), tert-amyl alcohol (tAmOH), 2-methyltetrahydrofuran (2- MeTHF), isopropyl acetate (IPAc), isopropyl alcohol (IPA), acetonitrile (MeCN), benzonitrile (PhCN), dimethylformamide (DMF), EtOH, or combinations thereof may also be present. The solvent may be PhCN. A base may also be present. The base may be a metal carbonate. The base may be present in excess relative to the amount of compound 2. The base may be potassium carbonate. A group (I) or (II) metal iodide may be present. The group (I) metal iodide may be sodium iodide or potassium iodide. The ratio of coppedigand in the copper catalyst may be 1 :X where X is greater than 1 . The ratio of copper:ligand may be 1 :X, where X is greater than 2, greater than 2.5, or greater than 3. The temperature may be from 105°C to 115°C.

[0170] Step (ii) may take place under conditions of:

[0171] 1 to 1.2 eq of 2-pyridone; a copper catalyst present in an amount of at least 0.01 eq;

[0172] 1 to 5 eq of a metal carbonate or metal phosphate; at least 0.5 eq of a group (I) or (II) metal iodide; and a temperature from 90°C to 130°C, wherein, the copper catalyst comprises copper(l) iodide and CyDMEDA in a ratio of from 1 :1 to 1 :10. In some cases the ratio of copper(l) iodide to CyDMEDA is 1 :X where X is greater than 2. In some cases the ratio of copper(l) iodide to CyDMEDA is 1 :X where X is greater than 2.5.

[0173] Step (ii) may take place under conditions including at least one of:

[0174] 1.1 eq of 2-pyridone;

[0175] 0.05 eq of a copper catalyst comprising copper (I) iodide and CyDMEDA in a ratio of about 1 :3;

[0176] 3 eq of potassium carbonate;

[0177] 2 eq of sodium iodide; a PhCN solvent; and a temperature of 110°C.

[0178] In some cases, step (ii) takes place under conditions including at least 2 of these parameters. In some cases, step (ii) takes place under conditions including all of these parameters.

[0179] The catalyst and any excess ligand from step (ii) may be removed by standard methods. For example, the catalyst and any excess ligand may be removed in aqueous work-up by washing with EDTA, HCI (aq.), and brine

[0180] Step (Hi): Fumaric acid / CSA salt formation compound 3 compound 4 where 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2-one (compound 4) is obtained as the fumaric acid or camphorsulfonic acid (CSA) salt.

[0181] In WO 2020 / 150473 and WO 2024 / 062090, compound 4 is obtained as the xHCI salt. The HCI salt forms in variable stoichiometry and is unstable due to being hygroscopic, which presents challenges for control and isolation. Isolation as the free base results in problems with oily phases in crystallisation and crusting. In contrast, the fumaric acid and camphorsulfonic acid salts of compound 4 reliably form a single stoichiometric salt and polymorph and are less hygroscopic. The CSA salt of compound 4 (e.g., compound 4a for CSA(+)), or fumaric acid salt of compound 4 (compound 4b) may subsequently be converted into compound 8. compound 4a compound 4b

[0182] In addition to reliably forming a 1 :1 salt, it is further found that the CSA(+) salt of 6'-(((1S,3S)- 3-aminocyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2-one (compound 4a) possesses advantageous physical properties for manufacturing. For example, the CSA(+) salt has excellent physical properties including excellent flow properties and solubility, particularly in n-butanol.

[0183] In the following description of step (iii), compound 3 is the limiting reagent against which molar equivalents (eq) are calculated. Molar equivalents refer to the amount of reagent at the start of the reaction.

[0184] Step (iii) may proceed via a Boc-deprotection, isolation of a free base, and formation of a CSA or fumaric acid salt of compound 4. These steps may take place without isolation of any of the intervening acid salt or free-base forms of compound 4. These steps may take place using standard reagents and conditions known in the art.

[0185] Methods for the removal of a tert-butoxycarbonyl (Boc) protecting group are well known, and any suitable method may be used. In an exemplary deprotection, the Boc protecting group may be removed by subjecting compound 3 to 37% w / w HCI aq. (2.5 eq) in water and at 20°C.

[0186] The Boc deprotection may take place in a variety of solvents. The solvent may be selected from dioxane, THF, ethanol, ethyl acetate, toluene, hexane, methanol, propanol, butanol, acetonitrile, chloroform, benzene, DCM, tetrahydrofuran, and water. The solvent may be water.

[0187] The Boc-deprotection takes place in the presence of an acid. The acid may be selected from a Bransted or Lewis acid. The acid may be a Bransted acid including sulfuric acid, p- toluenesulfonic acid (TsOH), methanesulfonic acid (MsOH), TFA, and HCI. The acid may be HCI.

[0188] The acid may be present in an amount of at least 1 eq, at least 1 .5 eq, or at least 2 eq. The acid may be present in an excess relative to the amount of compound 3. The acid may be present in an amount of up to 10 eq, up to 5 eq, or up to 3 eq. The acid may be present in an amount of from 1 eq to 10 eq, from 1 eq to 5 eq, from 1.5 eq to 5 eq, or from 2 eq to 3 eq. The acid may be present in an amount of about 2.5 eq.

[0189] The Boc-deprotection may take place at a temperature of at least 20°C. The Boc- deprotection may take place at a temperature of up to 80°C, up to 70°C, up to 60°C or up to 40°C The Boc-deprotection may take place at a temperature of from 20°C to 80°C, such as about 60°C.

[0190] Methods for the isolation of a free base are well known, and any suitable method may be used. In an exemplary work-up, the reaction mixture of the deprotection step is mixed with n- butanol (nBuOH) and 46% w / w K3PO4before agitating. The agitated mixture is left to separate into an aqueous phase and an organic phase, before removing the aqueous phase.

[0191] A base may be used in the work-up to generate the free-base. The base may be an organic or inorganic base. The base may be an inorganic base selected from a metal carbonate, metal bicarbonate, or metal phosphate. The base may be a metal phosphate. The base may be K3PO4.

[0192] The base may be present in an amount sufficient to neutralize the acid from the Boc- deprotection. The base may be present in an amount of at least 1 eq, at least 1 .3 eq, or at least 1 .5 eq. The base may be present in an amount of up to 5 eq, up to 3 eq, up to 2.5 eq, or up to 2.2 eq. The base may be present in an amount of from 1 eq to 5 eq, from 1 .3 eq to 3 eq, or from 1 .5 eq to 2.2 eq. The base may be present in an amount of about 1 .9 eq.

[0193] Methods for the formation of a salt are well known, and any suitable method may be used. In an exemplary case, the fumaric acid or CSA salt may be prepared by mixing the organic phase containing the free base with methanol and either CSA or fumaric acid. The CSA or fumaric acid salt of compound 4 crystallises from the obtained solution before filtration and drying at 60°C under reduced pressure.

[0194] The CSA or fumaric acid may be present in an amount of at least 1 eq. The CSA or fumaric acid may be present in an amount of up to 2 eq, up to 1 .5 eq, up to 1 .3 eq, up to 1 .2 eq, or up to 1.1 eq. The CSA or fumaric acid may be present in an amount of from 1 eq to 1.2 eq, or from 1 eq to 1 .1 eq. The CSA or fumaric acid may be present in an amount of about 1 .05 eq.

[0195] The organic phase may be concentrated by partial distillation prior to formation of the fumaric acid or CSA salt. The partial distillation may take place under reduced pressure and at a temperature suitable for the chosen solvent. The rate and yield of re-crystallisation may be improved by seeding the solution for re-crystallisation.

[0196] Step (iv): SNAr reaction compound 6 compound 4

[0197] Compound 8 where compound 4 is present as the fumaric acid salt or CSA salt.

[0198] In WO 2020 / 150473, the reaction of 2-chloro-5-(difluoromethoxy)pyrimidine (compound 6) with tert-butyl((1S, 3S)-3-aminocyclopentyl) carbamate takes place in the presence of DIPEA at 110°C and 12 hours (see Reference Example Step (iv) WO 2020 / 150473). The reaction in WO 2020 / 150473 is a small multigram scale reaction. In a multigram scale reaction, the reaction of 2-chloro-5-(difluoromethoxy)pyrimidine (compound 6) with compound 4 took place in the presence of DIPEA at 115°C and 48 hours. Reaction of compound 6 with compound 4 in the presence of an inorganic base can take place at a lower temperature (95°C) and at a faster rate (about 30 hours on a multi-kilogram scale). Compound 8 may be obtained as a salt or co-crystal.

[0199] In the following description of step (iv), the fumaric acid salt or CSA salt of compound 4 is the limiting reagent against which molar equivalents (eq) are calculated. Molar equivalents refer to the amount of solvent or reagent at the start of the reaction.

[0200] The amount of compound 6 in step (iv) may be at least 1 eq, at least 1 .025 eq, or at least 1 .05 eq. Compound 6 may be in excess relative to the amount of compound 4. The amount of compound 6 may be up to 1.5 eq, up to 1.3 eq, up to 1.2 eq, or up to 1.15 eq. The amount of compound 6 may be from 1 eq to 1 .5 eq, from 1 eq to 1 .3 eq, or from 1 eq to 1 .2 eq. The amount of compound 6 may be from 1 eq to 1.15 eq, or from 1.05 eq to 1.15 eq. The amount of compound 6 may be about 1.1 eq.

[0201] Step (iv) takes place in the presence of an inorganic base. The amount of inorganic base in step (iv) may be at least 2 eq, at least 3 eq, at least 3.5 eq, or at least 3.8 eq. The inorganic base may be in excess relative to the amount of compound 4. The amount of inorganic base may be up to 6 eq, up to 5 eq, up to 4.5 eq, or up to 4.2 eq. The amount of inorganic base may be from 2 eq to 6 eq, from 3 eq to 5 eq, or from 3.5 eq to 4.5 eq. The amount of inorganic base may be from 3.8 eq to 4.2 eq. The amount of inorganic base may be about 4 eq.

[0202] The inorganic base in step (iv) may be selected from a metal carbonate or a metal bicarbonate. The inorganic base may be selected from a group (I) or (II) metal carbonate or bicarbonate. The inorganic base may be selected from a metal carbonate. The inorganic base may be selected from a group (I) or (II) metal carbonate. The inorganic base may be selected from a group (I) metal carbonate. The inorganic base may be sodium carbonate or potassium carbonate. The inorganic base may be sodium carbonate.

[0203] Step (iv) may take place in a variety of solvents. The solvent may be a polar solvent. The solvent may be selected from an alcohol or anisole. The alcohol solvent may be selected from methanol, ethanol, isomers of propanol, isomers of butanol, isomers of pentanol, isomers of hexanol, or combinations thereof. The solvent may be n-butanol (nBuOH), anisole, or sec-butanol (sBuOH). The solvent may be nBuOH. A second solvent, which is water, may also be present.

[0204] Step (iv) may be heated. The reaction of step (iv) may be heated to at least 80°C, at least 85°C, or at least 90°C. The reaction of step (iv) may be heated up to 100°C, or up to 99°C. Exceeding a reaction temperature of 100°C may increase side-reactions, such as that of the solvent and compound 6. The reaction of step (iv) may be heated at from 80°C to 100°C, or from 85°C to 100°C. The reaction of step (iv) may be heated at from 90°C to 99°C. The reaction of step (iv) may be heated at about 95°C.

[0205] Step (iv) may take place under conditions including at least one of: an excess of compound 6; an excess of an inorganic base; an alcohol or anisole solvent; a temperature from 80°C to 100°C.

