WO2026041663A1

WO2026041663A1 - P2x7 receptor antagonists

Info

Publication number: WO2026041663A1
Application number: PCT/EP2025/073696
Authority: WO
Inventors: Lieven Meerpoel; Mariangela SODANO
Original assignee: Breye Therapeutics ApS
Current assignee: Breye Therapeutics ApS
Priority date: 2024-08-22
Filing date: 2025-08-19
Publication date: 2026-02-26
Anticipated expiration: 2027-02-22

Abstract

Described herein are compounds of formula (I), where the substituents are disclosed herein, and exhibit antagonistic and/or inhibitory activity against the P2X7 receptor. These compounds, and their pharmaceutically acceptable salts, hydrates, solvates, and compositions thereof, are suitable for use in the prevention and treatment of diseases and conditions modulated by inhibition of the P2X7 receptor.

Description

008806333

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P2X7 Receptor Antagonists

Field of the Invention

The present invention relates to compounds which exhibit antagonistic and/or inhibitory activity, particularly to the P2X7 receptor. These compounds, and their pharmaceutically acceptable salts, hydrates, and compositions thereof, are suitable for use in the prevention and treatment of diseases and conditions modulated by inhibition of the P2X7 receptor.

Background

Age-related macular degeneration (AMD) affects one in eight people 60 years of age or older and is the most common cause of irreversible blindness in older persons in developed countries. According to thorough estimates, 200 million people worldwide are estimated to have AMD, and by 2040, this number is projected to rise to close to 300 million (Vyawahare and Shinde 2022).

AMD is essentially a disease of a single layer of cells termed the retinal pigment epithelium (RPE), and the onset of AMD is associated with dysfunction of the RPE. Intermediate AMD can be characterised as an earlier stage of disease before progression to more advanced forms of AMD termed choroidal neovascular AMD and geographic atrophy AMD, which are associated with significant anatomical changes and irreversible visual loss. Early AMD is typically defined as the presence of medium drusen (> 63-124 pm) without pigmentary abnormalities (Garcia-Layana et al., 2017; Ferris et al., 2013). Intermediate AMD is defined as the presence of at least one large druse (125 pm or larger in size) and/or pigmentary abnormalities associated with at least one medium drusen (Garcia-Layana et al., 2017; Ferris et al., 2013). A clear hallmark of early and intermediate AMD is the presence of drusen, which are extracellular deposits that accumulate between the retinal pigmented epithelium (RPE) and Bruch’s membrane and have been shown to be able to activate the inflammasome (Doyle et al., 2012; Sakurai et al., 2003). Increased numbers and size of drusen correlate with increased risk of developing advanced AMD.

Evidence suggests that monocyte/macrophage activity is a normal physiological process aimed at phagocytosing retinal debris and drusen, but in AMD there is an overactivation of those processes, potentially in response to increased drusen, leading to immune-mediated retinal damage. Indeed, there is overwhelming evidence that human AMD has a systemic immunoinflammatory component, and in animal models of AMD, ablation, or restriction of recruitment of monocyte/macrophages to the neural retina is associated with protection from retinal damage (Sennlaub et al., 2013; Cruz-Guilloty et al., 2013; Doyle et al., 2012; Moriguchi et al., 2018; Sakurai et al., 2003; Espinosa-Heidmann et al., 2003). An epidemiological study determined that the highest systemic risk factor associated with the development of intermediate AMD was increased blood monocyte count (Xue et al., 2013). Moreover, there is significant propensity for the development of AMD to be associated with other concomitant systemic immune- 008806333

2 mediated diseases such as lupus, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, sarcoidosis, giant cell arteritis, and vasculitis (Shukla et al., 2024).

The P2X purinoceptor 7 (P2X7R) receptor is a protein that in humans is encoded by the P2RX7 gene. P2X7R belongs to the family of P2X ionotropic receptors. P2X7R is activated by extracellular nucleotides, notably adenosine triphosphate (ATP). P2X7R is distinguished from other P2X-family. members by the specific localization (CNS and immunocompetent cells in particular) and by the high concentrations of ATP (in the mM range) required for full activation.

Monocytes/macrophages are found within the retina of several animal models of AMD, are noted to be NLRP3 positive and caspase-1 positive, resulting from inflammasome activation (Hollyfield et al., 2008; Doyle et al., 2012), which are key intracellular signalling components initiated following P2X7R activation. This activation of the NLRP3 pathway results in the secretion of mature IL-1 p, which is the putative ultimate effector of retinal cell damage, and indeed increased levels of IL1B mRNA in the RPE of donor eyes from individuals with geographic atrophy have been demonstrated (Tarallo et al., 2012), which indicates that IL-1 p might be involved in the development of AMD. P2X7R is therefore proposed to be a key effector mechanism resulting in retinal cell loss in AMD.

Direct evidence suggesting an involvement of P2X7 in AMD is found in mouse P2X7 homozygous deleted (P2X7 ^A) models where a lack of the murine P2X7 leads to protection from the onset of AMD-like phenotype in a NalOs oxidative stress model. It notable in this model that protection is also afforded by monocyte macrophage deletion (Seeker et al., 2023). A combined P2X7 ^/7Cx3CrT^/_ (fractalkine) knock out mouse was also protected by either P2X7 gene deletion or monocyte/macrophage ablation (Hu et al., 2015). A combined P2X7 ^/7SOD ^/- (superoxide dismutase) knock-out oxidative stress mouse model also showed protection against AMD-like symptoms (Carver et al., 2017). Alternative murine AMD models which manifest as a RPE toxicity such as a p-amyloid model, mice are also protected against AMD when performed in a P2X7 ^/_ mouse, or when the P2X7 is specifically deleted in the RPE (Tarallo et al., 2012). Treatment of wild type mice with a P2X7 receptor antagonist also replicates either the full or RPE- selective P2X7 gene deletion (Tarallo et al., 2012). Induction of AMD-like symptoms in mice treated with sub-retinal oxidised-LDL is also attenuated by treatment with a P2X7 receptor antagonist (Yang et al, 2021).

A significant body of data links the development of intermediate AMD and the progression to more advanced forms of AMD to a normal physiological process designed to clear drusen from the retina, which appears to be overactivated, but which is mediated by P2X7 present on systemic monocytes and resident RPE cells. Inhibiting P2X7R on systemic monocytes and resident RPE with specific, selective, potent and orally available P2X7 antagonists is proposed to result in an inhibition of the aberrant immunoinflammatory mechanisms in human AMD that lead to RPE dysfunction and ultimately to progression to irreversible retinal tissue destruction and visual loss. It is believed that treating intermediate AMD with P2X7R antagonists will prevent the immune-mediated effector phase of the destruction of RPE and neural retina, and moreover by an oral therapeutic modality that will lead to widespread use and compliance. 008806333

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As well as AMD, another ophthalmic condition primarily affecting working age adults, is diabetic retinopathy. Diabetic retinopathy (DR) is a global health burden (Barret et al., 2017; Klein et al., 2007) resulting from chronic hyperglycaemia. In its earliest manifestation, there are dilatation of capillaries and small veins in the retinal microcirculation, evidence of vascular leakage and the presence of microaneurysms, and small haemorrhages. This earlier stage is noted as non-proliferative diabetic retinopathy (NPDR), but which can progress to proliferative diabetic retinopathy (PDR) when significant new vessel growth is observed in the retina. An additional complication in this condition is the progression to centre-involved diabetic macular edema (DME) which can occur concurrently with NPDR or PDR. In general terms, NPDR is not considered vision-threatening but continued progression to either PDR or centre-involved DME are associated with significant vision loss (Arabi et al., 2022). Specifically, the role of P2X7 in models of DR and DME are evidenced in an ability of P2X7 antagonists (A740003) to reduce diabetes induced up-regulation of P2X7, NLRP3, IL-1 p and IL-18 (Kong et al., 2022 in mice), and further to show that this leads to a significant reduction in hyperglycaemia-induced cellular apoptosis in cultured retinal endothelial cells (Kong et al., 2022). As P2X7 is proposed to directly activate the NLRP3 pathway, pharmacological inhibitors of NLRP3 such as Mcc950 and 3TC (lamivudine) were also as effective as P2X7 antagonism in controlling hyperglycaemia-induced up-regulation P2X7, NLRP3, IL-1 p and IL-18 as well as increased cellular apoptosis. Similar outcomes were noted on the induction of a range of other inflammatory markers (Kong et al., 2022). There is also evidence that P2X7/NLRP3 is neuroprotective in models of diabetic retinopathy. Studies in diabetic animals demonstrated that oral treatment with NLRP3 inhibitor 3TC/lamivudine reduced the depression of electroretinogram observed in diabetic animals and decreased the accumulation of acellular capillaries (Pavlou et al., 2019). Finally, P2X7 antagonism was shown induce a strong suppression of P2X7 up-regulation, VEGF accumulation and importantly vascular leakage the hallmark of DME, in diabetic mice (Clapp et al., 2019). These pre- clinical data suggesting a role for NLRP3 and therefore P2X7 in diabetic eye disease was further exemplified in clinical studies in which treatment with oral 3TC/lamivudine showed a significant treatment effect in DME patients, consistent the effectiveness of current intravitreal medications (Pereira et al., 2024, ARVO abstract).

A further role for P2X7 antagonism has centred around the protection of retinal ganglion cells and therefore as a therapeutic modality for glaucoma, in which retinal ganglion cells are lost through a combination of cellular stress and ocular hypertension. It was recently demonstrated that a P2X7R antagonist can protect the loss of retinal ganglion cells in a mouse chronic ocular hypertensive model (Dong et al., 2018).

Furthermore, P2X7 receptors (P2X7Rs) are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells. P2X7R is also known to be a pain sensor in the nervous system. Experiments using P2X7-deficient mice demonstrated the role of P2X7 in the development of pain as these mice were protected from the development of both adjuvant- induced inflammatory pain and partial nerve ligation induced neuropathic pain. There is also growing evidence that P2X7 or its downstream effectors, such as IL-lp, are involved in the pathophysiology of 008806333

4 several neurological disorders, such as Alzheimer's Disease (J. I. Diaz-Hernandez et al., 2012). P2X7 is thought to have an important function in neurotransmission within the CNS through its activation on postsynaptic and/or presynaptic neurons and glia. Data has emerged using in situ hybridization that P2X7R mRNA is widely distributed throughout the rat brain. Specifically, areas of high P2X7R mRNA expression were found in the anterior olfactory nucleus, cerebral cortex, piriform cortex (Pir), lateral septal nucleus (LS), hippocampal pyramidal cell layers of CA1 , CA3, CA4, pontine nuclei, external cuneate nucleus, and medial vestibular nucleus. P2X7 hybridization signals were also observed in the motor neurons of the trigeminal motor nucleus, facial nucleus, hypoglossal nucleus, and the anterior horn of the spinal cord.

Hence there is a therapeutic rationale for the use of P2X7R antagonists in the treatment of a variety of disease states. These states include but are not limited to diseases associated with the CNS such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, spinal cord injury, cerebral ischemia, head trauma, meningitis, sleep disorders, mood and anxiety disorders, epilepsy, HIV-induced neuro inflammation and CNS damage, and chronic neuropathic and inflammatory pain. Furthermore, peripheral inflammatory disorders and autoimmune diseases including but not limited to rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, bronchitis, glomerulonephritis, irritable bowel syndrome, fatty liver disease, liver fibrosis, skin injury, lung emphysema, muscular dystrophy, fibrosis, atherosclerosis, burn injury, Crohn's Disease, ulcerative colitis, age-related macular degeneration, growth and metastasis of malignant cells, Sjogren's syndrome, myoblastic leukaemia, diabetes, osteoporosis, ischemic heart disease are all examples where the involvement of P2X7 receptors has been implicated.

WO 03/042191 A1 describes benzamide and heteroarylamide P2X7R inhibitor compounds of formula (I) defined therein. The compounds are described as useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases, and other disorders. The substituent on the nitrogen of the amide in the exemplified compounds is typically an optionally substituted alkyl group, with the alkyl group optionally terminating in an optionally substituted phenyl ring or cycloalkyl group. Additionally, the exemplified compounds typically have a 1 ,2,4-triazine- 3, 5-dione moiety at R¹, meta to the amide group on the benzamide ring.

US 2005/0009900 A1 describes benzamide P2X7R inhibitor compounds of formula (I) defined therein. The compounds are described as useful in the treatment of IL-1 mediated disorders including inflammatory diseases such as osteoarthritis and rheumatoid arthritis, allergies, asthma, COPD, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases, and other disorders. The substituent on the nitrogen of the amide in the exemplified benzamide compounds is typically an optionally substituted alkylene group terminating in an optionally substituted phenyl ring and/or cycloalkyl group.

WO 2015/118019 A1 describes substituted thiazole and oxazole P2X7 receptor antagonists of formula (I) as defined therein, for use in the prevention and/or treatment of various P2X7 receptor mediated conditions or diseases, including ophthalmic diseases. The compounds of formula (I) contain a nitrogen- 008806333

5 containing ring A, such as a substituted piperidinyl or morpholinyl ring, adjacent to the substituted thiazole or oxazole ring.

EP 3290417 A1 describes substituted piperidine and morpholine compounds of formula (I) as defined therein. These compounds are described as having P2X7 receptor antagonistic properties and are useful in the treatment or prophylaxis of diseases associated with P2X7 receptor activity, such as ophthalmic diseases. The compounds of formula (I) contain a piperidine or morpholine ring adjacent to a substituted thiazole ring.

WO 2018/041563 A1 describes substituted phenoxy- and benzyloxy-piperidine compounds of formula (I) defined therein, which exhibit P2X7 receptor antagonistic properties useful in the prevention and/or treatment of various P2X7 receptor mediated conditions or diseases, including ophthalmic diseases. The compounds of formula (I) contain a phenoxy- or benzyloxy-substituted piperidine ring adjacent to a substituted thiazole ring.

WO 2022/129365 A1 describes 1 ,4-substituted piperidine compounds of formula (I) defined therein having P2X7 receptor antagonistic properties useful in the treatment or prophylaxis of various diseases associated with P2X7 receptor activity, including ophthalmic diseases. The compounds of formula (I) contain a 1 ,4-substituted piperidine adjacent to a difluoromethyl-substituted thiazole ring.

WO 2018/202694 A1 describes substituted 1 ,2,4-oxadiazolone and 1 ,2,4-thiadiazolone compounds as P2X7R antagonists, which are useful in the treatment of various conditions or diseases mediated by the P2X7 receptor. Similarly, WO 2023/031319 A1 describes substituted 1 ,2,4-triazolone compounds as P2X7 antagonists useful in the treatment of various conditions or diseases mediated by the P2X7 receptor.

However, there is still an unmet need for compounds which are able to efficiently antagonize or inhibit P2X7R and that can be delivered in the different target organs which are sites of a P2X7-mediated pathology, including the eye and the brain. The present invention has been devised in light of the above considerations.

Summary of the Invention

When looking at the global challenge of AMD and diabetic eye disease (such as DR, DME, and other diseases mediated by modulation of the P2X7 receptor), and the number of patients in need of therapy over the next decades, the inventors believe that an oral therapy working at the very core of the disease process is optimal. The purpose of treating AMD at the intermediate stage and diabetic retinopathy at the pre-proliferative stage is to prevent the further progression to advanced disease, improve the partially compromised visual function, but specifically halt the tissue destruction and consequent irreversible visual loss associated with progression of these two major ophthalmic diseases. 008806333

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Furthermore, P2X7 receptors are implicated in many other conditions and diseases as mentioned above.

Thus, further P2X7R antagonists or inhibitors may be useful in the treatment of other conditions and diseases associated with P2X7R.

The inventors have surprisingly discovered novel compounds that inhibit the P2X7R and that such compounds disclosed herein may be useful in the treatment of diseases and conditions that are modulated by inhibition of the P2X7R, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), choroidal neovascular myopia, and other conditions such as for neurological, neurodegenerative, neuroinflammatory, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, other ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer, and proliferative diseases.

Accordingly, a first aspect of the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

W is CR⁸ or N;

X and Y are independently CR⁹ or N;

Z is S, NR¹⁰, or O; wherein at least two heteroatoms are present in X, Y, and Z;

R¹, R², R⁴, and R⁸ are independently selected from the group consisting of H, D, C1-6 alkyl, halo, and C1-6 haloalky I, and -O(Ci-6 alkyl);

R³ is selected from the group consisting of: 008806333

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R⁵ is H or C1-4 alkyl;

R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, -O(Ci-6 alkylene)OH, and -(C1-4 alkylene)-O-(Ci-4 alkyl); or R⁵ and R⁶ are taken together to form a carbonyl;

R⁷ and each R⁹ are independently selected from the group consisting of H, D, C1-4 alkyl, halo, C1-6 haloalkyl, -(C1-4 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), and cyano;

R¹⁰ is H, C1-4 alkyl, C1-4 haloalkyl, -(C1-4 alkylene)OH, or -(C1-4 alkylene)-O-(Ci-4 alkyl);

A is NR¹², S, or O; m is 1 , 2, or 3; and each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalky I, -O(Ci-6 alkyl), -O(C3-8 cycloalkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)- O-(Ci-4 alkyl), amino, -NH(CI-₆ alkyl), -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-₄ alkyl), -(C1-6 alkylene)NH₂, -C(=O)OH, -C(=O)O(Ci-₄ alkyl), -C(=O)NH₂, -C(=O)NH(CI-₄ alkyl), -C(=O)N(Ci- 4 alky 1)2, cyano, -SO2(Ci-6 alkyl), -SO(Ci-6 alkyl), -S(Ci-6 alkyl), -SO2NH(CI-6 alkyl), -SO2N(CI-6 alky 1)2 , -SONH(CI-6 alkyl), -SON(CI-6 alkyl)2, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10- membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; and

R¹² is selected from the group consisting of H, D, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), -(C1-6 alkylene)NH2, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of R¹² is optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl. 008806333

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In any embodiment, formula (I) may be formula (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), or (It) as defined herein.

In some embodiments, Z is S or O, at least one of X or Y is N. In some embodiments, Z is NR¹⁰, X is not N. In some embodiments, the XYZ ring in formula (I) is not furanyl, thiophenyl, or pyrrolyl. In some embodiments, the XYZ ring in formula (I) is not furanyl, thiophenyl, pyrrolyl, or imidazolyl.

In some embodiments, W is CR⁸. In some embodiments, W is CH.

In some embodiments, X is N. In some embodiments, Y is CR⁹. In some embodiments, Z is S.

In some embodiments, the XYZ ring in formula (I) is selected from the group consisting of:

In some embodiments, the XYZ ring in formula (I) is

In some embodiments, R¹ is C1-6 alkyl, halo, or C1-6 haloalky I. In some embodiments, R¹ is methyl, fluoro, chloro, or trifluoromethyl. In some embodiments, R¹ is methyl or chloro. In some embodiments, R¹ is methyl.

In some embodiments, R² is H.

In some embodiments, R³ is selected from the group consisting of: 008806333

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In some embodiments, R³ is:

In some embodiments, R³ is selected from the group consisting of: 008806333

10 In some embodiments, R³ is: 008806333

11

In some embodiments, m is 1 or 2. In some embodiments, m is 1 .

In some embodiments, each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, amino, -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-₄ alkyl), -C(=O)OH, -C(=O)O(Ci-₄ alkyl), cyano, -SO2(Ci-6 alkyl), and 3- to 8-membered heterocycloalkyl; wherein the carbon ring atoms of C3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me, 1- piperidinyl, 3-hydroxypiperidin-1-yl, D, -(CH₂)₂OH, -CH₂CH(CH3)OH, -CH2CHF2, and -CH₂CH(CH3)OH.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C-i- 6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some embodiments, R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, -CH(CH3)OH, and -OCH2CH2OH. In some embodiments, R⁶ is OH.

In some embodiments, R⁷ is H, C1-4 alkyl, or C1-4 difluoroalkyl. In some embodiments, R⁷ is H or Me. In some embodiments, R⁷ is Me.

In some embodiments, R⁸ is H.

In some embodiments, R⁹ is H or C1-4 alkyl. In some embodiments, R⁹ is H or Me. In some embodiments, R⁹ is Me. In some embodiments, R⁹ is H.

In some embodiments, R¹⁰ is H or C1-4 alkyl. In some embodiments, R¹⁰ is H or Me. In some embodiments, R¹⁰ is Me.

In some embodiments, A is NR¹².