[0206] In some of these cases, the reaction takes place under all these conditions. In some cases, the amount of compound 6 may be up to 1 .5 eq. In some cases, the inorganic base may be selected from a metal carbonate or a metal bicarbonate. The inorganic base may be selected from a metal carbonate. The inorganic base may be sodium or potassium carbonate. The solvent may be nBuOH. The temperature may be from 90°C to 100°C. Step (iv) may take place under conditions including at least one of:

[0207] 1 eq to 1 .2 eq of compound 6;

[0208] 4 eq of an inorganic base; nBuOH or anisole solvent; a temperature from 90°C to 100°C. In some of these cases, the reaction takes place under all these conditions. In some cases, the inorganic base is a metal carbonate or metal bicarbonate. In some cases, the inorganic base is a metal carbonate. The metal carbonate may be sodium or potassium carbonate.

[0209] Step (iv) may take place under conditions of:

[0210] 1 eq to 1 .2 eq of compound 6; a base which is a metal carbonate; nBuOH solvent; a temperature from 90°C to 100°C; and a second solvent, which is water.

[0211] In some of these cases, the metal carbonate is sodium or potassium carbonate. In some cases, the metal carbonate is sodium carbonate. In some cases, the amount of compound 6 is 1 .1 eq. In some cases, the amount of metal carbonate is 4 eq. In some cases, the temperature is 95°C.

[0212] Compound 8 may be obtained as the succinic acid co-crystal. The succinic acid co-crystal is advantageously easier to isolate than the free base of compound 8, which may suffer from poor filtration rates and uncontrolled crystallisation. The succinic acid co-crystal may be prepared by mixing of the free base of compound 8 with succinic acid and a solvent. A suitable solvent may be methanol. To form the succinic acid co-crystal, succinic acid may be added in an amount of at least 1 eq, at least 1.05 eq, at least 1.1 eq, or at least 1.15 eq. Adding succinic acid in an amount of at least 1 .08 eq may advantageously increase yield. Succinic acid may be added in an amount of up to 1 .4 eq, up to 1 .35 eq, or up to 1 .3 eq. Succinic acid may be added in an amount of from 1 eq to 1 .4 eq, from 1 .05 eq to 1 .35 eq, from 1.1 eq to 1.3 eq, or from 1.15 eq to 1.3 eq. Succinic acid may be added in an amount of about 1.25 eq. Compound 6 (2-chloro-5-(difluoromethoxy)pyrimidine) compound 5 compound 7 compound 6

[0213] Preparations of 2-chloro-5-(difluoromethoxy)pyrimidine (compound 6) use difluoromethylation reagents including sodium chlorodifluoroacetate, bromodifluoroacetate, and methyl chlorodifluoroacetate. However, these reagents typically require high temperatures (up to 100°C), unsustainable or unscalable solvents (e.g., DMF), unsustainable bases (e.g., cesium carbonate), long reaction times, unscalable purifications (e.g., column chromatography) and low yields (34-56%). For example, in WO 2020 / 150473, the multigram scale reaction of 2- chloropyrimidin-5-ol (compound 5) with sodium 2-chloro-2,2-difluoroacetate uses cesium carbonate, DMF, requires purification by column chromatography and only affords compound 6 in 51% yield.

[0214] The use of diethyl (bromodifluoromethyl)phosphonate (compound 7) as the difluoromethylation reagent in the preparation of compound 6 allows the reaction to proceed using readily available materials (e.g., potassium hydroxide base and acetonitrile / water solvent), low temperatures (less than 20°C), short reaction times (less than 3 hours), scalable purification (by distillation) and excellent yields (greater than 70%).

[0215] In the following description of the preparation of compound 6, compound 5 is the limiting reagent against which molar equivalents (eq) are calculated. Molar equivalents refer to the amount of reagent at the start of the reaction.

[0216] The amount of compound 7 in the preparation of compound 6 may be at least 1 eq, at least 1.1 eq, at least 1.15 eq, or at least 1.2 eq. Compound 7 may be present in excess relative to the amount of compound 5. The amount of compound 7 may be up to 1 .6 eq, up to 1 .5 eq, up to 1 .45 eq, or up to 1.4 eq. The amount of compound 7 may be from 1 eq to 1 .6 eq, from 1.1 eq to 1.5 eq, or from 1.15 eq to 1.45 eq. The amount of compound 7 may be from 1.2 eq to 1 .4 eq. The amount of compound 7 may be about 1 .25 eq.

[0217] The preparation of compound 6 may use a base. The base used for the preparation of compound 6 may be an organic base or an inorganic base. The organic base may be DIPEA. The inorganic base used for the preparation of compound 6 may be a metal hydroxide. The metal hydroxide may be selected from a group(l) or (II) metal hydroxide. The metal hydroxide may be a group(l) metal hydroxide. The metal hydroxide may be selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide. The base used for the preparation of compound 6 may be potassium hydroxide.

[0218] The base may be present in excess relative to the amount of compound 5. The amount of base may be at least 5 eq, at least 10 eq, at least 15 eq, or at least 18 eq. The amount of base may be up to 35 eq, up to 30 eq, p to 25 eq, or up to 22 eq. The amount of base may be from 5 eq to 35 eq, from 10 eq to 30 eq, or from 15 eq to 25 eq. The amount of base may be from 18 eq to 22 eq. The amount of base may be from 5 eq to 20 eq. The amount of base may be about 10 eq, about 15 eq, or about 20 eq. The amount of base may be about 10 eq. The amount of base may be about 15 eq.

[0219] The preparation of compound 6 may take place in a variety of solvents. The preparation of compound 6 may take place in a solvent selected from ethanol (EtOH), water, isopropanol (iPrOH), 2-ethoxyethanol, benzonitrile (PhCN), propionitrile (PrCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile (MeCN), dioxane, tetrahydrofuran (THF), or combinations thereof. The preparation of compound 6 may take place in a mixture of solvents. The mixture of solvents may be a mixture of 2 solvents. The solvent used in the preparation of compound 6 may be a mixture of acetonitrile and water.

[0220] The reaction for the preparation of compound 6 may take place at a temperature of less than 10°C, less than 0°C, less than -2°C, or less than -5°C. The reaction for the preparation of compound 6 may take place at a temperature of at least -20°C, at least -15°C, or at least - 10°C. The reaction for the preparation of compound 6 may take place at a temperature from - 20°C to 0°C, from -15°C to -2°C, or from -10°C to -5°C. The reaction for the preparation of compound 6 may take place at a temperature of about -7°C.

[0221] The reaction for the preparation of compound 6 may take place in the presence of a phase transfer catalyst. The phase transfer catalyst may advantageously reduce the relative volumes of solvent and equivalents of base required. The phase transfer catalyst may be present in an amount of from 0.1 eq, from 0.2 eq, from 0.5 eq, or from 0.8 eq. The phase transfer catalyst may be present in an amount of up to 100 eq, up to 50 eq, up to 10 eq, up to 5 eq, or up to 2 eq. The phase transfer catalyst may be present in an amount of from 0.1 eq to 10 eq, from 0.1 eq to 5 eq, from 0.5 eq to 2 eq, or from 0.8 eq to 1.5 eq. The phase transfer catalyst may be present in an amount of about 1 eq. The phase transfer catalyst may be selected from any phase transfer catalyst known in the art. For example, the phase transfer catalyst may be a quaternary ammonium salt, such as tetrabutylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride and methyltributylammonium chloride. The phase transfer catalyst may be benzyltriethylammonium chloride (BTEAC).

[0222] The reaction for the preparation of compound 6 may take place under conditions comprising: at least 1 eq of compound 7; an inorganic base; a mixture of water and acetonitrile; and a temperature of less than 0°C.

[0223] The base may be a metal hydroxide. The base may be potassium hydroxide. A phase transfer catalyst may also be present. The phase transfer catalyst may be present in at least 0.1 eq. The phase transfer catalyst may be a quaternary ammonium salt. The phase transfer catalyst may be BTEAC.

[0224] Examples

[0225] General conditions

[0226] (i) operations were carried out at room temperature (rt), i.e. in the range 17 to 28°C and where needed under an atmosphere of an inert gas such as N2;

[0227] (ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g));

[0228] (iii) when necessary, organic solutions were dried over anhydrous MgSO4or Na2SO4, or by using ISOLUTE® Phase Separator, and work-up procedures were carried out using traditional phase separating techniques. When a drying agent such as e.g. MgSO4or Na2SO4is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer;

[0229] (iv), evaporations were carried out either by rotary evaporation in vacuo or in a Genevac HT-41 EZ-2 or Biotage V10, unless specified otherwise;

[0230] (v) yields, where present, are not necessarily the maximum attainable, and when necessary, reactions were repeated if a larger amount of the reaction product was required;

[0231] In general, chemical structures of compounds containing the label '&' at a stereocenter, means the configuration of such compound at that stereocenter is a mixture of both (R) and (S); and a label 'or' means the configuration of such compound at that stereocenter is either (S) or (R). Absolute, unspecified, '&', and 'or1stereocenters can all be present in a single structure.

[0232] In general, for structures of compounds where all of the stereocenters are designated as '&', the structure is named with a “rac-” prefix. For structures of compounds where all of the stereocenters are designated as 'or1, the structure is named with a “rel-” prefix.

[0233] In general, for compounds containing more than one stereocenter the relative stereochemistry is described using configurational descriptors ‘S’ and ‘R’ for the stereogenic centers and using the “rac-“ or “rel-“ prefix cited at the front of the name.

[0234] The following abbreviations are used herein:

[0235] 2-Me-THF 2-Methyltetrahydrofuran

[0236] ACN / MeCN Acetonitrile

[0237] BuOAc n-Butyl acetate

[0238] DCM Dichloromethane

[0239] DMF Dimethylformamide

[0240] DMSO Dimethyl sulfoxide

[0241] Et Ethyl

[0242] EtOAc Ethyl acetate

[0243] EtOH Ethanol i PrO Ac Isopropyl acetate g Gram h Hour(s)

[0244] IPA 2-propyl alcohol

[0245] L Litre

[0246] LDL-C LDL cholesterol

[0247] M Molar Me Methyl

[0248] MEK Methyl ethyl ketone

[0249] MIBK Methyl isobutyl ketone

[0250] MTBE Methyl tert-butyl ether mL Millilitre mol eq Molar equivalents pL Microlitre Min Minutes mmol Millimole NMR Nuclear magnetic resonance

[0251] RH Relative Humidity rt Room temperature rel vol / RV Relative volume rel wt / RW Relative weight

[0252] THF Tetrahydrofuran

[0253] %w / v Percent Weight / Volume

[0254] %v / v Percent Volume / Volume

[0255] Example 1

[0256] AZD0780 (30 mg) was dissolved in a mixture of tetrahydrofuran and water (2:1) (3 mL) and the solution filtered through a 0.2 mm filter into a 4 mL vial. This was immersed in liquid nitrogen until frozen. The vial was covered in filter paper and was lyophilised under vacuum for 18 hours at 20°C. This yielded AZD0780 in amorphous form.

[0257] Example 2

[0258] AZD0780 as an amorphous solid was agitated in ethyl acetate as a slurry at 5°C for 7 days. The solid was analysed by X-ray powder diffraction and determined to be Form A.

[0259] Example 3

[0260] AZD0780 as an amorphous solid was agitated at 5°C in acetonitrile for 7 days. The solid was then analysed by X-ray powder diffraction and determined to be Form B.