In some embodiments, R¹² is selected from the group consisting H, C1-6 alkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), and -(C1-6 008806333

12 alkylene)NH2. In some embodiments, R¹² is selected from the group consisting H, methyl, -(CH2)2OH, -

CH₂CH(CH₃)OH, -CH₂C(CH₃)2OH, -CH₂CH(CH₂CH₃)OH, -CH₂OCH₃, -CH₂CH(CH₃)OCH₃, -

CH₂CH(CH₂F)OH, -CH₂CHFCH₂OCH₃, and -(CH₂)₂NH2. In some embodiments, R¹² is H or Me.

In some embodiments, X is N, Y is CR⁹, and Z is S. In some of these embodiments, R⁹ is H. Alternatively or additionally, R⁷ is Me.

In some embodiments,

In some embodiments, R³ is m is 1 or 2, and R¹¹ is fluoro.

In some embodiments, R³ is m is 1 , and R¹¹ is fluoro.

In some embodiments, R¹ is Me, R² is H, and R⁴ is H. In some of these embodiments, W is CR⁸, such as

CH.

In some embodiments, R⁵ is H and R⁶ is OH.

In some embodiments, the compound is a compound in TABLE 2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

A second aspect of the present invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to the first aspect, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable carrier.

A third aspect of the present invention provides a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, for use as a medicament.

A fourth aspect of the present invention provides a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to the first aspect, or a pharmaceutical composition according to the 008806333

13 second aspect, for use in the prevention and/or treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor. That is, the condition is a P2X7 receptor mediated condition or disease. In other words, the condition may be modulated by inhibition of the P2X7 receptor.

A fifth aspect of the present invention provides a use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, for the manufacture of a medicament for a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor. That is, the condition is a P2X7 receptor mediated condition or disease. In other words, the condition may be modulated by inhibition of the P2X7 receptor.

A sixth aspect of the present invention provides a method of treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor, wherein the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, to a patient in need thereof. That is, the condition is a P2X7 receptor mediated condition or disease. In other words, the condition may be modulated by inhibition of the P2X7 receptor.

In some embodiments of the fourth, fifth and sixth aspect, the condition is selected from all forms of age- related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases.

In some embodiments of the fourth, fifth and sixth aspect, the condition is selected from age-related macular degeneration (AMD), optionally wherein the age-related macular degeneration (AMD) is selected from early AMD, intermediate AMD, late AMD, choroidal neovascular AMD, geographic atrophy AMD, central geographic atrophy AMD, peripheral geographic atrophy AMD, exudative AMD, and nonexudative AMD; diabetic retinopathy (DR), optionally wherein the diabetic retinopathy (DR) is selected from early DR, nonproliferative diabetic retinopathy (NPDR), early non-proliferative diabetic retinopathy (NPDR), moderate non-proliferative diabetic retinopathy (NPDR), moderate-severe non-proliferative diabetic retinopathy (NPDR), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), early proliferative diabetic retinopathy (PDR), moderate proliferative diabetic retinopathy (PDR), moderate-severe proliferative diabetic retinopathy (PDR), and severe proliferative diabetic retinopathy (PDR); diabetic macular edema (DME), optionally wherein the diabetic macular edema (DME) is selected from centre-involved DME, peripheral DME, early DME, early centre-involved DME, and early peripheral DME; 008806333

14 glaucoma, optionally wherein the glaucoma is selected from glaucoma secondary to ocular hypertension, and normal tension glaucoma; retinal vein occlusion (RVO), optionally wherein the retinal vein occlusion (RVO) is selected from branched vein RVO and central vein RVO; and choroidal neovascular myopia.

The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

Detailed Description of the Invention

Aspects and embodiments of the present invention will now be discussed. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

Substituent definitions

“H” refers to a hydrogen atom.

“D” refers to a deuterium atom or deuteron, a stable isotope of hydrogen (H) containing one proton and one neutron in the nucleus.

"Alkyl” is a hydrocarbon radical substituent derived from an alkane by removal of a hydrogen atom, often further defined by the number of carbon atoms present. For example, C1-6 alkyl groups are alkyl groups containing 1 to 6 carbon atoms. The alkyl group may be linear or branched. Each alkyl group may have one or more deuterium (D) substituents. C1-6 alkyl includes C1-5 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, and Ci alkyl. C1-6 alkyl includes Ce alkyl, C5 alkyl, C alkyl, C3 alkyl, C2 alkyl, and Ci alkyl. Non-limiting examples of alkyl groups are as follows. Ce alkyl may be 1 -hexyl (n-hexyl). C5 alkyl may be 1 -pentyl (n- pentyl). C alkyl may be 1 -butyl (n-butyl or n-Bu), isobutyl (/-butyl or /-Bu), sec-butyl (s-butyl or s-Bu), or te/Y-butyl (t-butyl or ABu). C3 alkyl may be 1 -propyl (n-propyl, n-Pr, or -CH2CH2CH3), or 2-propyl (isopropyl, /-Pr, or -CH(CH3)2). C2 alkyl may be ethyl (Et or -CH2CH3). Ci alkyl may be methyl (Me or -CH3). Such alkyl groups may be present in, for example, C1-6 alkyl, C1-4 alkyl, -O(Ci-6 alkyl), -(C1-4 alkylene)-O-(Ci-4 alkyl), -NH(CI-₆ alkyl), -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)O(Ci-₄ alkyl), -C(=O)O(Ci-₄ alkyl), -C(=O)NH(CI-4 alkyl), -C(=O)N(CI-₄ alkyl)₂, -SO₂(Ci-₆ alkyl), -SO(Ci-₆ alkyl), -S(Ci-₆ alkyl), -SO₂NH(CI-6 alkyl), -SO₂N(CI-6 alkyl)₂, -SONH(CI-₆ alkyl), and -SON(CI-₆ alkyl)₂.

“Alkylene” is a divalent alkyl (or hydrocarbon) radical, often further defined by the number of carbon atoms present. For example, C1-6 alkylene groups are alkylene groups containing 1 to 6 carbon atoms. The alkylene group may be linear or branched, preferably linear. Linear alkylenes may be denoted - (CH2)n-, where n is the number of carbon atoms in the alkylene group. C1-6 alkylene includes C1-5 008806333

15 alkylene, C1-4 alkylene, C1-3 alkylene, C1-2 alkylene, and Ci alkylene. C1-6 alkylene includes Ce alkylene, C5 alkylene, C alkylene, C3 alkylene, C2 alkylene, and Ci alkylene. Non-limiting examples of alkylene groups are as follows. Ce alkylene may be -(CH2)e- (hexylene). C5 alkylene may be -(CH2)e- (pentylene). C alkylene may be -(CH2) - (butylene), 2,2-dimethylethylene, or 2-methylpropylene. C3 alkylene may be -(CH2)3- (propylene). C2 alkylene may be -(CH2)2- (ethylene). Ci alkylene may be -CH2- (methylene). Preferably, alkylene groups are C1-4 alkylene, such as C1-3 alkylene, such as C1-2 alkylene. Such alkylene groups may be present in, for example, -(C1-6 alkylene)OH, -O(Ci-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -NH(CI-₆ alkylene)OH, and -NH(CI-₆ alkylene)O(Ci-₄ alkyl).

“Alkenyl” is a hydrocarbon group formed when a hydrogen atom is removed from an alkene (or olefin) group. An alkene group is an unsaturated hydrocarbon or alkyl group containing a carbon-carbon double bond. The alkenyl group may be further defined by the number of carbon atoms present. Each alkenyl group may have one or more deuterium (D) substituents. For example, C2-6 alkenyl groups are alkenyl groups containing 2 to 6 carbon atoms. The alkenyl group may be linear or branched. C2-6 alkenyl includes C2-5 alkenyl, C2-4 alkenyl, C2-3 alkenyl, and C2 alkenyl. C2-6 alkenyl includes Ce alkenyl, C5 alkenyl, C alkenyl, C3 alkenyl, and C2 alkenyl. Non-limiting examples of alkenyl groups are as follows. Ce alkenyl may be 1 -hexenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1 -pentenyl, 3-methyl-1 -pentenyl, 4-methyl- 1 -pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2,3-dimethyl-1-butenyl, 3,3- dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, or 2-ethyl-1 -butenyl. C5 alkenyl may be 1 -pentenyl, 2- pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, or 2-methyl-2-butenyl. C alkenyl may be 1-butenyl, 2- butenyl, or isobutylenyl. C3 alkenyl may be propylenyl (-CH2CH=CH2). C2 alkenyl may be ethylenyl (vinyl or -CH=CH2). Preferably, alkenyl groups are C2-4 alkenyl, such as C2-3 alkenyl, such as C2 alkenyl.

“Alkynyl” is a hydrocarbon group formed when a hydrogen atom is removed from an alkyne group. An alkyne group is an unsaturated hydrocarbon or alkyl group containing a carbon-carbon triple bond. The alkynyl group may be further defined by the number of carbon atoms present. For example, C2-6 alkynyl groups are alkynyl groups containing 2 to 6 carbon atoms. The alkynyl group may be linear or branched. Each alkynyl group may have one or more deuterium (D) substituents. C2-6 alkynyl includes C2-5 alkynyl, C2-4 alkynyl, C2-3 alkynyl, and C2 alkynyl. C2-6 alkynyl includes Ce alkynyl, C5 alkynyl, C alkynyl, C3 alkynyl, and C2 alkynyl. Non-limiting examples of alkynyl groups are as follows. Ce alkynyl may be 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-methyl-1 -pentynyl, 4-methyl-2-pentynyl, 3-methyl-1 -pentynyl, or 3,3- dimethyl-1-butynyl. C5 alkynyl may be 1 -pentynyl, 2-pentynyl, or 3-methyl-1-butynyl. C alkenyl may be 1-butynyl or 2-butynyl. C3 alkynyl may be propynyl. C2 alkynyl may be ethynyl (-C=CH or -CCH). Preferably, alkynyl groups are C2-4 alkynyl, such as C2-3 alkynyl, such as C2 alkynyl.