[0261] Example 4

[0262] AZD0780 (1.1 g, 1 mol eq) was charged to a vial and dissolved in methanol (2.2 mL, 2 rel vol) and the solution was magnetically stirred at room temperature. In a separate vial, fumaric acid (0.3 g, 1.1 mol eq) was dissolved in methanol (7.7 mL, 7 rel vol).

[0263] The solution of fumaric acid was added to the solution of AZD0780 leading to spontaneous formation of solid. The slurry was stirred for < 2 hours and then the solid was collected by filtration. The solid was dried in a vacuum oven to yield AZD0780 fumaric acid form.

[0264] Example 5

[0265] AZD0780 (20.3 g, 1 mol eq) was stirred in ethanol (203 mL, 10 rel vol) and the mixture heated to 50°C to form a solution. A solution of fumaric acid in ethanol (9.5 mL at 30 mg / mL, 0.05 mol eq) was added followed by AZD0780 fumaric acid form seed (269 mg, 0.01 mol eq). The mixture was stirred at 50°C for approximately 18 hours. A solution of fumaric acid in ethanol (180 mL at 30 mg / mL, 0.95 mol eq) was charged over 8 hours. The mixture was stirred at 50°C for 8 hours and then cooled to 20°C over 8 hours. After stirring at 20°C for a further 16 hours, the solid was collected by filtration. The solid was washed twice with ethanol (80 mL, 4 rel vol) and then dried to constant weight to yield AZD0780 fumaric acid form (21.8 g, 83 mol%).

[0266] Example 6

[0267] AZD0780 succinic acid form

[0268] To a mixture of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2-one.xHCI (11) (25.00 g, 65.2 mmol, 1 mol eq) in n-butanol (149 ml_, 6 rel vol) at 25°C was charged N,N- diisopropylethylamine (68.2 ml_, 6 mol eq) and 2-chloro-5-(difluoromethoxy)pyrimidine (I2 or Compound 6) (13.08 g, 1.1 mol eq). The mixture was heated to approximately 116°C and stirred until complete reaction (typically around 40 hours). The mixture was cooled to 20°C. Ethyl acetate (371 ml_, 15 rel vol) was added and then a solution of citric acid (24.8 g, 1.0 rel wt) in water (248 ml_, 10 rel vol) was added. The mixture was stirred and then the phases allowed to settle and the lower aqueous phase was removed. Water (248 ml_, 10 rel vol) was mixed with the organic phase, the phases allowed to settle and the lower aqueous phase removed. The two aqueous phases were combined and extracted with ethyl acetate (173 ml_, 7 rel vol). The organic phases were combined and stirred with a thiol-based scavenger resin (4.95 g, 0.2 rel wt) and stirred for at least 3 hours. The mixture was filtered to remove the resin and the residue was washed with ethyl acetate (25 ml_, 1 rel vol). The combined filtrate was concentrated to approximately 10 rel vol by vacuum distillation. Ethyl acetate (124 ml_, 5 rel vol) was added and the mixture was concentrated to approximately 10 rel vol by vacuum distillation. A further portion of ethyl acetate (124 ml_, 5 rel vol) was added and the mixture was again concentrated to approximately 10 rel vol by vacuum distillation. The mixture was analysed for residual water. If the level was sufficiently low then the mixture was stirred at 25°C and a solution of succinic acid (8.31 g, 1 .08 mol eq) in methanol (62 ml_, 2.5 rel vol) was added over approximately 45 minutes. The mixture was stirred at 25°C for 2 hours and then cooled to 15°C over 30 minutes and stirred for at least 2 hours. The solid was collected by filtration and the solid was washed three times with ethyl acetate (50 mL, 2 rel vol). The solid was dried to constant weight to yield AZD0780 succinic acid form (25.27 g, 71%).

[0269] Example 7

[0270] To a stirred mixture of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2-one.xHCI (11) (57.5 g, 82.9%w / w, 0.13 mol, 1 mol eq) in 1-butanol (345 mL) was charged N,N- diisopropylethylamine (127 mL, 5.8 mol eq). 2-chloro-5-(difluoromethoxy)pyrimidine (I2 or Compound 6) (23.4 g, 1.02 mol eq) was added washing the residue into the reactor with 1- butanol (11 .5 mL). The mixture was heated to approximately 113°C and stirred for 2 days. The mixture was cooled to 25°C. Ethyl acetate (1330 mL) and water (500 mL) was added. The phases were mixed and then allowed to separate. The mixture was filtered and the lower aqueous phase was removed. The remaining organic phase was mixed with 10%w / v sodium chloride in water (500 mL) and the phases allowed to separate. The mixture was filtered and the lower aqueous phase was removed. The remaining organic phase was mixed with water (500 mL) and the phases allowed to separate. The mixture was filtered and the lower aqueous phase was removed. The remaining organic phase was concentrated to approximately 5 rel vol. n-Butyl acetate (715 mL) was added and the mixture was concentrated to approximately 5 rel vol. AZD0780 Form A Seed (approximately 30 mg) was added to the stirred dark solution. The slurry was transferred to a vessel (washing the mixture into the vessel with n-butyl acetate (10 mL). The stirred mixture was heated to 90°C over 10 hours and then stirred at 90°C for 30 minutes. The mixture was then set to cool to 70°C over 3 hours and stirred at 70°C for 2.25 hours. AZD0780 Form A Seed was added and the mixture stirred at 70°C for 10 hours. The mixture was cooled to 40°C over 3 hours, stirred at 40°C for 16 hours and then cooled to 20°C over 16.7 hours. The mixture was stirred at 20°C for 29 hours. The mixture was heated to 40°C over 1 hour. n-Heptane (50 ml_, 1 rel vol) was added over 2 hours. After stirring for 1 .3 hours, n-heptane (25 ml_, 0.5 rel vol) was added over 1 hour. The mixture was stirred at 40°C for 1 hour and then cooled to 20°C over 5 hours. After stirring at 20°C for 15 hours, the solid was collected by filtration. The solid was washed twice with a mixture of n-butyl acetate and n-heptane (1 : 1 v / v, 50 mL for each wash). The solid was dried to yield AZD0780 Form A (42.2 g, 78% yield).

[0271] Example 8

[0272] To a stirred mixture of AZD0780 succinic acid form (3.0 kg) and 2-butanone (34.2 L, 11.4 rel vol) was slowly added a mixture of water (21.6 L, 7.2 rel vol), sodium chloride (0.6 kg, 0.2 rel wt) and aqueous ammonium hydroxide (25 wt% in water, 0.96 kg, 2.5 mol eq). After stirring for at least 1 hour, the stirrer was stopped and the phases allowed to separate. The lower aqueous phase was removed. A solution of sodium chloride (3.0 kg, 1 rel wt) in water (16.8 L, 5.6 rel vol) was added to the retained organic phase and the phases were mixed for at least 1 hour. The stirrer was stopped and the phases were allowed to separate. The lower aqueous phase was removed. The retained organic phase was concentrated to 5 rel vol under reduced pressure. 2-Butanone (15.0 L, 5 rel vol) was charged and the mixture was concentrated to 5 rel vol under reduced pressure. 2-Butanone (13.5 L, 4.5 rel vol) was added to the retained organic phase and the mixture was heated to 50°C. The mixture was passed through a filter, 2-butanone (1.5 L, 0.5 rel vol) was charged as a line wash, filtered and combined with the bulk filtrate. The combined filtrate was concentrated to 5 rel vol under reduced pressure. The mixture was heated to 55°C and then cooled to 40°C. AZD0780 Form B seed (0.06 kg, 0.02 rel wt) was charged and then 2-butanone (0.3 L, 0.10 rel vol) was applied as a line wash. The mixture was stirred at 40°C for at least 8 hours. The mixture was then cooled to 20°C over 200 minutes and stirred for at least 2 hours. The slurry was circulated through a wet mill. The slurry was then heated to 43°C over 115 minutes, stirred for 2 hours, cooled to 20°C over 230 minutes and then stirred at 20°C for at least 1 hour. The heat cool cycle was repeated a further two times. The wet milling and heat / cool cycling was repeated until the required particle size distribution was achieved. n-Heptane (15.0 L, 5 rel vol) was charged over at least 2.5 hours at 20°C and the mixture was stirred for at least 3 hours at 20°C. The solid was collected by filtration and was washed with a mixture of 2- butanone (3.3 L, 1.1 rel vol) and n-heptane (2.7 L, 0.9 rel vol). The solid was dried to constant weight to yield AZD0780 form B (2.15 kg, 92% yield).

[0273] Example 9

[0274] A solution of potassium carbonate (44.95 kg, 1 .5 mol eq) in water (805.3 kg, 7 rel vol) was charged to a stirred mixture of AZD0780 crude succinic acid co-crystal (117.50 kg at 98% w / w, 1 mol eq) in ethyl acetate (930.5 kg, 9 rel vol). The stirrer was stopped and the lower aqueous phase was removed. The remaining organic phase was concentrated to approximately 5.5 rel vol. 2-Butanol (720.7 kg, 7.8 rel vol) was added and the mixture was concentrated to approximately 5.5 rel vol. 2-Butanol (280.0 kg, 3 rel vol) was added and the mixture was concentrated to approximately 5.5 rel vol. The temperature of the mixture was adjusted to 70°C and stirred. The solution was filtered, washing the filter with 2-butanol (18.5 kg, 0.2 rel vol). The combined filtrate was stirred at 70°C and then cooled to 60°C. AZD0780 Form B seed (0.449 kg, 0.5 mol%) was added to the mixture. The mixture was stirred at 60°C for 12 hours and then cooled to 20°C at a rate of approximately 5°C / hour. The mixture was stirred at 20°C for 2 hours and then sampled for losses to liquors. The solid was collected by filtration. The solid was washed with a mixture of 2-butanol (36.80 kg, 0.4 rel vol) and MTBE (102.40 kg, 1.2 rel vol) and then with MTBE (135.80 kg, 1.6 rel vol). The solid was dried to yield AZD0780 Form B (80.6 kg, 90% yield).

[0275] Example 10

[0276] Competitive slurries of AZD0780 Form A and Form B were carried out in dry EtOAc, 1% v / v water in EtOH, 1% v / v water in IPA, 1% v / v water in 1-PrOH, 4% v / v water in EtOH and MEK:water (40:1) which all yielded Form B at 25°C and 50°C. Slurries in BuOAc:heptane (10:3) yielded a mixture of Form A and Form B at both 25°C and 50°C. This shows that Form B is the most stable form.

[0277] The solvents were dried over molecular sieves and saturated suspensions of AZD0780 Form A and Form B were prepared. The vials were sealed and stirred for 7 days. After 7 days the solids were isolated by centrifugation and decantation and analysed by XRPD.

[0278] Analysis of different forms

[0279] G 'S

[0280] Gravimetric vapour sorption (GVS) analysis was performed using a TA Instrument GVS, model Discovery SA.

[0281] A sample (approximately 5-10 mg) is transferred to a fared sample holder. The instrument is purged with nitrogen, (chamber 200 mL / min and balance 20 mL / min) at 25°C and data are collected at different relative humidity (%RH). Starting at 20%RH and going stepwise up to 80%RH, down stepwise to 0%RH, and eventually a second cycle going up to 90%RH and back to 0%RH. The equilibrium criteria for moving to next %RH is reached when the drift criteria (dm / dt) is below 0.002 for 10 min. Hygroscopicity can be assessed according to European Pharmacopoeia (EP) classification: non-hygroscopic: <0.2%; slightly hygroscopic: 0.2% to <2%; hygroscopic: 2% to <15%; very hygroscopic: >15%; deliquescent: sufficient water absorbed to form a liquid; all values measured as weight increase at 80%RH and 25°C.