“Cycloalkyl” is a cyclic saturated hydrocarbon radical formed by the removal of a hydrogen atom from a carbon ring atom. The cycloalkyl group may be further defined by the number of carbon atoms present. For example, C3-8 cycloalkyl groups are cycloalkyl groups containing 3 to 8 carbon atoms in a ring. C3-8 cycloalkyl includes C3-7 cycloalkyl, C3-6 cycloalkyl, C3-5 cycloalkyl, C3-4 cycloalkyl, and C3 cycloalkyl. C3-8 cycloalkyl includes Cs cycloalkyl, C7 cycloalkyl, Ce cycloalkyl, C5 cycloalkyl, C cycloalkyl, and C3 cycloalkyl. The cycloalkyl may be monocyclic or polycyclic (such as bicyclic or spirocyclic). Non-limiting 008806333

16 examples of cycloalkyl groups are as follows. Ca cycloalkyl may be cyclooctyl. C7 cycloalkyl may be cycloheptyl. Ce cycloalkyl may be cyclohexyl. C5 cycloalkyl may be cyclopentyl. C4 cycloalkyl may be cyclobutyl. C3 cycloalkyl may be cyclopropyl. Preferably, cycloalkyl groups are C3-6 cycloalkyl, such as C3-5 cycloalkyl, such as C3-4 cycloalkyl, such as C3 cycloalkyl. Such cycloalkyl groups may be optionally substituted at a carbon ring atom by another substituent (that is, replacing another hydrogen atom at said carbon ring atom); such as D, OH, amino, halo, and C1-3 fluoroalkyl; or such as D, OH, amino, fluoro, and C1-3 fluoroalkyl.

“Hydroxy” is the group -OH (or sometimes just OH).

"Alkyloxy” or “alkoxy” is a substituent that is made of an oxygen radical that is singularly bonded to an alkyl (that is, -O(alkyl)), often further defined by the number of carbon atoms present in the alkyl. For example, C1-6 alkoxy groups are alkoxy groups containing 1 to 6 carbon atoms (that is, -O(Ci-6 alkyl)). C-i- 6 alkoxy includes C1-5 alkoxy, C1-4 alkoxy, C1-3 alkoxy, C1-2 alkoxy, and Ci alkoxy. C1-6 alkoxy includes Ce alkoxy, C5 alkoxy, C4 alkoxy, C3 alkoxy, C2 alkoxy, and Ci alkoxy. Non-limiting examples of alkoxy groups are as follows. Ce alkoxy may be -0(1 -hexyl). C5 alkoxy may be -0(1 -pentyl). C4 alkoxy may be -0(n- Bu), -O(/-Bu), -O(s-Bu), or -O(f-Bu). C3 alkoxy may be -O(CH2CH2CH3), or -O(CH(CH3)2). C2 alkoxy may be -O(CH2CH3). CI alkoxy may be -OCH3 (methoxy or -OMe).

“Halo” is a halogen radical substituent. For example, halo may be fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).

"Haloalkyl” is an alkyl group having one or more hydrogen atoms replaced by a halogen atom (that is, a halo group), often further defined by the number of carbon atoms present in the alkyl. For example, C1-6 haloalkyl groups are haloalkyl groups containing 1 to 6 carbon atoms. C1-6 haloalkyl includes C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl, C1-2 haloalkyl, and Ci haloalkyl. C1-6 haloalkyl includes Ce haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, and Ci haloalkyl. The halo in the haloalkyl group may be specified, for example, fluoroalkyl, chloroalkyl, bromoalkyl, or iodoalkyl. The number of halo groups present in the haloalkyl may be specified, for example monohaloalkyl (that is, one halo group is present), dihaloalkyl (that is, two halo groups are present), or trihaloalkyl (that is, three halo groups are present). In such cases where multiple halo groups are present, each halo group may be the same or different. Both the halo group and the number of halo groups present in the haloalkyl group may be specified, for example, monofluoroalkyl (that is, one fluoro group is present), difluoroalkyl (that is, two fluoro groups are present), or trifluoroalkyl (that is, three fluoro groups are present). Non-limiting examples of haloalkyl groups are as follows. C3 haloalkyl (or C3 fluoroalkyl) may be -CH2CH2CF3, - CH2CH2CHF2, or -CH2CH2CH2F. C₂ haloalkyl (or C₂ fluoroalkyl) may be -CH2CF3, -CH2CHF2, or - CH2CH2F. Ci haloalkyl (or Ci fluoroalkyl) may be -CF3, -CHF2, or -CH2F. C3 monohaloalkyl (or C3 monofluoroalkyl) may be -CH2CH2CH2F. C2 monohaloalkyl (or C2 monofluoroalkyl) may be -CH2CH2F. Ci monohaloalkyl (or Ci monofluoroalkyl) may be -CH2F. C3 dihaloalkyl (or C3 difluoroalkyl) may be - CH2CH2CHF2. C2 dihaloalkyl (or C2 difluoroalkyl) may be -CH2CHF2. Ci dihaloalkyl (or Ci difluoroalkyl) may be -CHF2. C3 trihaloalkyl (or C3 trifluoroalkyl) may be -CH2CH2CF3. C2 trihaloalkyl (or C2 trifluoroalkyl) may be -CH2CF3. Ci trihaloalkyl (or Ci trifluoroalkyl) may be -CF3. 008806333

17

"Haloalkylene” is an alkylene group having one or more hydrogen atoms replaced by a halogen atom (that is, a halo group), often further defined by the number of carbon atoms present in the alkylene. For example, C1-6 haloalkylene groups are haloalkylene groups containing 1 to 6 carbon atoms. C1-6 haloalkylene includes C1-5 haloalkylene, C1-4 haloalkylene, C1-3 haloalkylene, C1-2 haloalkylene, and Ci haloalkylene. C1-6 haloalkylene includes Ce haloalkylene, C5 haloalkylene, C haloalkylene, C3 haloalkylene, C2 haloalkylene, and Ci haloalkylene. The halo in the haloalky I group may be specified, for example, fluoroalkylene, chloroalkylene, bromoalkylene, or iodoalkylene. The number of halo groups present in the haloalkylene may be specified, for example monohaloalkylene (that is, one halo group is present), dihaloalkylene (that is, two halo groups are present), or trihaloalkylene (that is, three halo groups are present). In such cases where multiple halo groups are present, each halo group may be the same or different. Both the halo group and the number of halo groups present in the haloalkylene group may be specified, for example, monofluoroalkylene (that is, one fluoro group is present), difluoroalkylene (that is, two fluoro groups are present), or trifluoroalkylene (that is, three fluoro groups are present). Nonlimiting examples of haloalkylene groups are as follows. C3 haloalkylene (or C3 fluoroalkylene) may be - CHFCH2CH2-, -CF2CH2CH2-, -CH2CHFCH2-, -CH2CF2CH2-, -CH2CH2CHF-, -CH2CH2CF2-, - CH₂CH(CH₂F)-, -CH2CF2CHF-, -CHFCF2CH2-, or -CH₂CH(CF₃)-. C₂ haloalkylene (or C₂ fluoroalkylene) may be -CHFCH2-, -CF2CH2-, -CH2CHF-, -CH2CF2-, -CH(CH₂F)-, -CH(CHF₂)-, or -CH(CF₃)-. Ci haloalkylene (or Ci fluoroalkylene) may be -CHF- or -CF2-. C3 monohaloalkylene (or C3 monofluoroalkylene) may be -CHFCH2CH2-, -CH2CHFCH2-, -CH2CH2CHF-, or -CH₂CH(CH₂F)-. C₂ monohaloalkylene (or C2 monofluoroalkylene) may be -CHFCH2-, -CH2CHF-, or -CH(CH2F)-. Ci monohaloalkylene (or Ci monofluoroalkylene) may be -CHF-. C3 dihaloalkylene (or C3 difluoroalkylene) may be -CF2CH2CH2-, -CH2CF2CH2-, or -CH2CH2CF2-. C2 dihaloalkylene (or C2 difluoroalkylene) may be -CF2CH2-, -CH2CF2-, or -CH(CHF2)-. CI dihaloalkylene (or Ci difluoroalkylene) may be -CF2-. C3 trihaloalkylene (or C3 trifluoroalkylene) may be -CH2CF2CHF-, -CHFCF2CH2-, or -CH2CH(CF3)-. C2 trihaloalkylene (or C2 trifluoroalkylene) may be -CH(CF3)-.

“Amino” is the amine group -NH2.

“Cyano” is the nitrile group -CN, containing a triple bond between the carbon and the nitrogen (-C=N).

“Heteroatom” is any atom that is not carbon or hydrogen. Heteroatoms include, but are not limited to, boron (B), nitrogen (N), oxygen (O), aluminium (Al), silicon (Si), phosphorus (P), sulfur (S), and a halogen (e.g., F, Cl, Br, and I). In some cases, the heteroatom may be nitrogen (N), oxygen (O), sulfur (S), or a halogen atom (e.g., F, Cl, Br, and I). In some cases, the heteroatom may be nitrogen (N), oxygen (O), and sulfur (S).

“Heterocycloalkyl” is a cycloalkyl group where one or more of the carbon ring atoms are replaced with a heteroatom. The heteroatom may be, for example, nitrogen (N), oxygen (O), and sulfur (S). Where more than one heteroatom is present in the heterocycloalkyl group, each heteroatom may be the same or different. The heterocycloalkyl group may be further defined by the number of ring atoms. For example, 3- to 8-membered heterocycloalkyl are heterocycloalkyl groups containing 3 to 8 ring atoms. 3- to 8- membered heterocycloalkyl includes 3- to 7-membered heterocycloalkyl, 3- to 6-membered 008806333

18 heterocycloalkyl, 3- to 5-membered heterocycloalkyl, 3- to 4-membered heterocycloalkyl, and 3- membered heterocycloalkyl. 3- to 8-membered heterocycloalkyl includes 8-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl, and 3-membered heterocycloalkyl. The heterocycloalkyl may be monocyclic or polycyclic (such as bicyclic or spirocyclic). Non-limiting examples of heterocycloalkyl groups are as follows. 8-membered heterocycloalkyl may be azocanyl, oxocanyl, or thiocanyl. 7-membered heterocycloalkyl may be azepanyl, oxepanyl, or thiepanyl. 6-membered heterocycloalkyl may be piperidinyl, piperazinyl, oxanyl, or thianyl. 5-membered heterocycloalkyl may be pyrrolindinyl, tetra hydrofuranyl, or tetrahydrothiophenyl. 4-membered heterocycloalkyl may be azetidinyl, oxetanyl, or thietanyl. 3-membered heterocycloalkyl may be aziridinyl, oxiranyl, or thiiranyl. Preferably, heterocycloalkyl groups are 3- to 6-membered heterocycloalkyl, such as 4- to 6-membered heterocycloalkyl, such as 5- to 6-membered heterocycloalkyl, such as 6-membered heterocycloalkyl. Such heterocycloalkyl groups may be optionally substituted at a ring atom by another substituent (for example, replacing a hydrogen atom at said ring atom); such as D, OH, amino, halo, and C1-3 fluoroalkyl; or such as D, OH, amino, fluoro, and C1-3 fluoroalkyl. For example, a 6-membered heterocycloalkyl group substituted with OH may be 3-hydroxypiperidinyl, such as 3-hydroxypiperidin-1-yl.