[0282] AZD0780 Form A exhibited a reversible moisture uptake of <0.2 % between 40% relative humidity and 80% relative humidity at 25°C ±0.1 °C. According to the European Pharmacopoeia (EP) classification, AZD0780 Form A is non-hygroscopic.

[0283] AZD0780 Form B exhibited a reversible moisture uptake of <0.2 % between 40% relative humidity and 80% relative humidity at 25°C ±0.1 °C. According to the European Pharmacopoeia (EP) classification, AZD0780 Form B is non-hygroscopic.

[0284] AZD0780 Succinic acid form exhibited a reversible moisture uptake of <0.2 % between 40% relative humidity and 80% relative humidity at 25°C ±0.1 °C. According to the European Pharmacopoeia (EP) classification, AZD0780 Succinic acid is non-hygroscopic.

[0285] AZD0780 Fumaric acid form exhibited a reversible moisture uptake of <0.2 % between 40% relative humidity and 80% relative humidity at 25°C ±0.1 °C. According to the European Pharmacopoeia (EP) classification, AZD0780 Fumaric acid is non-hygroscopic.

[0286] X-ray diffraction

[0287] The capillary transmission powder X-ray diffraction was recorded with a two theta scan axis and in one dimensional scan with Rigaku SmartLab (nickel-Filtered Cu Karadiation, 40 kV, 50 mA) equipped with D / tex Ultra 250 detector and CBO-E optic. The samples were rotated at 30 revolution per minute during measurement. Samples were scanned from 3-40° 2-theta using a 0.01 ° and 0.27min step width and scan speed, respectively. The powder samples were packed in long glass capillary with 0.9 mm outer diameter.

[0288] Definition of intensity

[0289] The relative intensities are derived from diffractograms measured with fixed slits It is known that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions. Therefore, it should be understood that the crystalline forms disclosed herein are not limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction patterns shown in the Figures. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of X-ray powder diffraction patterns.

[0290] Persons skilled in the art of X-ray powder diffraction will realize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios, which may affect analysis of samples. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values. (Jenkins & Snyder 1996, Bunn 1961 , Klug & Alexander 1974).

[0291] Form A

[0292] AZD0780 Form A has an X-ray powder diffraction pattern substantially as shown in Figure 1 . The ten most prominent peaks are: Form B

[0293] AZD0780 Form B has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0294] The ten most prominent peaks are: AZD0780 fumaric acid form

[0295] AZD0780 fumaric acid form has an X-ray powder diffraction pattern substantially as shown in

[0296] Figure 3. The ten most prominent peaks are: AZD0780 succinic acid form

[0297] AZD0780 succinic acid form has an X-ray powder diffraction pattern substantially as shown in Figure 4. The ten most prominent peaks are:

[0298] Solid-state NMR

[0299] Variable contact time15N cross-polarisation magic angle spinning (CPMAS) solid-state NMR spectra are consistent with AZD0780 succinate form and AZD0780 fumarate form being cocrystals rather than salts.

[0300] Solubility

[0301] The solubility of AZD0780 Form A and Form B were assessed in 3 different solvents and solvent mixtures (IPA, EtOAc and BuOAc:heptane (10:3)).

[0302] AZD0780 Form A material had a solubility of 7.8mg / ml_ in BuOAc:heptane (10:3), 24.1 mg / ml_ in IPA and 46.5mg / ml_ in EtOAc. AZD0780 Form B material had a solubility of 3.9mg / ml_ in butylacetate:heptane (10:3), 13.8mg / ml_ in IPA and 24.7mg / ml_ in EtOAc. This demonstrates the greater stability of Form B.

[0303] Degradation

[0304] The stability of AZD0780 Form B, AZD0780 fumaric acid form and AZD0780 succinic acid form was measured in a forced degradation study. The study was carried out over a 3 week period at 70°C / 11%RH or 70°C / 75%RH, and none of the tested forms showed any degradation. Reference Example 1 Step (I) WO 2020 / 150473

[0305] A suspension of 131 C (150 mg, 0.669 mmol, 1.0 eq), 2-fluoro-5-iodopyridine (178.9 mg, 0.802 mmol, 1.2 eq) and K2CO3(277.2 mg, 2.006 mmol, 3.0 eq) in DMSO (5 mL) was stirred at 140°C under N2for 16.5 hours. The reaction mixture was cooled down to room temperature and filtered. The filtrate was diluted with ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced vacuum. The crude residue was purified by flash chromatography on silica gel (PE: EA = 1 :1) to give (1S,3S)-N1- (5-iodopyridin-2-yl)-N3-(5-(methylthio)pyrimidin-2-yl)cyclopentane-1 ,3-diamine (compound 463A, 125.5 mg, 44% yield). MS (ESI): m / z [M+H]+= 428.1.

[0306] Reference Example 2 Step (I) WO 2024 / 062090

[0307] Step A i-1 a

[0308] 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (2.23 g, 9.99 mmol) was added to tertbutyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (2.00 g, 9.99 mmol) and K2CO3(2.76 g, 20 mmol) in DMSO (30 mL). The resulting solution was stirred at 125°C for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give tert-butyl ((1S,3S)-3-((5-iodopyridin-2- yl)amino)cyclopentyl)carbamate (compound i-1 a, 2.70 g, 67% yield) as a pale yellow solid. MS (ESI): m / z [M+H]+= 403.9.

[0309] Example 11 Step (I)

[0310] A vessel was charged with DMSO (2200 L, 5.0 RV*) and agitated. To the vessel was added amine 1 (449 kg, 1.0 eq) and sodium carbonate (256 kg, 1.1 eq). The vessel was inerted with nitrogen after which was added compound 1 (464 kg, 1.2 eq) and the reaction mixture heated to 105°C and agitated for 16 hours. The reaction mixture was then cooled to 80°C, charged with water (220 L, 0.5 RV) and further cooled to 20°C over 150 min. Water (4180 L, 9.5 RV) was then added and the mixture stirred for 4 hr at 20°C. The crude mixture was filtered, washed with water (1x1320 L, 3 RV and 2x2640 L, 6 RV) and the wet cake dried at 60°C under reduced pressure until the Karl-Fischer water content was <0.8%w / w to afford tertbutyl ((1S,3S)-3-((5-bromopyridin-2-yl)amino)cyclopentyl)carbamate (compound 2, 749.4 kg, 92.9% yield),1H NMR (400 MHz, DMSO, 24°C) 1.32 - 1.43 (11 H, m), 1.65 - 2.08 (4H, m), 3.89 - 3.94 (1 H, m), 4.09 - 4.18 (1H, m), 6.42 (1 H, d), 6.78 (1 H, d), 6.89 (1 H, d), 7.48 (1 H, dd), 8.00 (1 H, d).

[0311] *the terms relative volume (RV) and relative weight (RW) are defined as the volume and weight of material required relative to the “weight at 100% purity” charge of amine 1 . In this example, the assayed purity was 98%, so the “weight at 100% purity” was 440 kg and relative volumes and weight are relative to this.

[0312] Control of Imp 1

[0313] Conditions for the control of the formation of Imp 1 in step (i) were investigated. Figure 5 shows the relationship between the rate of formation of compound 2 and the amount of compound 1 , base and temperature relative to standard conditions of 1 eq amine 1 , 1.1 eq. compound 1 , 1.1 eq base, and a temperature of 110°C. Compared to standard conditions, the rate of formation of compound 2 increased under excess compound 1 or high T (120°C). Compared to standard conditions, the rate of formation of compound 2 decreased at low T (100°C) and remains the same for an excess of base. Figure 6 shows the relationship between the rate of formation of Imp 1 for the same conditions as in Figure 5. However, the formation of Imp 1 increased significantly under high T (120°C) and was almost unchanged by excess base or compound 1. Formation of Imp 1 decreased at low T (100°C), but these conditions showed slower formation of compound 2 and a lower overall conversion after 25 hours.

[0314] Figures 7A and 7B are two heat maps of conditions predicted to afford <0.2% yield of Imp 1 and >96% yield of compound 2 using 1 .1 eq base after 20 hours (top) and 24 hours (bottom).

[0315] As shown by the region indicated by the star in Figure 7A, by carefully balancing temperature, stoichiometry of compound 1 and reaction time it is possible to afford compound 2 in high yields whilst also minimising the amount of Imp 1 to <0.2%. The reaction time must be controlled to reduce Imp 1 levels, as the region where Imp 1 < 0.2% and Compound 2 > 96% changes with the effect of reaction time (see Figures 7A and 7B, the stars represent the same set of conditions at different reaction time; for Figure 7A it falls in the region where Imp 1 <0.2% but in Figure 7B it does not.). A set of conditions falling within this starred area of 1.2 eq compound 1 , 1.1 eq base, and a temperature of 105°C were experimentally validated, as shown in Figure 8, and afforded compound 2 with <0.2% Imp 1 if the reaction was stopped before 24 hours.

[0316] Reference Example Step (ii) WO 2020 / 150473

[0317] Example 400A

[0318] A mixture of compound 2-chloro-5-iodopyridine (191 mg, 0.8 mmol, 1.0 eq), 5- methoxypyridin-2(1 H)-one (100 mg, 0.8 mmol, 1.0 eq), Cui (15 mg, 0.08 mmol, 0.1 eq), N,N'- Dimethyl-1 , 2-cyclohexanediamine (23 mg, 0.16 mmol, 0.2 eq) and K3PO4(339 mg, 1.6 mmol, 2 eq) in DMSO (5 mL) was stirred at 120 °C under N2atmosphere overnight. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x2), The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel eluting with PE: EA = 1 :1 to afford 6'-chloro-5-methoxy-2H-[1 ,3'-bipyridin]-2-one (compound 400A, 60 mg, 0.23 mmol, 32%) as an off-white solid.

[0319] Example 11 Step (II)

[0320] A vessel was charged with benzonitrile (2490 L, 8.0 RV*) and agitated. To the vessel was added potassium carbonate (361 kg, 3.0 eq), sodium iodide (261 kg, 2.0 eq), compound 2 (317 kg, 1 eq) and 2-pyridone (92.0 kg, 1.1 eq). The vessel headspace was inerted with nitrogen, and nitrogen was bubbled through the mixture to inert the contents, after which was added copper (I) iodide (8.28 kg, 0.05 eq) and CyDMEDA (18.6 kg, 0.15 eq). The contents of the vessel were inerted for a second time by bubbling nitrogen through the mixture. The reaction mixture was then heated to 110°C and agitated for 8 hours. The reaction mixture was then cooled to 50°C, charged with n-butanol (2790 L, 9 RV) and further cooled to 20°C. The mixture was washed four times: the first two times each with an aqueous solution of 0.25 M Na4EDTA (1550 L, 5 RV), the third time with an aqueous solution of 0.1 M HCI (1490 L, 4.8 RV), and the fourth time with an aqueous solution of 0.5 wt% NaCI (1550 L, 5 RV). The organic phase was concentrated under reduced pressure and a maximum temperature of 80°C to 7 RVs (2170 L). The mixture was then heated to 85°C and cooled to 0°C over 12 h. The mixture was then filtered, washed with isopropyl acetate (2x931 L, 3.0 RV) and dried at 60°C under reduced pressure until the Karl-Fischer water content was <0.8%w / w to afford tert-butyl {(1S,3S)-3-[(2-oxo-2H-[1 ,3'-bipyridin]-6'- yl)amino]cyclopentyl}carbamate (compound 3, 276 kg, 83% yield),1H NMR (500 MHz, DMSO, 27°C) 1.36 - 1.45 (11 H, m), 1.68 - 1.82 (2H, m), 1.90 - 1.99 (1 H, m), 2.00 - 2.11 (1 H, m), 3.88 - 3.98 (1 H, m), 4.16 - 4.27 (1 H, m), 6.23 - 6.28 (1 H, m), 6.41 - 6.45 (1 H, m), 6.47 - 6.51 (1 H, m), 6.85 (1 H, br d), 6.89 (1 H, br d), 7.37 (1 H, dd) 7.46 (1 H, ddd), 7.56 - 7.60 (1 H, m), 7.90 (1 H, d).