“Aryl” is a radical derived from an aromatic hydrocarbon ring by removal of a hydrogen atom. The aryl group may be further defined by the number of carbon atoms present. For example, Ce- aryl groups are aryl groups containing 6 to 10 carbon atoms in a ring. Ce-io aryl includes C10 aryl, C9 aryl, Ca aryl, C7 aryl, and Ce aryl. The aryl may be monocyclic or polycyclic (such as bicyclic). Non-limiting examples of aryl groups are as follows. C10 aryl may be naphthalenyl. Ce aryl may be phenyl. Preferably, aryl groups are Ce aryl, such as phenyl. Such aryl groups may be optionally substituted at a carbon ring atom by another substituent (that is, replacing another hydrogen atom at said carbon ring atom); such as D, OH, amino, halo, and C1-3 fluoroalkyl; or such as D, OH, amino, fluoro, and C1-3 fluoroalkyl.

“Heteroaryl” is an unsaturated heterocycloalkyl group that is aromatic. Heteroaryl may also be defined as an aryl group where one or more of the carbon ring atoms are replaced with a heteroatom. The heteroatom may be, for example, nitrogen (N), oxygen (O), and sulfur (S). Where more than one heteroatom is present in the heteroaryl group, each heteroatom may be the same or different. The heteroaryl group may be further defined by the number of ring atoms. For example, 5- to 10-membered heteroaryl are heteroaryl groups containing 5 to 10 ring atoms. 5- to 10-membered heteroaryl includes 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 5- to 6-membered heteroaryl, and 5-membered heteroaryl. 5- to 10-membered heteroaryl includes 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, and 5-membered heteroaryl. The heteroaryl may be monocyclic or polycyclic (such as bicyclic). Non-limiting examples of heteroaryl groups are as follows. 10-membered heteroaryl may be quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, or cinnolinyl. 9-membered heteroaryl may be indolinyl, benzimidazolyl, 4-azaindolinyl, 5-azaindolinyl, 6-azaindolinyl, 7-azaindolinyl, 7- azaindazolyl, pyrazolo[1 ,5-a]pyrimidinyl, purinyl, benzofuranyl, or benzothiophenyl. 6-membered heteroaryl may be pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl. 5- 008806333 membered heteroaryl may be pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,4-triazoly I, 1 ,2,5-triazoly I, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4- thiadiazoly I, or 1 ,2,5-thiadiazoly I. Preferably, heteroaryl groups are 5- to 6-membered heteroaryl. Such heteroaryl groups may be optionally substituted at a ring atom by another substituent (for example, replacing a hydrogen atom at said ring atom); such as D, OH, amino, halo, and C1-3 fluoroalkyl; or such as D, OH, amino, fluoro, and C1-3 fluoroalkyl.

“Carbonyl” or “oxo” group is an organic functional group composed of a carbon atom double-bonded to an oxygen atom and may be represented as >C=O, -(C=O)-, -C(=O)-, -C(O)-, or simply C=O.

The present invention provides compounds of formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

W is CR⁸ or N;

X and Y are independently CR⁹ or N;

R³ is selected from the group consisting of: 008806333

20

R⁵ is H or C1-4 alkyl;

R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, -O(Ci-6 alkylene)OH, and -(C1- alkylene)-O-(Ci-4 alkyl); or R⁵ and R⁶ are taken together to form a carbonyl;

R⁷ and each R⁹ are independently selected from the group consisting of H, D, C1-4 alkyl, halo, Ci-e haloalkyl, -(C1- alkylene)OH, -(C1- alkylene)-O-(Ci-4 alkyl), and cyano;

R¹⁰ is H, C1-4 alkyl, C1-4 haloalkyl, -(C1- alkylene)OH, or -(C1- alkylene)-O-(Ci-4 alkyl);

A is NR¹², S, or O; m is 1 , 2, or 3; and each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(C3-8 cycloalkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)- O-(Ci-4 alkyl), amino, -NH(CI-₆ alkyl), -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-₄ alkyl), -(C1-6 alkylene)NH₂, -C(=O)OH, -C(=O)O(Ci-₄ alkyl), -C(=O)NH₂, -C(=O)NH(CI-₄ alkyl), -C(=O)N(Ci- 4 alky 1)2, cyano, -SO2(Ci-6 alkyl), -SO(Ci-6 alkyl), -S(Ci-6 alkyl), -SO2NH(CI-6 alkyl), -SO2N(CI-6 alky 1)2 , -SONH(CI-6 alkyl), -SON(CI-6 alkyl)2, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10- membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; and

R¹² is selected from the group consisting of H, D, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), -(C1-6 alkylene)NH2, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹² is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, when Z is S or O in the in XYZ ring formula (I), at least one of X or Y is N.

In some embodiments, when Z is NR¹⁰ in the in XYZ ring formula (I), X is not N.

In some embodiments, the XYZ ring in formula (I) is not furanyl, thiophenyl, or pyrrolyl.

In some embodiments, the XYZ ring in formula (I) is not furanyl, thiophenyl, pyrrolyl, or imidazolyl.

In some embodiments, a compound of formula (I) may be a compound of formula (la): 008806333

21 wherein X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined in formula (I). In some preferred embodiments of a compound of formula (la), R⁸ is H. In some preferred embodiments of a compound of formula (la), R⁷ is H or C1-4 alkyl.

In some preferred embodiments of a compound of formula (la), R¹ is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalkyl. In some preferred embodiments of compound of formula (la), R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl. In some preferred embodiments of compound of formula (la), R¹ is C1- 6 alkyl or halo. In some preferred embodiments of compound of formula (la), R¹ is methyl, fluoro, chloro, or trifluoromethyl. In some preferred embodiments of compound of formula (la), R¹ is methyl, fluoro, or chloro.

In some preferred embodiments of a compound of formula (la), R² is H. In some preferred embodiments of a compound of formula (la), R⁴ is H. In some preferred embodiments of a compound of formula (la), R⁵ is H or C1-4 alkyl. In some preferred embodiments of a compound of formula (la), R⁵ is H.

In some preferred embodiments of a compound of formula (la), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some preferred embodiments of a compound of formula (la), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some preferred embodiments of a compound of formula (la), R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, -CH(CH3)OH, and -OCH2CH2OH. In some preferred embodiments of a compound of formula (la), R⁶ is OH.

In some alternative embodiments of a compound of formula (la), R⁵ and R⁶ are taken together to form a carbonyl.

In some embodiments, a compound of formula (I) may be a compound of formulae (lb), (Ic), (Id), (le), or (If): 008806333

22 wherein W, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁹, and R¹⁰ are as defined in formula (I). Preferably, a compound of formula (I) may be a compound of formulae (lb) or (If). Even more preferably, a compound of formula (I) may be a compound of formula (lb). In some preferred embodiments of a compound of formula (lb), R⁷ is Me and R⁹ is H.

In some embodiments, a compound of formula (I) may be a compound of formula (Ig): wherein W, X, Y, Z, R¹, R², R⁴, R⁵, R⁶, R⁷, R¹¹, and m are as defined in formula (I).

In some embodiments, a compound of formula (I) may be a compound of formulae (Ih), (li), (Ij), (Ik), or (II): 008806333

23 wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as defined in formula (I). Preferably, a compound of formula (I) may be a compound of formulae (Ih) or (II). Even more preferably, a compound of formula (I) may be a compound of formula (Ih). In some preferred embodiments of a compound of formula (Ih),

R⁷ is Me and R⁹ is H.

In some embodiments, a compound of formula (I) may be a compound of formula (Im): wherein X, Y, Z, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹ , and m are as defined in formula (I).

In some embodiments, a compound of formula (I) may be a compound of formulae (In), (Io), (Ip), (Iq), or (Ir): 008806333

24 wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and m are as defined in formula (I). Preferably, a compound of formula (I) may be a compound of formulae (In) or (Ir). Even more preferably, a compound of formula (I) may be a compound of formula (In). In some preferred embodiments of a compound of formula (In), R⁷ is Me and R⁹ is H.

In some embodiments, a compound of formula (I) may be a compound of formula (Is): wherein X, Y, Z, R¹, R³, R⁵, R⁶, and R⁷ are as defined in formula (I).

In some preferred embodiments of a compound of formula (Is), R¹ is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalkyl. In some preferred embodiments of compound of formula (Is), R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl. In some preferred embodiments of compound of formula (Is), R¹ is Ci- 6 alkyl or halo. In some preferred embodiments of compound of formula (Is), R¹ is methyl, fluoro, chloro, or trifluoromethyl. In some preferred embodiments of compound of formula (Is), R¹ is methyl, fluoro, or chloro.

In some preferred embodiments of a compound of formula (Is), R⁵ is H or C1-4 alkyl. In some preferred embodiments of a compound of formula (Is), R⁵ is H.

In some preferred embodiments of a compound of formula (Is), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some preferred 008806333

25 embodiments of a compound of formula (Is), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some preferred embodiments of a compound of formula (Is), R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, -CH(CH3)OH, and -OCH2CH2OH. In some preferred embodiments of a compound of formula (Is), R⁶ is OH.

In some alternative embodiments of a compound of formula (Is), R⁵ and R⁶ are taken together to form a carbonyl.

In some preferred embodiments of a compound of formula (Is), R⁷ is H or C1-4 alkyl.

In some embodiments, a compound of formula (I) may be a compound of formula (It): wherein X, Y, Z, R¹, R³, R⁶, and R⁷ are as defined in formula (I).

In some preferred embodiments of a compound of formula (It), R¹ is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalkyl. In some preferred embodiments of compound of formula (It), R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl. In some preferred embodiments of compound of formula (It), R¹ is C1-6 alkyl or halo. In some preferred embodiments of compound of formula (It), R¹ is methyl, fluoro, chloro, or trifluoromethyl. In some preferred embodiments of compound of formula (It), R¹ is methyl, fluoro, or chloro.