[0321] *the terms relative volume (RV) and relative weight (RW) are defined as the volume and weight of material required relative to the “weight at 100% purity” charge of compound 2. In this example, the assayed purity was 98%, so the “weight at 100% purity” was 310 kg and relative volumes and weight are relative to this.

[0322] Catalyst loading

[0323] Reactions were performed with three different ligand loadings (mol%) for a 5 mol% loading of Cu(l) I according to table 1 . EoR LCAP = Extent of Reaction measured by Liquid Chromatography Area Percent.

[0324] • Table 1

[0325] The results of these reactions are shown in Figure 9. The rate of formation of compound 3 almost doubled for a Cu / L ratio of 1 :2 compared to a Cu / L ratio of 1 :1 , with more than twice as much conversion after 21 hours. The rate of reaction was almost 9 times faster for a Cu / L ratio of 1 :3 compared to a Cu / L ratio of 1 :1 with almost full conversion after 21 hours despite the low catalyst loading. Example 11 Step (Hi) compound 3 compound 4 where compound 4 is obtained as the fumaric acid or camphorsulfonic acid (CSA) salt. The exemplified method below provides the camphorsulfonic acid salt (compound 4a). The fumaric acid salt may be prepared in an analogous fashion.

[0326] A vessel was charged with compound 3 (352 kg, 1 eq) and water (1760 L, 5 RV). The vessel headspace was inerted with nitrogen, and the contents heated to 60°C. The vessel was then charged with 37% w / w HCI (277 L, 2.5 eq) over 1 hour. The mixture was then cooled to 10°C and the vessel charged with n-butanol (3520 L, 10 RV) and 46% w / w K3PO4aq. (1410 L, 4 RV). The resultant mixture was heated to 20°C and agitated for 30 min before leaving to settle. The aqueous phase was removed, n-butanol (1760 L, 5 RV) was added, the mixture was stirred for 15 min, and the remaining organic phase was concentrated under reduced pressure to 6.5 RV before filtration (washed with n-butanol, 352 L, 1 RV). The filtrate was heated to 40°C and a solution of [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1- yl]methanesulfonic acid) (CSA(+), 232 kg, 1.05 eq) in methanol (2150 L, 6.1 RV) was added slowly. The resultant mixture was cooled to 20°C and filtered (washed once with a mixture of n-butanol and methanol, 1 :1 , 1590 L, 4.5 RV, and once with MTBE, 1060 ml_, 3 RV). The cake was dried under reduced pressure at 60°C and a nitrogen atmosphere until a constant weight was obtained, to afford the CSA(+) salt of 6'-{[(1S,3S)-3-aminocyclopentyl]amino}-2H- [1 ,3'-bipyridin]-2-one (compound 4a, 436 kg, 91.1% yield),1H NMR (400 MHz, D2O, 23°C) 0.82 (3H, s), 1.03 (3H, s), 1.41 - 1.79 (4H, m), 1.95 - 2.08 (2H, m), 2.11 - 2.16 (3H, m), 2.25 - 2.45 (4H, m), 2.85 (1 H, d), 3.27 (1H, d), 3.82 - 4.36 (2H, m), 6.61 - 6.65 (1 H, m), 6.70 - 6.73 (2H, m), 7.51 - 7.54 (1 H, m), 7.59 - 7.61 (1 H, m), 7.72 - 7.77 (1 H, m), 7.96 - 7.97 (1 H, m).

[0327] *the terms relative volume (RV) and relative weight (RW) are defined as the volume and weight of material required relative to the “weight at 100% purity” charge of compound 3. In this example, the assayed purity was 100.0%, so the “weight at 100% purity” was 352.4 kg and relative volumes and weight are relative to this. Salt Investigation

[0328] Various salts of compound 4 were prepared and their polymorphic complexity (i.e., number of polymorphs observed) and stability investigated as shown in table 2.

[0329] Table 2

[0330] The CSA(+), fumaric, and L-tartaric acid salts showed only 1 or 2 polymorph patterns and low initial mass loss and hygroscopicity. Despite good properties, in larger scale test crystallisations the L-tartaric acid produced very thick / immobile slurries, material coating agitators, sticky / gummy solids, and cake cracking. The fumaric acid and CSA(+) salts performed better than L-tartaric acid in the recrystallisation in terms of slurry properties, impurity purging, processability and yield recovery. Unexpectedly, in step (iv), the CSA(+) salt of compound 4 was found to have superior flow properties and superior solubility in n-butanol than the fumaric acid salt; the CSA(+) salt required only 6 relative volumes (RV) of n-butanol to mobilise the slurry compared to 9 RV for the fumaric acid salt. Reference Example Step (iv) WO 2020 / 150473

[0331] A mixture of 410A (40 g, 260 mmol, 1 eq) tert-butyl ((1S, 3S)-3-aminocyclopentyl) carbamate (55 g, 275 mmol, 1.05 eq) and DIPEA (105 g, 814 mmol, 3.13 eq) in DMSO (400 mL) was stirred at 110°C for 12 hours under N2. The mixture was then cooled down to room temperature and diluted with water (1000 mL). The resulting mixture was extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (eluting with hexane: ethyl acetate=5:1 to 4:1) to afford tert-butyl ((1S,3S)-3-((5- cyclopropylpyrimidin-2-yl)amino)cyclopentyl)carbamate (compound 410B, 55 g, 66% yield) as a pale solid. LCMS [M+H]+=319.

[0332] Example 11 step (iv)

[0333] AZD0780. succinic acid co-crystal

[0334] A vessel was charged in succession with n-butanol (2010 L, 6 RV), water (168 L, 0.5 RV), Na2CO3(283 kg, 4.0 eq), the CSA(+) salt of compound 4 (338 kg, 1 eq), compound 6 (134 kg, 1.1 eq), heated to 95°C, and agitated for 36 hours. The vessel was cooled to 20°C and charged with isopropyl acetate (1340 L, 4 RV) and 1.7% w / w citric acid aq. (2010 L, 6 RV) added slowly. The contents were agitated until complete dissolution observed and then left to settle. The aqueous layer was removed, and the organic layer washed with water (2x3350 L, 10 RV) and separated. The remaining organic phase was concentrated under reduced pressure to 10 RV. The organic layer was cooled to 20°C and mixed with a solution of succinic acid (85 kg, 1.08 eq) in methanol (838 L, 2.5 RV) and stirred. The mixture was filtered and the cake washed with isopropyl acetate (2x1005 L, 3 RV). The wet cake was dried under reduced pressure at 50°C and a nitrogen atmosphere until a constant weight was obtained, to afford the succinic acid co-crystal of 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)-2- pyrimidinyl]amino}cyclopentyl]amino}-2H-[1 ,3'-bipyridin]-2-one (AZD0780. succinic acid cocrystal, 302 kg, 84.4% yield), 1 H NMR (500 MHz, DMSO, 27°C) 1.42 - 1.59 (2H, m), 1.81 - 1.94 (2H, m), 2.04 - 2.19 (2H, m), 2.41 (4H, s), 4.24 - 4.36 (2H, m), 6.23 - 6.28 (1 H, m), 6.43 (1 H, d), 6.51 (1 H, d), 6.84 - 7.19 (2H, m), 7.38 (1 H, dd), 7.43 - 7.49 (2H, m), 7.58 (1 H, dd), 7.91 (1 H, d), 8.22 (2H, s), 12.13 (2H, br s).

[0335] *the terms relative volume (RV) and relative weight (RW) are defined as the volume and weight of material required relative to the “weight at 100% purity” charge of compound 4. In this example, the assayed purity was 99.0%, so the “weight at 100% purity” was 335 kg and relative volumes and weight are relative to this.

[0336] Example 12 - preparation of compound 6 compound 5 compound 7 compound 6

[0337] A vessel was charged with acetonitrile (2560 L, 19 RV) and compound 5 (135 kg, 1 eq) whilst agitating. The mixture was cooled to -7°C and, whilst maintaining this temperature, a solution of 30% w / w KOH aq. (2250 L, 15 eq, 17 RV) was added. Whilst maintaining a temperature of -7°C, compound 7 (351 kg, 1 .25 eq) was added and the reaction mixture agitated for 30 min. The mixture was heated to 20°C, and to this was added MTBE (1350 L, 10 RV) and 10% w / w NaCI aq. (851 L, 6.3 RV). The mixture was agitated for 30 min and then left to settle. The aqueous phase was removed, and to the organics was added 20% w / w NaCI aq. (451 L, 3.3 RV). The mixture was agitated for 30 min and then left to settle. The aqueous phase was removed, and to the organics was added 20% w / w NaCI aq. (1430 L, 10.6 RV) and 5.6% w / w citric acid aq. (27 L, 0.2 RV) to reach a pH of 6-7. The mixture was agitated for 30 min and then left to settle. The aqueous phase was removed and the organics concentrated under reduced pressure to 1-1 .5 RV to afford a crude product. The crude product was purified by fractional distillation under reduced pressure and a temperature of <120°C, to afford 2-chloro- 5-(difluoromethoxy)pyrimidine (compound 6, 146 kg, 78.9% yield,),1H NMR (400 MHz,

[0338] CDC , 27 C) 6.63 (1 H, t), 8.53 (2H, s). *the terms relative volume (RV) and relative weight (RW) are defined as the volume and weight of material required relative to the “weight at 100% purity” charge of compound 5. In this example, the assayed purity was 99.3%, so the “weight at 100% purity” was 134 kg and relative volumes and weight are relative to this.

[0339] References

[0340] All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety for all purposes. Numbered Statements A

[0341] A1 . Crystalline 6'-([( 1 S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (AZD0780) in form B:

[0342] A2. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 29±0.2° at 21 .9°.

[0343] A3. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 29±0.2° at 19.1 °.

[0344] A4. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 29±0.2° at 11 .6°.

[0345] A5. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 21 .9° and 19.1 °.

[0346] A6. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 21 .9° and 11.6°.

[0347] A7. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 19.1 ° and 11.6°.

[0348] A8. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising at least three peaks expressed as 29±0.2° at 21.9°, 19.1 ° and 11.6°. A9. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising the following six peaks expressed as 29±0.2°: 4.9, 11.6, 19.1 , 21.9, 22.8 and 24.5.

[0349] A10. Crystalline AZD0780 Form B according to statement A1 , characterised by an X-ray powder diffraction pattern comprising the following ten peaks expressed as 29±0.2°: 4.9, 11.6, 15.2, 16.0, 19.1 , 19.5, 21.1 , 21.9, 22.8 and 24.5.

[0350] A11 . Crystalline AZD0780 Form B according to statement A1 , wherein the X-ray powder diffraction pattern is substantially similar to Figure 2.

[0351] A12. Crystalline 6'-([( 1 S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (AZD0780): and succinic acid as a co-crystal.

[0352] A13. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 26±0.2° at 7.6°.

[0353] A14. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 26±0.2° at 7.9°.