In some preferred embodiments of a compound of formula (It), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some preferred embodiments of a compound of formula (It), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some preferred embodiments of a compound of formula (It), R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, - CH(CH3)OH, and -OCH2CH2OH. In some preferred embodiments of a compound of formula (It), R⁶ is OH.

In some preferred embodiments of a compound of formula (It), R⁷ is H or C1-4 alkyl.

In some embodiments, a compound of formula (I) is a compound selected from TABLE 2 in the Examples. 008806333

26

It will be understood that the invention encompasses salts, hydrates, and solvates of the compounds described herein. Suitable salts, hydrates, and solvates are known in the art.

The compounds of the present invention may contain one or more asymmetric atoms (also referred to as chiral centres or stereocenters), giving rise to the possibility of the occurrence of stereoisomers, such as diastereomers and enantiomers. For example, in compounds of formula (I), a stereocenter may be present at the carbon adjacent to R⁵ and R⁶ where R⁵ and R⁶ are not the same substituent. Compounds suited for use in the present invention include such stereoisomers, such as diastereomers and enantiomers.

Any and all references to formula (I) herein is to be interpreted as also referring to any one of formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), or (It). It will also be understood that any of the following references to embodiments (such as those with particular substituent definitions) may be applicable and are combinable with any of the formulae described herein, unless they are to be understood by the skilled person to be chemically incompatible.

In compounds of formula (I), W is CR⁸ or N. In some embodiments, W is CR⁸. In some embodiments, W is CH (that is, W is CR⁸ wherein R⁸ is H). In some embodiments, W is N.

The XYZ ring

The XYZ ring in compounds of formula (I) is the moiety: , where X, Y, Z, and R⁷ are as defined in formula (I).

In some embodiments, the XYZ ring in formula (I) is selected from the group consisting of: 008806333

27

That is, the XYZ ring in formula (I) is selected from the group consisting of: X is N, Y is CR⁹, and Z is S; X is CR⁹, Y is N, and Z is S; X is N, Y is CR⁹, and Z is O; X is CR⁹, Y is N, and Z is S; and X is CR⁹, Y is N, and Z is NR¹⁰.

In some embodiments, the XYZ ring in formula (I) is:

That is, the XYZ ring in formula (I) is selected from X is N, Y is CR⁹, and Z is S; or X is CR⁹, Y is N, and Z is NR¹⁰.

That is, the XYZ ring in formula (I) is selected from the group consisting of: X is N, Y is CH, Z is S, and R⁷ is Me; X is N, Y is CH, Z is S, and R⁷ is H; X is N, Y is CMe, Z is S, and R⁷ is H; and X is CH, Y is N, Z is NMe, and R⁷ is H.

In some embodiments, the XYZ ring in formula (I) is:

That is, the XYZ ring in formula (I) is X is N, Y is CR⁹, and Z is S.

In some embodiments, the XYZ ring in formula (I) is:

That is, the XYZ ring in formula (I) is selected from the group consisting of: X is N, Y is CH, Z is S, and R⁷ is Me; X is N, Y is CH, Z is S, and R⁷ is H; and X is N, Y is CMe, Z is S, and R⁷ is H.

In some embodiments, the XYZ ring in formula (I) is:

That is, the XYZ ring in formula (I) is X is N, Y is CH, Z is S, and R⁷ is Me. 008806333

28

X

In compounds of formula (I), X is CR⁹ or N. In some embodiments, X is N. In some embodiments, X is CR⁹. In some embodiments, X is CH (that is, X is CR⁹ wherein R⁹ is H).

Y

In compounds of formula (I), Y is CR⁹ or N. In some embodiments, Y is CR⁹. In some embodiments, Y is N. In some embodiments, Y is CH or CMe (that is, Y is CR⁹ wherein R⁹ is H or Me).

Z

In compounds of formula (I), Z is S, NR¹⁰, or O. In some embodiments, Z is S or NR¹⁰. In some embodiments, Z is S. In some embodiments, Z is NR¹⁰. In some embodiments, Z is O. In some embodiments, Z is NMe (that is, Z is NR¹⁰ wherein R¹⁰ is Me).

In compounds of formula (I), R¹ is selected from the group consisting of H, D, Ci-e alkyl, -O(Ci-6 alkyl), halo, and C1-6 haloalky I.

In some embodiments, R¹ is selected from the group consisting of C1-6 alkyl, -O(Ci-6 alkyl), halo, and C1-6 haloalkyl.

In some embodiments, R¹ is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalkyl.

In some embodiments, R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl. In some embodiments, R¹ is Ci-e alkyl, such as C1-5 alkyl, such as C1-4 alkyl, such as C1-3 alkyl, such as C1-2 alkyl, such as Ci alkyl. In some embodiments, R¹ is halo, such as fluoro, chloro, bromo, or iodo. In some embodiments, R¹ is halo, such as fluoro or chloro. In some embodiments, R¹ is fluoro. In some embodiments, R¹ is chloro. In some embodiments, R¹ is C1-6 haloalkyl, such as C1-5 haloalkyl, such as C1-4 haloalkyl, such as C1-3 haloalkyl, such as C1-2 haloalkyl, such as Ci haloalkyl. In some embodiments, R¹ is C1-6 fluoroalkyl, such as C1-5 fluoroalkyl, such as C1-4 fluoroalkyl, such as C1-3 fluoroalkyl, such as C1-2 fluoroalkyl, such as Ci fluoroalkyl.

In some embodiments, R¹ is C1-6 alkyl or halo. In some embodiments, R¹ is methyl, fluoro, chloro, or trifluoromethyl. In some embodiments, R¹ is methyl, fluoro, or chloro. In some embodiments, R¹ is methyl or chloro. In some embodiments, R¹ is methyl.

In compounds of formula (I), R² is selected from the group consisting of H, D, C1-6 alkyl, C1-6 alkoxy, halo, and C1-6 haloalkyl.

In some embodiments, R² is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalkyl. In some embodiments, R² is H. 008806333

29

In compounds of formula (I), R³ is selected from the group consisting of:

In some embodiments, R³ is selected from the group consisting of: In some embodiments, R³ is selected from the group consisting of: 008806333

30

In some embodiments, R³ is selected from the group consisting of:

In some embodiments, R³ is selected from the group consisting of: In some embodiments, R³ is selected from the group consisting of:

In some embodiments, R³ is selected from the group consisting of:

In some embodiments, R³ is selected from the group consisting of: 008806333 008806333 008806333

33

In some embodiments, R³ is:

In some embodiments, R³ is selected from the group consisting of: 008806333 008806333

35 In some embodiments, R³ is selected from the group consisting of:

A

In compounds of formula (I), A is present in specific embodiments of R³. Where present, A is NR¹², S, or

O. In some embodiments, A is NR¹². In some embodiments, A is S In some embodiments, A is O. 008806333

36

In compounds of formula (I), R⁴ is selected from the group consisting of H, D, Ci-e alkyl, C1-6 alkoxy, halo, and C1-6 haloalky I.

In some embodiments, R⁴ is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalky I. In some embodiments, R⁴ is H. In some embodiments, R⁴ is C1-6 alkyl. In some embodiments, R⁴ is C1-6 alkoxy. In some embodiments, R⁴ is halo. In some embodiments, R⁴ is C1-6 haloalkyl.

In compounds of formula (I), R⁵ is H or C1-4 alkyl. Alternatively, R⁵ and R⁶ are taken together to form a carbonyl.

In some embodiments, R⁵ is H. In some embodiments, R⁵ is C1-4 alkyl, such as methyl. In some embodiments, R⁵ and R⁶ are taken together to form a carbonyl.

In compounds of formula (I), R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, -O(Ci-6 alkylene)OH, and -(C1- alkylene)-O-(Ci-4 alkyl). Alternatively, R⁵ and R⁶ are taken together to form a carbonyl.

In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C-i- 6 alkylene)OH, and -O(Ci-6 alkylene)OH.

In some embodiments, R⁶ is C1-6 alkyl, such as C1-5 alkyl, such as C1-4 alkyl, such as C1-3 alkyl, such as C1-2 alkyl, such as Ci alkyl. In some embodiments, R⁶ is halo, such as fluoro, chloro, bromo, or iodo. In some embodiments, R⁶ is halo, such as fluoro or chloro. In some embodiments, R⁶ is fluoro. In some embodiments, R⁶ is -0(0-6 alkyl), such as -0(0-5 alkyl), such as -0(0-4 alkyl), such as -0(0-3 alkyl), such as -O(Ci-2 alkyl), such as -O(Ci alkyl). In some embodiments, R⁶ is -O(Ci alkyl) (that is, -OMe). In some embodiments, R⁶ is -(C1-6 alkylene)OH, such as -(C1-5 alkylene)OH, such as -(C1-4 alkylene)OH, such as -(C1-3 alkylene)OH, such as -(C1-2 alkylene)OH, such as -(Ci alkylene)OH. In some embodiments, R⁶ is -CH2OH or -CH(CH3)OH. In some embodiments, R⁶ is -CH2OH. In some embodiments, R⁶ is -CH(CH3)OH. In some embodiments, R⁶ is -0(0-6 alkylene)OH, such as -0(0-5 alkylene)OH, such as -0(0-4 alkylene)OH, such as -0(0-3 alkylene)OH, such as -0(0-2 alkylene)OH. In some embodiments, R⁶ is -0(0-2 alkylene)OH, such as -O(C2 alkylene)OH, such as -OCH2CH2OH.

In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), and -(C1-6 alkylene)OH. In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH. In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, and -(C1-6 alkylene)OH. In 008806333

37 some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, and -O(Ci-6 alkyl). In some embodiments, R⁶ is selected from the group consisting of OH, C1-6 alkyl, and halo.

In some embodiments, R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, - CH(CH3)OH, and -OCH2CH2OH. In some embodiments, R⁵ and R⁶ are taken together to form a carbonyl.

In some embodiments, R⁶ is OH.

R

In compounds of formula (I), R⁷ is selected from the group consisting of H, D, C1-4 alkyl, halo, C1-6 haloalkyl, -(C1-4 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), and cyano.

In some embodiments, R⁷ is not H. That is, R⁷ is selected from the group consisting of D, C1-4 alkyl, halo, C1-6 haloalkyl, -(C1-4 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), and cyano.