[0354] A15. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 26±0.2° at 19.2°.

[0355] A16. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 7.6° and 19.2°.

[0356] A17. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 7.6° and 7.9°.

[0357] A18. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 7.9° and 19.2°.

[0358] A19. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising at least three peaks expressed as 29±0.2° at 7.6°, 7.9° and 19.2°.

[0359] A20. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising the following five peaks expressed as 29±0.2°: 7.6, 7.9, 15.2, 15.9 and 19.2.

[0360] A21 . Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, characterised by an X-ray powder diffraction pattern comprising the following ten peaks expressed as 26±0.2°: 7.6, 7.9, 10.6, 11.3, 15.2, 15.9, 17.0, 19.2, 24.6 and 28.4.

[0361] A22. Crystalline AZD0780 and succinic acid as a co-crystal according to statement A12, wherein the X-ray powder diffraction pattern is substantially similar to Figure 3.

[0362] A23. Crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (AZD0780): and fumaric acid as a co-crystal. A24. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 29±0.2° at 25.7°.

[0363] A25. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 29±0.2° at 15.9°.

[0364] A26. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising at least one peak expressed as 29±0.2° at 20.6°.

[0365] A27. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 25.7° and 15.9°.

[0366] A28. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 25.7° and 20.6°.

[0367] A29. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising at least two peaks expressed as 29±0.2° at 20.6° and 15.9°.

[0368] A30. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising the following five peaks expressed as 26±0.2°: 6.1 , 15.9, 20.6, 21.3 and 25.7.

[0369] A31 . Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, characterised by an X-ray powder diffraction pattern comprising the following ten peaks expressed as 26±0.2°: 6.1 , 10.3, 11.1 , 15.9, 19.9, 20.6, 21.3, 22.6, 25.7 and 27.9.

[0370] A32. Crystalline AZD0780 and fumaric acid as a co-crystal according to statement A23, wherein the X-ray powder diffraction pattern is substantially similar to Figure 4.

[0371] A33. A pharmaceutical composition comprising crystalline AZD0780 in Form B according to any one of statements A1 to A11 , and a pharmaceutically acceptable excipient, carrier or diluent.

[0372] A34. Crystalline AZD0780 in Form B according to any one of statements A1 to A11 for use in a method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease in a subject.

[0373] A35. Crystalline AZD0780 in Form B for use according to statement A34, wherein the use is in a method of lowering LDL-C levels.

[0374] A36. Crystalline AZD0780 in Form B for use according to statement A35, wherein the subject is an adult with primary hyperlipidemia.

[0375] A37. Crystalline AZD0780 in Form B for use according to any one of statements A34 to

[0376] A36, wherein the LDL-C level is reduced to:

[0377] (a) less than 100 mg / dL;

[0378] (b) less than 70 mg / dL;

[0379] (c) less than 55 mg / dL; or

[0380] (d) less than 40 mg / dL.

[0381] A38. Crystalline AZD0780 in Form B for use according to any one of statements A34 to A37, wherein the reduction of the untreated level of LDL-C is by:

[0382] (a) greater than or equal to 30%;

[0383] (b) greater than or equal to 40%;

[0384] (c) greater than or equal to 50%;

[0385] (d) greater than or equal to 60%;

[0386] (e) greater than or equal to 65%;

[0387] (f) greater than or equal to 70%; or

[0388] (g) great than or equal to 75%.

[0389] A39. Crystalline AZD0780 in Form B for use according to statement A34, wherein the use is in a method of reducing cardiovascular risk.

[0390] A40. Crystalline AZD0780 in Form B for use according to statement A39, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event. A41. Crystalline AZD0780 in Form B for use according to statement A34, wherein the use is in treating a cardiovascular disease.

[0391] A42. Crystalline AZD0780 in Form B for use according to statement A41 , wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

[0392] A43. Crystalline AZD0780 in Form B for use according to either statement A41 or statement A42, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

[0393] A44. Crystalline AZD0780 in Form B for use according to any one of statements A41 to A43, wherein the cardiovascular disease to be treated is:

[0394] (a) hypercholesterolemia, such as familial hypercholesterolemia;

[0395] (b) hyperlipidemia; or

[0396] (c) coronary artery disease.

[0397] A45. The use of crystalline AZD0780 in Form B according to any one of statements A1 to A11 in the manufacture of a medicament for use in the lowering of LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease in a subject.

[0398] A46. The use of AZD0780 in Form B according to statement A45, wherein the medicament is for use in lowering LDL-C levels.

[0399] A47. The use of AZD0780 in Form B according to statement A46, wherein the subject is an adult with primary hyperlipidemia.

[0400] A48. The use of AZD0780 in Form B according to any one of statements A45 to A47, wherein the LDL-C level is reduced to:

[0401] (a) less than 100 mg / dL;

[0402] (b) less than 70 mg / dL;

[0403] (c) less than 55 mg / dL; or (d) less than 40 mg / dL.

[0404] A49. The use of AZD0780 in Form B according to any one of statements A45 to A48, wherein the reduction of the untreated level of LDL-C is by:

[0405] (a) greater than or equal to 30%;

[0406] (b) greater than or equal to 40%;

[0407] (c) greater than or equal to 50%;

[0408] (d) greater than or equal to 60%;

[0409] (e) greater than or equal to 65%;

[0410] (f) greater than or equal to 70%; or

[0411] (g) great than or equal to 75%.

[0412] A50. The use of AZD0780 in Form B according to statement A45, wherein the medicament is for use in reducing cardiovascular risk.

[0413] A51 . The use of AZD0780 in Form B according to statement A50, wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

[0414] A52. The use of AZD0780 in Form B according to statement A45, wherein the medicament is for use in treating a cardiovascular disease.

[0415] A53. The use of AZD0780 in Form B according to statement A52, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

[0416] A54. The use of AZD0780 in Form B according to either statement A52 or statement A53, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

[0417] A55. The use of AZD0780 in Form B according to any one of statements A52 to A54, wherein the cardiovascular disease to be treated is:

[0418] (a) hypercholesterolemia, such as familial hypercholesterolemia; (b) hyperlipidemia; or

[0419] (c) coronary artery disease.

[0420] A56. A method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease, comprising administering to a subject in need thereof crystalline AZD0780 in Form B according to any one of statements A1 to A11 .

[0421] A57. The method according to statement A56, which is a method of lowering LDL-C levels.

[0422] A58. The method according to statement A57, wherein the subject is an adult with primary hyperlipidemia.

[0423] A59. The method according to any one of statements A56 to A58, wherein the LDL-C level is reduced to:

[0424] (a) less than 100 mg / dL;

[0425] (b) less than 70 mg / dL;

[0426] (c) less than 55 mg / dL; or

[0427] (d) less than 40 mg / dL.

[0428] A60. The method according to any one of statements A56 to A59, wherein the reduction of the untreated level of LDL-C is by:

[0429] (a) greater than or equal to 30%;

[0430] (b) greater than or equal to 40%;

[0431] (c) greater than or equal to 50%;

[0432] (d) greater than or equal to 60%;

[0433] (e) greater than or equal to 65%;

[0434] (f) greater than or equal to 70%; or

[0435] (g) great than or equal to 75%.

[0436] A61 . The method according to statement A56, which is a method of reducing cardiovascular risk.

[0437] A62. The method according to statement A61 , wherein the subject is an adult with atherosclerotic cardiovascular disease (ASCVD) or at high or intermediate risk for a first ASCVD event.

[0438] A63. The method according to statement A56, which is treating a cardiovascular disease. A64. The method according to statement A63, wherein the cardiovascular disease treated is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure and congestive heart failure.

[0439] A65. The method according to either statement A63 or statement A64, wherein the cardiovascular disease to be treated is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

[0440] A66. The method according to any one of statements A63 to A65, wherein the cardiovascular disease to be treated is:

[0441] (a) hypercholesterolemia, such as familial hypercholesterolemia;

[0442] (b) hyperlipidemia; or

[0443] (c) coronary artery disease.

[0444] A67. A method of obtaining AZD0780 in crystalline Form B of any one of statements A1 to A11.

[0445] A68. A method according to statement A67 comprising the step of converting the AZD0780 succinic acid form or AZD0780 fumaric acid form to crystalline AZD0780 in Form B.

[0446] A69. A method of making crystalline AZD0780 succinic acid form of any one of statements A12 to A22.

[0447] A70. A method of making crystalline AZD0780 fumaric acid form of any one of statements A23 to A32.

[0448] Numbered Statements B

[0449] B1 . A process for preparing 6'-([(1 S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:

[0450] Compound 8 comprising one or more of steps (i) to (iv):

[0451] (i) contacting compound 1 and amine 1 to form compound 2:

[0452] (ii) contacting compound 2 and 2-pyridone to form compound 3: compound 2 2-pyridone compound 3

[0453] (iii) deprotecting compound 3 with an acid and forming a fumaric acid or camphorsulfonic acid salt of compound 4:

[0454] compound 3 compound 4

[0455] (iv) contacting compound 6 and the fumaric acid or camphorsulfonic acid salt of compound 4 in the presence of an inorganic base to form compound 8 or a salt or cocrystal thereof:

[0456] Compound 8 wherein compounds 1 to 3 and 6, and amine 1 may be provided as a salt.

[0457] B2. A process for preparing compound 8 or a salt or co-crystal thereof according to statement B1 , comprising two or more of steps (i) to (iv).

[0458] B3. A process for preparing compound 8 or a salt or co-crystal thereof according to statement B1 , comprising three or more of steps (i) to (iv).

[0459] B4. A process for preparing compound 8 or a salt or co-crystal thereof according to statement B1 , comprising one of steps (i) to (iv).

[0460] B5. A process for preparing compound 8 or a salt or co-crystal thereof according to statement B1 , comprising two of steps (i) to (iv).

[0461] B6. A process for preparing compound 8 or a salt or co-crystal thereof according to statement B1 , comprising three of steps (i) to (iv). B7. A process for preparing compound 8 or a salt or co-crystal thereof according to statement B1 , comprising all of steps (i) to (iv).

[0462] B8. A process for preparing 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:

[0463] Compound 8 comprising step (i):

[0464] (i) contacting compound 1 and amine 1 to form compound 2: compound 1 amine 1 compound 2 wherein compound 1 , amine 1 and compound 2 may be provided as a salt.

[0465] B9. The process according to statement B8, further including the step of converting compound 2 into compound 8 or a salt or co-crystal thereof.

[0466] B10. A process for preparing 6'-([(1 S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:

[0467] Compound 8 comprising step (ii):

[0468] (ii) contacting compound 2 and 2-pyridone to from compound 3: compound 2 2-pyridone compound 3 wherein compound 2 and 3 may be provided as a salt.

[0469] B11. The process according to statement B10, further including the step of converting compound 3 into compound 8 or a salt or co-crystal thereof.

[0470] B12. A process for preparing 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:

[0471] Compound 8 comprising step (iii): deprotecting compound 3 with an acid and forming a fumaric acid or camphorsulfonic acid salt of compound 4: compound 3 compound 4 wherein compound 3 may be provided as a salt. B13. The process according to statement B12, further including the step of converting compound 4 into compound 8 or a salt or co-crystal thereof.

[0472] B14. A process for preparing 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:

[0473] Compound 8 comprising step (iv):

[0474] (iv) contacting compound 6 and the fumaric acid or camphorsulfonic acid salt of compound 4 in the presence of an inorganic base to form compound 8 or a salt or cocrystal thereof: wherein compound 6 may be provided as a salt.