In some embodiments, R⁷ is H, C1-4 alkyl, or C1-6 haloalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-6 dihaloalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-4 haloalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-4 dihaloalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-6 fluoroalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-6 difluoroalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-4 fluoroalkyl. In some embodiments, R⁷ is H, C1-4 alkyl, or C1-4 difluoroalkyl.

In some embodiments, R⁷ is H or C1-4 alkyl. In some embodiments, R⁷ is C1-4 alkyl, such as C1-3 alkyl, such as C1-2 alkyl, such as Ci alkyl. In some embodiments, R⁷ is H or C1-3 alkyl. In some embodiments, R⁷ is H or C1-2 alkyl. In some embodiments, R⁷ is H or Me. In some embodiments, R⁷ is Me. In some embodiments, R⁷ is H.

R

In compounds of formula (I), R⁸ is present when W is CR⁸. Where present, R⁸ is selected from the group consisting of H, D, C1-6 alkyl, C1-6 alkoxy, halo, and C1-6 haloalkyl.

In some embodiments, R⁸ is selected from the group consisting of H, C1-6 alkyl, halo, and C1-6 haloalkyl. In some embodiments, R⁸ is H. In some embodiments, R⁸ is C1-6 alkyl. In some embodiments, R⁸ is C1-6 alkoxy. In some embodiments, R⁸ is halo. In some embodiments, R⁸ is C1-6 haloalkyl.

R

In compounds of formula (I), R⁹ is present when X and/or Y is CR⁹. Where present, each R⁹ is independently selected from the group consisting of H, D, C1-4 alkyl, halo, C1-6 haloalkyl, -(C1-4 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), and cyano.

In some embodiments, each R⁹ is independently selected from the group consisting of H, D, C1-4 alkyl, halo, C1-6 haloalkyl, and cyano. 008806333

38

In some embodiments, each R⁹ is H or C1-4 alkyl. In some embodiments, each R⁹ is H or Me (methyl). In some embodiments, each R⁹ is Me. In some embodiments, each R⁹ is H.

In compounds of formula (I), R¹⁰ is present when Z is CR¹⁰. When present, R¹⁰ is H, C1-4 alkyl, C1-4 haloalkyl, -(C1- alkylene)OH, or -(C1- alkylene)-O-(Ci-4 alkyl).

In some embodiments, R¹⁰ is H or C1-4 alkyl. In some embodiments, R¹⁰ is H or Me (methyl). In some embodiments, R¹⁰ is Me. In some embodiments, R¹⁰ is H. m

In compounds of formula (I), m is 1 , 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 .

R¹¹

In compounds of formula (I), each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(C3-s cycloalkyl), - O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), amino, -NH(CI-6 alkyl), -N(CI-6 alky 1)2, -NH(CI-6 alkylene)OH, -NH(CI-6 alkylene)O(Ci-4 alkyl), -(C1-6 alkylene)NH₂, -C(=O)OH, -C(=O)O(Ci-₄ alkyl), -C(=O)NH₂, -C(=O)NH(CI-₄ alkyl), -C(=O)N(CI-4 alkyl)₂, cyano, -SO₂(Ci-₆ alkyl), -SO(Ci-₆ alkyl), -S(Ci-₆ alkyl), -SO₂NH(CI-6 alkyl), -SO₂N(CI-6 alky 1)2 , -SONH(CI-6 alkyl), -SON(CI-6 alky 1)2 , 3- to 8-membered heterocycloalkyl, Ce- aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with one to three groups selected from D, OH, amino, halo, and C1-3 fluoroalkyl. In some embodiments, each R¹¹ is independently optionally substituted with one or two of said groups. In some embodiments, each R¹¹ is independently optionally substituted with one of said groups.

In some embodiments, the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, fluoro, and C1-3 fluoroalkyl.

In some embodiments, the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with one to 008806333

39 three groups selected from D, OH, amino, fluoro, and C1-3 fluoroalkyl. In some embodiments, each R¹¹ is independently optionally substituted with one or two of said groups. In some embodiments, each R¹¹ is independently optionally substituted with one of said groups.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C2-6 alkynyl, halo, C1-6 haloalky I, -O(Ci-6 alkyl), -O(Ci-6 haloalky I) , -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), amino, -NH(CI-₆ alkyl), -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-4 alkyl), -C(=O)OH, -C(=O)O(Ci-4 alkyl), cyano, -SO2Me, cyclopropyl, and piperidinyl optionally substituted with OH.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, OH, C1-6 alkyl, C3-8 cycloalkyl, halo, C1-6 haloalky I, -O(Ci-6 alkyl), -O(Ci-6 haloalky I) , -(C1-6 alkylene)OH, amino, -N(CI-6 alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-4 alkyl), -C(=O)OH, -C(=O)O(Ci-₄ alkyl), and cyano.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, halo, C1-6 haloalky I, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, amino, -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-4 alkyl), -C(=O)OH, -C(=O)O(Ci-₄ alkyl), cyano, -SO2(Ci-6 alkyl), and 3- to 8-membered heterocycloalkyl; wherein the carbon ring atoms of C3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, D, OH, C1-3 alkyl, C3-6 cycloalkyl, C2 alkynyl, fluoro, C1-6 fluoroalkyl, -O(Ci-2 alkyl), -O(Ci-6 fluoroalkyl), -(C1-2 alkylene)OH, amino, -N(CI-₄ alkyl)₂, -NH(CI-₄ alkylene)OH, -NH(CI-₄ alkylene)O(Ci-4 alkyl), -C(=O)OH, - C(=O)O(Ci-3 alkyl), cyano, -SO2(Ci-2 alkyl), and 3- to 6-membered heterocycloalkyl; wherein the carbon ring atoms of C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, D, OH, C1-3 alkyl, cyclopropyl, -CCH, fluoro, Ci fluoroalkyl, -OMe, -O(Ci-2 fluoroalkyl), -CH2OH, amino, -N(CI-2 alkyl)2, -NH(CI-₂ alkylene)OH, -NH(CI-₃ alkylene)O(Ci-₂ alkyl), -C(=O)OH, -C(=O)O(Ci-₂ alkyl), cyano, -SO₂(Ci alkyl), and 6-membered heterocycloalkyl; wherein the carbon ring atoms of cyclopropyl and 6-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, D, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me, and piperidinyl optionally substituted with OH.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me, 1- piperidinyl, 3-hydroxypiperidin-1-yl, D, -(CH₂)₂OH, -CH₂CH(CH₃)OH, -CH2CHF2, and -CH₂CH(CH₃)OH. 008806333

40

In some embodiments, each R¹¹ is independently selected from the group consisting of H, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me, 1- piperidinyl, and 3-hydroxypiperidin-1-yl.

In some embodiments, each R¹¹ is independently selected from the group consisting of H, fluoro, methyl, cyano, trifluoromethyl, and -CH2OH.

In some embodiments, each R¹¹ is independently H. In some embodiments, each R¹¹ is independently fluoro. In some embodiments, R¹¹ is fluoro.

In compounds of formula (I), R¹² is present in certain embodiments of R³ (for example, when A is NR¹²). When present, R¹² is selected from the group consisting of H, D, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alky ny I, C1-6 haloalky I, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), -(C1-6 alkylene)NH2, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of R¹² may be optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

In some embodiments, the carbon ring atoms of C3-8 cycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of R¹² is optionally substituted with one to three groups selected from D, OH, amino, halo, and C1-3 fluoroalkyl. In some embodiments, R¹² is optionally substituted with one or two of said groups. In some embodiments, R¹² is optionally substituted with one of said groups.

In some embodiments, the carbon ring atoms of C3-8 cycloalkyl, Ce- aryl, and 5- to 10-membered heteroaryl of R¹² is optionally substituted with a group selected from D, OH, amino, fluoro, and C1-3 fluoroalkyl.

In some embodiments, the carbon ring atoms of C3-8 cycloalkyl, Ce- aryl, and 5- to 10-membered heteroaryl of R¹² is optionally substituted with one to three groups selected from D, OH, amino, fluoro, and C1-3 fluoroalkyl. In some embodiments, R¹² is optionally substituted with one or two of said groups.

In some embodiments, R¹² is optionally substituted with one of said groups.

In some embodiments, R¹² is selected from the group consisting of H, D, C1-6 alkyl, C2-6 alky ny I, C1-6 haloalkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), and cyclopropyl.

In some embodiments, R¹² is selected from the group consisting of H, D, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)OH, and -(C1-4 alkylene)-O-(Ci-4 alkyl).

In some embodiments, R¹² is selected from the group consisting of H, D, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R¹² is selected from the group consisting of H, D, methyl, ethyl, trifluoromethyl, and 008806333

41 difluoromethyl. In some embodiments, R¹² is selected from the group consisting of H, D, methyl, and trifluoromethyl.

In some embodiments, R¹² is selected from the group consisting of H, C1-6 alkyl, -(0-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), and -(0-6 alkylene)NH2.

In some embodiments, R¹² is selected from the group consisting of H, methyl, -(CH2)2OH, - CH₂CH(CH₃)OH, -CH₂C(CH₃)2OH, -CH₂CH(CH₂CH₃)OH, -CH₂OCH₃, -CH₂CH(CH₃)OCH₃, - CH₂CH(CH₂F)OH, -CH₂CHFCH₂OCH₃, and -(CH₂)₂NH2.

In some embodiments, R¹² is H or Me (methyl). In some embodiments, R¹² is Me (methyl). In some embodiments, R¹² is H.

"Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a patient or subject, such as a human. Compounds suited for use in accordance with the invention may have an acidic or basic moiety, such that they can form pharmaceutically acceptable salts. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt.

When a compound suited for use in accordance with the invention contains an acidic moiety, salts can be formed using organic or inorganic bases. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di-, or tri-lower alkylamine (e.g., ethyl-, te/Y-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or tri-hydroxy lower alkylamine (e.g., mono-, di-, or triethanolamine), and the like. Other known pharmaceutically acceptable bases may also be employed.

Alternatively, when a compound suited for use in accordance with the invention contains a basic moiety, salts can be formed using organic or inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), citric, tartaric, succinic (i.e. butanedioic), fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, napthalenesulfonic, benzenesulfonic, p-toluenesulfonic, camphorsulfonic, salicyclic, p-aminosalicyclic, pamoic, and the like. Other known pharmaceutically acceptable acids may also be employed.