[0475] B15. The process according to statement B14, wherein compound 8 is provided as the succinic acid co-crystal.

[0476] B16. A process for preparing 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:

[0477] Compound 8 comprising steps (i) to (iv):

[0478] (i) contacting compound 1 and amine 1 to form compound 2: compound 1 amine 1 compound 2

[0479] (ii) contacting compound 2 and 2-pyridone to form compound 3:

[0480] (iii) deprotecting compound 3 with an acid and forming a fumaric acid or camphorsulfonic acid salt of compound 4: compound 3 compound 4

[0481] ; and

[0482] (iv) contacting compound 6 and the fumaric acid or camphorsulfonic acid salt of compound 4 in the presence of an inorganic base to form compound 8 or a salt or cocrystal thereof: wherein compounds 1 to 3 and 6, and amine 1 may be provided as a salt.

[0483] B17. The process according to any one of statements B1 to B8 or B16, wherein step (i) takes place in the presence of at least 1 .2 equivalents of compound 1 .

[0484] B18. The process according to any one of statements B1 to B8, B16, or B17, wherein step (i) takes place in the presence of up to 1 .5 equivalents of compound 1 .

[0485] B19. The process according to any one of statements B1 to B8 or B16, wherein step (i) takes place in the presence of from 1 to 1.5 equivalents of compound 1.

[0486] B20. The process according to any one of statements B1 to B8, and B16 to B19, wherein step (i) takes place in the presence of a base.

[0487] B21 . The process according to statement B20, wherein the base is an inorganic base.

[0488] B22. The process according to statement B21 , wherein the inorganic base is selected from a metal carbonate, a metal bicarbonate, or combinations thereof.

[0489] B23. The process according to statement B22, wherein the inorganic base is a group(l) or (II) metal carbonate.

[0490] B24. The process according to statement B23, wherein the inorganic base is sodium carbonate or potassium carbonate. B25. The process according to any one of statements B20 to B24, wherein the base is present in an amount of at least 0.6 equivalents.

[0491] B26. The process according to any one of statements B20 to B24, wherein the base is present in excess relative to the amount of amine 1 .

[0492] B27. The process according to any one of statements B20 to B26, wherein the base is present in an amount of up to 1 .5 equivalents.

[0493] B28. The process according to any one of statements B20 to B24, wherein the base is present in an amount of from 1 to 1.5 equivalents.

[0494] B29. The process according to any one of statements B1 to B8 and B16 to B28, wherein step (i) takes place in the presence of a solvent selected from dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, 2-methyltetrahydrofuran (2-MeTHF), a mixture of tetrahydrofuran (THF) and water, isopropylacetate (IPAc), acetonitrile (MeCN), toluene (PhMe), anisole, cyclopentyl methyl ether (CPME), diglyme, 3-pentanone, N,N-dimethylformamide (DMF) or combinations thereof.

[0495] B30. The process according to statement B29, wherein the solvent is DMSO solvent.

[0496] B31. The process according to any one of statements B1 to B8 and B16 to B30, wherein step (i) takes place at a temperature of at least 100°C.

[0497] B32. The process according to any one of statements B1 to B8 and B16 to B31 , wherein step (i) takes place at a temperature of up to 110°C.

[0498] B33. The process according to any one of statements B1 to B8 and B16 to B30, wherein step (i) takes place at a temperature of from 100°C to 110°C.

[0499] B34. The process according to any one of statements B1 to B8 and B16, wherein step (i) takes place under conditions comprising: 1 to 1 .5 equivalents of compound 1 ;

[0500] 0.6 to 1 .5 equivalents of a base; and a temperature from 100 to 110°C. B35. The process according to any one of statements B1 to B8 and B16, wherein step (i) takes place under conditions comprising:

[0501] 1 to 1 .5 equivalents of compound 1 ;

[0502] 0.6 to 1 .5 equivalents of a base selected from sodium carbonate or potassium carbonate; a temperature from 100 to 110°C; and a solvent selected from dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), sulfolane, 2-methyltetrahydrofuran (2-MeTHF), a mixture of tetrahydrofuran (THF) and water, isopropylacetate (IPAc), acetonitrile (MeCN), toluene (PhMe), anisole, cyclopentyl methyl ether (CPME), diglyme, 3- pentanone, N,N-dimethylformamide (DMF) or combinations thereof.

[0503] B36. The process according to any one of statements B1 to B8 and B16, wherein step (i) takes place under conditions comprising:

[0504] 1 .2 equivalents of compound 1 ;

[0505] 1.1 equivalents of a base; a temperature of about 105°C; and a DMSO solvent.

[0506] B37. The process according to any one of statements B1 to B7, B10 and B16, wherein step (ii) takes place in the presence of a transition metal catalyst comprising a metal and a ligand.

[0507] B38. The process according to statement B37, wherein the ratio of transition metal to ligand comprising the catalyst is 1 :X where X is greater than 1 .

[0508] B39. The process according to statement B38, wherein the ratio of transition metal to ligand comprising the catalyst is 1 :X where X is greater than 2.

[0509] B40. The process according to statement B39, wherein the ratio of transition metal to ligand comprising the catalyst is 1 :X where X is equal to or greater than 3.

[0510] B41 . The process according to any one of statements B37 to B40, wherein the transition metal catalyst is a copper catalyst.

[0511] B42. The process according to statement B41 , wherein the copper catalyst comprises a copper(l) salt. B43. The process according to statement B42, wherein the copper catalyst comprises a copper(l) halide salt.

[0512] B44. The process according to any one of statements B41 to B43, wherein the copper catalyst comprises a ligand selected from N,N'-dimethyl-1 ,2-cyclohexanediamine (CyDMEDA), N,N-dimethylethylenediamine (DMEDA), 4,7-dimethoxy-1 ,10- phenanthroline, 2-methylquinolin-8-ol„ or combinations thereof.

[0513] B45. The process according to statement B44, wherein the copper catalyst comprises a ligand, which is CyDMEDA.

[0514] B46. The process according to any one of statements B37 to B45, wherein the catalyst is present in an amount of from 0.005 equivalents.

[0515] B47. The process according to any one of statements B37 to B45, wherein the ligand is present in an amount of from 0.05 equivalents to 0.5 equivalents.

[0516] B48. The process according to any one of statements B1 to B7, B10, B16, and B37 to B47, wherein 2-pyridone is present in an amount of from 1 equivalent.

[0517] B49. The process according to any one of statements B1 to B7, B10, B16, and B37 to B47, wherein the 2-pyridone is present in excess relative to the amount of compound 2.

[0518] B50. The process according to any one of statements B37 to B49, wherein 2-pyridone is present in an amount of up to 1 .2 equivalents.

[0519] B51 . The process according to any one of statements B37 to B49, wherein 2-pyridone is present in an amount of from 1 equivalent to 5 equivalents.

[0520] B52. The process according to any one of statements B37 to B49, wherein 2-pyridone is present in an amount of about 1.1 equivalents.

[0521] B53. The process according to any one of statements B1 to B7, B10, B16, and B37 to B52, wherein step (ii) takes place in the presence of a base. B54. The process according to statement B53, wherein the base is selected from a metal phosphate, metal carbonate, metal bicarbonate or combinations thereof.

[0522] B55. The process according to statement B54, wherein the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, or potassium bicarbonate.

[0523] B56. The process according to statement B55, wherein the base is selected from sodium carbonate or potassium carbonate.

[0524] B57. The process according to any one of statements B53 to B56, wherein the base is present in an amount of from 1 equivalent.

[0525] B58. The process according to any one of statements B53 to B56, wherein the base is present in excess relative to the amount of compound 2.

[0526] B59. The process according to any one of statements B53 to B56, wherein the base is present in an amount of from 1 equivalent to 5 equivalents.

[0527] B60. The process according to statement B59, wherein the base is present in an amount of from 2.5 equivalents to 3.5 equivalents.

[0528] B61. The process according to statement B60, wherein the base is present in an amount of about 3 equivalents.

[0529] B62. The process according to any one of statements B1 to B7, B10, B16, and B37 to B61 , wherein step (ii) takes place in the presence of a group(l) or (II) metal iodide salt.

[0530] B63. The process according to statement B62, wherein the group(l) or (II) metal iodide salt is sodium or potassium iodide.

[0531] B64. The process according to either statement B62 or statement B63, wherein the group(l) or (II) metal iodide salt is present in an amount of from 1 .5 equivalents to 2.5 equivalents.

[0532] B65. The process according to statement B64, wherein the group(l) or (II) metal iodide salt is present in an amount of about 2 equivalents. B66. The process according to any one of statements B1 to B7, B10, B16, and B37 to B65, wherein step (ii) takes place in a solvent selected from anisole, dimethyl sulfoxide (DMSO), butyronitrile, n-butanol (nBuOH), cyclopentyl methyl ether (CPME), tert-amyl alcohol (tAmOH), 2-methyltetrahydrofuran (2-MeTHF), isopropyl acetate (IPAc), isopropyl alcohol (IPA), acetonitrile (MeCN), benzonitrile (PhCN), dimethylformamide (DMF), EtOH, or combinations thereof.

[0533] B67. The process according to statement B66, wherein the solvent is PhCN.

[0534] B68. The process according to any one of statements B1 to B7, B10, B16, and B37 to B67, wherein step (ii) takes place at a temperature of at least 90°C.

[0535] B69. The process according to any one of statements B1 to B7, B10, B16, and B37 to B68, wherein step (ii) takes place at a temperature of up to 130°C.

[0536] B70. The process according to any one of statements B1 to B7, B10, B16, and B37 to B67, wherein step (ii) takes place at a temperature from 100°C to 120°C.

[0537] B71 . The process according to statement B70, wherein step (ii) takes place at a temperature of about 110°C.

[0538] B72. The process according to any one of statements B1 to B7, B10, and B16, wherein step (ii) takes place under conditions comprising: excess 2-pyridone; a copper catalyst in an amount of at least 0.01 equivalents; and a temperature from 90°C to 130°C.

[0539] B73. The process according to any one of statements B1 to B7, B10, and B16, wherein step (ii) takes place under conditions comprising:

[0540] 1 to 1.2 eq of 2-pyridone; a copper catalyst present in an amount of at least 0.01 eq;

[0541] 1 to 5 eq of a metal carbonate or metal phosphate; at least 0.5 eq of a group (I) or (II) metal iodide; and a temperature from 90°C to 130°C, wherein, the copper catalyst comprises copper(l) iodide and CyDMEDA in a ratio of from 1 :1 to 1 :10. B74. The process according to any one of statements B1 to B7, B10, and B16, wherein step (ii) takes place under conditions comprising:

[0542] 1.1 eq of 2-pyridone;

[0543] 0.05 eq of a copper catalyst comprising copper (I) iodide and CyDMEDA in a ratio of about 1 :3;

[0544] 3 eq of potassium carbonate;

[0545] 2 eq of sodium iodide; a PhCN solvent; and a temperature of 110°C.

[0546] B75. The process according to any one of statements B1 to B7, B12, and B16, wherein step (iii) comprises sequentially a Boc-deprotection, work-up of the free-base, and formation of a CSA or fumaric acid salt of compound 4.

[0547] B76. The process according to any one of statements B1 to B7, B12, B16, and B75, wherein compound 4 is obtained as the CSA(+) salt.

[0548] B77. The process according to any one of statements B1 to B7, B14, and B16, wherein compound 6 is present in at least 1 equivalent.

[0549] B78. The process according to any one of statements B1 to B7, B14, and B16, wherein compound 6 is present in excess relative to the amount of compound 4.

[0550] B79. The process according to any one of statements B1 to B7, B14, B16, B77 and B78 wherein compound 6 is present in up to 1.5 equivalents.

[0551] B80. The process according to statement B79, wherein compound 6 is present from 1 equivalent to 1.2 equivalents.

[0552] B81. The process according to statement B80, wherein compound 6 is present in about 1.1 equivalents.

[0553] B82. The process according to any one of statements B1 to B7, B14, B16, and B77 to B81 , wherein the inorganic base is present in excess relative to the amount of compound 4. B83. The process according to any one of statements B1 to B7, B14, B16, and B77 to B82, wherein the inorganic base is present in an amount of at least 2 equivalents.

[0554] B84. The process according to any one of statements B1 to B7, B14, B16, and B77 to B83, wherein the inorganic base is present in an amount of up to 6 equivalents.

[0555] B85. The process according to any one of statements B1 to B7, B14, B16, and B77 to B83, wherein the inorganic base is present in an amount of from 3 equivalents to 5 equivalents.

[0556] B86. The process according to statement B85, wherein the inorganic base is present in an amount of about 4 equivalents.

[0557] B87. The process according to any one of statements B1 to B7, B14, B16, and B77 to B86, wherein the inorganic base is selected from a group (I) or (II) metal carbonate or bicarbonate.

[0558] B88. The process according to statement B87, wherein the inorganic base is selected from a group (I) metal carbonate.

[0559] B89. The process according to statement B88, wherein the inorganic base is sodium carbonate or potassium carbonate.

[0560] B90. The process according to any one of statements B1 to B7, B14, B16, and B77 to B89, wherein step (iv) takes place in an alcohol or anisole solvent.

[0561] B91 . The process according to statement B90, wherein the solvent is n-butanol.

[0562] B92. The process according to statement B90 or B91 , wherein step (iv) takes place in the presence of a second solvent, which is water.

[0563] B93. The process according to any one of statements B1 to B7, B14, B16, and B77 to B92, wherein step (iv) takes place at a temperature of at least 80°C.

[0564] B94. The process according to any one of statements B1 to B7, B14, B16, and B77 to B93, wherein step (iv) takes place at a temperature of up to 100°C. B95. The process according to any one of statements B1 to B7, B14, B16, and B77 to B92, wherein step (iv) takes place at a temperature of from 90°C to 100°C.

[0565] B96. The process according to any one of statements B1 to B7, B14, and B16, wherein step (iv) takes place under conditions comprising: an excess of compound 6; an excess of an inorganic base; an alcohol or anisole solvent; and a temperature from 80°C to 100°C.

[0566] B97. The process according to statements B1 to B7, B14, and B16, wherein step (iv) takes place under conditions comprising:

[0567] 1 equivalent to 1 .2 equivalents of compound 6;

[0568] 4 equivalents of an inorganic base; nBuOH solvent; a temperature from 90°C to 100°C; and a second solvent, which is water.

[0569] B98. The process according to statements B1 to B7, B14, and B16, wherein step (iv) takes place under conditions comprising:

[0570] 1 equivalent to 1 .2 equivalents of compound 6;

[0571] 3.5 equivalents to 4.5 equivalents of a metal carbonate; nBuOH solvent; a temperature from 90°C to 100°C; and a second solvent, which is water.

[0572] B99. The process according to statements B1 to B7, B14, B16, and B77 to B98 wherein compound 8 is obtained as a succinic acid co-crystal.

[0573] B100. Compound 2, or a salt thereof: compound 2 B101. Compound 2:

[0574] B102. Compound 2: in the presence of less than 0.5 wt% of Imp1 :

[0575] Imp 1, where the wt% relates to the amount of compound 2 and Imp1 .

[0576] B103. Compound 4a: compound 4a B104. A method for preparing compound 6, or a salt thereof, by contacting compound 5, or a salt thereof, and compound 7: compound 5 compound 7 compound 6

[0577] B105. The method according to statement B104, wherein compound 7 is present in an amount of at least 1 equivalent.

[0578] B106. The process according to statement B104, wherein compound 7 is present in excess relative to the amount of compound 5.

[0579] B107. The method according to any one of statements B104 to B106, wherein compound 7 is present in an amount of up to 1 .6 equivalents.

[0580] B108. The method according to statement B104, wherein compound 7 is present in an amount of from 1.1 equivalents to 1.5 equivalents.

[0581] B109. The method according to statement B104, wherein compound 7 is present in an amount of about 1 .25 equivalents.

[0582] B110. The method according to any one of statements B104 to B109, wherein a base is present.

[0583] B111. The method according to statement B110, wherein the base is a group(l) or (II) metal hydroxide.

[0584] B112. The method according to statement B111 , wherein the base is selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0585] B113. The method according to statement B112, wherein the base is potassium hydroxide. B114. The method according to any one of statements B110 to B113, wherein the base is present in an amount of at least 5 equivalents.

[0586] B115. The method according to any one of statements B110 to B114, wherein the base is present in an amount of up to 35 equivalents.

[0587] B116. The method according to any one of statements B110 to B113, wherein the base is present in an amount of from 15 equivalents to 25 equivalents.

[0588] B117. The method according to any one of statements B110 to B115, wherein the base is present in an amount of about 15 equivalents.

[0589] B118. The method according to any one of statements B104 to B117, wherein the reaction takes place in a solvent selected from EtOH, water, iPrOH, 2-ethoxyethanol, benzonitrile (PhCN), propionitrile (PrCN), DMF, DMSO, MeCN, dioxane, THF, or combinations thereof.

[0590] B119. The method according to statement B118, wherein the solvent is a mixture of acetonitrile and water.

[0591] B120. The method according to any one of statements B104 to B119, wherein the reaction takes place at a temperature of less than 10°C.

[0592] B121. The method according to statement B120, wherein the reaction takes place at a temperature of less than 0°C.

[0593] B122. The method according to either statement B120 or statement B121 , wherein the temperature is from -15°C to -2°C.

[0594] B123. The method according to statement B122, wherein the reaction takes place at a temperature of about -7°C.

[0595] B124. The method according to any one of statements B104 to B123, wherein the reaction takes place in the presence of a phase transfer catalyst.

[0596] B125. The method according to statement B124, wherein the phase transfer catalyst is a quaternary ammonium salt. B126. The method according to statement B125, wherein the phase transfer catalyst is selected from a tetrabutylammonium chloride (TBAC), benzyltriethylammonium chloride, methyltricaprylammonium chloride and methyltributylammonium chloride.

[0597] B127. The method according to statement B126, wherein the phase transfer catalyst is benzyltriethylammonium chloride (BTEAC).

[0598] B128. Compound s: in the presence of less than 0.5 wt% of Imp1 :

[0599] Imp 1, where the wt% relates to the amount of compound 8 and Imp1 .

Claims

CLAIMS1 . Crystalline 6'-([( 1 S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (AZD0780) in form B:

2. Crystalline AZD0780 Form B according to claim 1 , characterised by an X-ray powder diffraction pattern comprising the following six peaks expressed as 29±0.2°: 4.9, 11.6, 19.1 , 21.9, 22.8 and 24.5.

3. Crystalline AZD0780 Form B according to claim 1 , characterised by an X-ray powder diffraction pattern comprising the following ten peaks expressed as 29±0.2°: 4.9, 11.6, 15.2, 16.0, 19.1 , 19.5, 21.1 , 21.9, 22.8 and 24.5.

4. Crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (AZD0780):and succinic acid as a co-crystal.

5. Crystalline AZD0780 and succinic acid as a co-crystal according to claim 4, characterised by an X-ray powder diffraction pattern comprising the following five peaks expressed as 26±0.2°: 7.6, 7.9, 15.2, 15.9 and 19.2.

6. Crystalline AZD0780 and succinic acid as a co-crystal according to claim 4,characterised by an X-ray powder diffraction pattern comprising the following ten peaks expressed as 26±0.2°: 7.6, 7.9, 10.6, 11.3, 15.2, 15.9, 17.0, 19.2, 24.6 and 28.4.

7. Crystalline 6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (AZD0780):and fumaric acid as a co-crystal.

8. Crystalline AZD0780 and fumaric acid as a co-crystal according to claim 7, characterised by an X-ray powder diffraction pattern comprising the following five peaks expressed as 26±0.2°: 6.1 , 15.9, 20.6, 21.3 and 25.7.

9. Crystalline AZD0780 and fumaric acid as a co-crystal according to claim 7, characterised by an X-ray powder diffraction pattern comprising the following ten peaks expressed as 26±0.2°: 6.1 , 10.3, 11.1 , 15.9, 19.9, 20.6, 21.3, 22.6, 25.7 and 27.9.

10. A pharmaceutical composition comprising pharmaceutical composition comprising crystalline AZD0780 in Form B according to any one of claims 1 to 3, and a pharmaceutically acceptable excipient, carrier or diluent.11 . Crystalline AZD0780 in Form B according to any one of claims 1 to 3 for use in a method of lowering LDL-C levels, reducing cardiovascular risk and / or treating a cardiovascular disease in a subject.

12. Crystalline AZD0780 in Form B for use according to claim 11 , wherein the use is in a method of lowering LDL-C levels wherein the subject is an adult with primary hyperlipidemia.

13. A process for preparing 6'-([(1 S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one (compound 8), or a salt or co-crystal thereof:Compound 8 comprising one or more of steps (i) to (iv):(i) contacting compound 1 and amine 1 to form compound 2:compound 1 amine 1 compound 2(ii) contacting compound 2 and 2-pyridone to form compound 3:(iii) deprotecting compound 3 with an acid and forming a fumaric acid or camphorsulfonic acid salt of compound 4:compound 3 compound 4(iv) contacting compound 6 and the fumaric acid or camphorsulfonic acid salt of compound 4 in the presence of an inorganic base to form compound 8 or a salt or cocrystal thereof:Compound 8 wherein compounds 1 to 3 and 6, and amine 1 may be provided as a salt.

14. A process for preparing compound 8 or a salt or co-crystal thereof according to claim13, comprising all of steps (i) to (iv).

15. Compound 2 (tert-butyl ((1 S,3S)-3-((5-bromopyridin-2-yl)amino)cyclopentyl)carbamate), or a salt thereof:compound 216. Compound 2 (tert-butyl ((1S,3S)-3-((5-bromopyridin-2-yl)amino)cyclopentyl)carbamate):compound 217. Compound 2 (tert-butyl ((1S,3S)-3-((5-bromopyridin-2-yl)amino)cyclopentyl)carbamate):compound 2 in the presence of less than 0.5 wt% of Imp1 (tert-butyl ((1 R,3S)-3-(3-((1S,3S)-3-((5- bromopyridin-2-yl)amino)cyclopentyl)ureido)cyclopentyl)carbamate):Imp 1, where the wt% relates to the total amount of compound 2 and Imp1 .

18. Compound 4a (6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2- one.CSA(+)):compound 4a19. A method for preparing compound 6, or a salt thereof, by contacting compound 5, or a salt thereof, and compound 7:compound 5 compound 7 compound 620. Compound 8 (6'-([(1S,3S)-3-([5-(difluoromethoxy)-2- pyrimidinyl]amino)cyclopentyl]amino)-2H-[1 ,3'-bipyridin]-2-one):in the presence of less than 0.5 wt% of Imp1 (tert-butyl ((1 R,3S)-3-(3-((1S,3S)-3-((5- bromopyridin-2-yl)amino)cyclopentyl)ureido)cyclopentyl)carbamate):Imp 1, where the wt% relates to the total amount of compound 8 and Imp1 .

Images