Internal salts also can be formed in compounds suited for use in accordance with the invention, between suitable acidic and basic moieties both present in said compounds. Examples of pharmaceutically acceptable salts may be found, for example, in the Handbook of pharmaceutical salts (2011) (Wiley ISBN 008806333

42

3906390519) and Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1- 19. Unless otherwise specified, a reference to a particular compound also include salt forms thereof.

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. Examples of solvents present in a solvate may include, but are not limited to, water and alcohols, such as ethanol and isopropanol. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a dihydrate, a tri-hydrate, etc. Unless otherwise specified, a reference to a particular compound also include solvate and hydrate forms thereof.

Pharmaceutical Compositions

Compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, employed in accordance with the present invention may be administered in the form of appropriate pharmaceutical compositions, which can be administered via any acceptable method known in the art, either singly or in combination. Pharmaceutical compositions of relevance in the present context may comprise a compound as disclosed herein for use in accordance with the invention in admixture with one or more pharmaceutically acceptable carriers, diluents, vehicles, or excipients. In general, the pharmaceutical compositions used in accordance with the present invention may be adapted for administration of the compound in tablets, capsules, gelcaps, eye drops, contact lenses, nasal spray, intravitreally, or systemically.

Useful formulations may include formulations that provide sustained release of the compounds of the present teachings. These may be particularly useful for subsequent administration (after the first administration). The compositions are preferably in the form of a solid, such as a tablets, capsules, or gellcaps, but alternatively the compositions may be in the form of liquid formulations, such as solutions, syrups, or suspensions. Methods for the preparation of these compositions are generally described in "Remington's Pharmaceutical Sciences", 17th Ed., Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, U.S.A., 1985. Such compositions generally contain an effective amount of the one or more active compounds of the present teachings, together with a suitable carrier in order to provide the dosage in a form compatible with the route of administration selected. Preferably, the carrier is in the form of a vehicle, a diluent, a buffering agent, a tonicity adjusting agent, a preservative, inhibitor, and/or a stabilizer. The excipients constituting the carrier must be compatible with the active pharmaceutical ingredient(s) and are preferably capable of stabilizing the compounds without being deleterious to the subject being treated .

A form of repository or sustained-release formulation can be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following administration of the compound or composition, e.g., by transdermal injection or deposition. Formulations 008806333

43 suitable for sustained release may comprise biodegradable polymers, such as L-lactic acid, D-lactic acid, DL-lactic acid, glycolide, glycolic acid, and isomers thereof. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

Other sustained release formulations can include, but are not limited to, formulations that include at least one of the compounds disclosed herein combined with liposomes, microspheres, emulsions or micelles and liquid stabilizers.

Administration of a compound (or pharmaceutical salt or hydrate thereof) in accordance with the invention may be conducted in a single unit dosage form (e.g. in the form of a bolus) or as a continuous therapy in the form of multiple doses over time. Alternatively, continuous infusion systems or slow-release depot formulations may be employed.

Two or more compounds for use in accordance with the invention (or pharmaceutical compositions thereof) may be co-administered simultaneously or sequentially in any order. The compounds disclosed herein, or their pharmaceutically acceptable salts, solvate, or hydrates thereof, or their pharmaceutical compositions, may be formulated for administration by a number of routes, including but not limited to, intravitreal, intracameral, ophthalmic topical instillation, peri-ocular, sub-tenon, sub-conjunctival, sub- retinal, retro-bulbar, juxtrascleral, iontophoresis, suprachoroidal, topical ophthalmic sustained delivery devices, in-dwelling ophthalmic sustained delivery devices, parenteral, intravenous, intra-arterial, intramuscular, oral and nasal. In addition, the compounds and compositions may be administered in a similar manner for prophylactic purposes, for example if a diabetic patient or a patient with drusen deposits deemed to be at risk of developing AMD or worsening of AMD or macular edema associated with AMD. A composition may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Ultimately, the best dosing regimen will be decided by the attending physician for each patient individually.

Therapeutic Uses

The compounds described herein, and their pharmaceutically salts, solvates, and hydrates thereof (e.g. in the form of an appropriate pharmaceutical composition), are useful in the prevention and/or treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor. In other words, the compounds specified herein, and their pharmaceutically salts, solvates, and hydrates thereof (e.g. in the form of an appropriate pharmaceutical composition), are useful as a medicine especially in the treatment of a condition or disease mediated by the P2X7 receptor, in particular P2X7 receptor antagonistic and/or inhibitory activity. Subsequently, the present compounds may be used for the manufacture of a medicine for treatment of a condition or a disease mediated by P2X7 receptor activity, in 008806333

44 particular P2X7 receptor antagonistic and/or inhibitory activity. That is, the condition is a P2X7 receptor mediated condition or disease. In other words, the condition may be modulated by inhibition of the P2X7 receptor.

Conditions which may be treated or prevented in accordance with the present invention using compounds as specified herein include P2X7 receptor mediated conditions such as age-related macular degeneration (AMD) [comprising early AMD, intermediate AMD, non-exudative AMD, advanced AMD which may include choroidal neovascular AMD and geographic atrophy AMD present in either the central or peripheral retina], diabetic retinopathy (DR) [including early DR, moderate, moderate-severe and severe non-proliferative DR, early to severe proliferative DR], peripheral or centre-involved diabetic macular edema (DME), glaucoma secondary to ocular hypertension and normal tension glaucoma, retinal vein occlusion (RVO), specifically central RVO and branched RVO, choroidal neovascular myopia, neurological, neurodegenerative, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases - especially in a mammalian or human subject or patient.

Age-related macular degeneration (AMD) is a degenerative disorder of the central retina (where the central vision is processed in the area known as the macula). The macula is important for the sharp, straight-ahead vision that is used for reading, recognizing faces, and driving. AMD can be classified as dry AMD (d-AMD; also known as non-neovascular AMD or non-exudative AMD) or neovascular AMD (n- AMD; also known as wet AMD or exudative AMD). Non-exudative AMD can also be characterized by early or intermediate AMD. Choroidal neovascular AMD is a vascular complication of underlying non- exudative AMD where choroidal vessels penetrate Bruch’s membrane and/or the retinal pigment epithelial layer therefore entering the retina. Geographic atrophy (GA) is a chronic progressive degeneration of the macula, as part of late age-related macular degeneration (AMD). Accordingly, all forms of AMD comprise early AMD, intermediate AMD, late AMD, choroidal neovascular AMD, geographic atrophy AMD, central geographic atrophy AMD, peripheral geographic atrophy AMD, exudative AMD, and non-exudative AMD.

Diabetic retinopathy (DR) involves changes to retinal blood vessels that can cause them to leak fluid, become dysfunctional and sometimes proliferate, thus distorting vision. Diabetic retinopathy is the most common cause of vision loss among people with diabetes and a leading cause of blindness among working-age adults. Diabetic is further characterised by early, moderate, and severe non-proliferative diabetic retinopathy (NPDR); and early, moderate, and severe proliferative diabetic retinopathy (PDR). Diabetic macular edema is a consequence of diabetic retinopathy that causes swelling in the macula region of the retina, due to fluid leakage and can co-exist with NPDR or PDR. Accordingly, all forms of DR comprise early DR, non-proliferative diabetic retinopathy (NPDR), early non-proliferative diabetic retinopathy (NPDR), moderate non-proliferative diabetic retinopathy (NPDR), moderate-severe nonproliferative diabetic retinopathy (NPDR), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), early proliferative diabetic retinopathy (PDR), moderate 008806333

45 proliferative diabetic retinopathy (PDR), moderate-severe proliferative diabetic retinopathy (PDR), and severe proliferative diabetic retinopathy (PDR).

Diabetic macular edema (DME) is the build-up of fluid (edema) in the retina which causes swelling. When this leakage is in a region of the retina called the macula, it is termed centre-involved DME. If it is located away from the macula, it is termed non-centre involved DME or peripheral DME. The macula is important for the sharp, straight-ahead vision that is used for reading, recognizing faces, and driving. DME is the most common cause of vision loss among people with diabetic retinopathy. Although it is more likely to occur as diabetic retinopathy worsens, DME can happen at any stage of the disease. Accordingly, all forms of DME comprise centre-involved DME, peripheral DME, early DME, early centre-involved DME, and early peripheral DME.

Glaucoma is a loss of retinal ganglion cell which conveys information from the light-sensitive cells in the retina through the optic tract to either the contralateral eye or the visual cortex. Such ganglion cell-loss leads to an early loss of peripheral visual field, which can then progress to central field resulting in blindness. In most cases, this is driven by ocular hypertension but may also occur in such subjects with normal intraocular pressures and is termed normal tension glaucoma. Accordingly, all forms of glaucoma comprise glaucoma secondary to ocular hypertension and normal tension glaucoma.

Retinal vein occlusion (RVO) occurs when a blood clot forms in a retinal vein. Blockage of one of the veins draining blood out of the eye causes blood and other fluids to leak into the retina causing bruising and swelling as well as lack of oxygen. This interferes with the function of the retina. Accordingly, all forms of RVO comprise branched vein RVO and central vein RVO.

Choroidal neovascular myopia, also called myopic choroidal neovascularization (CNV), is a sightthreatening condition which occurs in eyes with myopia, particularly in those with pathologic myopia, in which a thinning retina results in a breakthrough of choroidal vessels into the neural retina, a condition not unlike choroidal neovascular AMD. Haemorrhage and exudation from the CNV lesion may eventually result in scarring or chorioretinal atrophy.

Neurological conditions are any conditions that affects the brain, spinal cord and/or nerves. Neurological conditions include, but are not limited to, epilepsy including simple partial seizure, complex partial seizure, secondary generalized seizure, further including absence seizure, myoclonic seizure, clonic seizure, tonic seizure, tonic clonic seizure and atonic seizure.

Neurodegenerative disorders are a type of disease in which cells of the central nervous system stop working or die and may arise from various origins. Neurodegenerative disorders include, but are not limited to, Alzheimer’s Disease and other dementia conditions such as Lewys body, fronto-temporal dementia and taupathies; amyotrophic lateral sclerosis, multiple sclerosis (MS), Parkinson’s disease and other parkinsonian syndromes; Huntington's Disease; HIV-induced neuroinflammation and CNS damage; essential tremors; other spino cerebellar degenerations and Charcot-Marie-Toot neuropathy. The compounds of the invention are also useful for the treatment of neurological conditions such as epilepsy including simple partial seizure, complex partial seizure, secondary generalized seizure, further including 008806333

46 absence seizure, myoclonic seizure, clonic seizure, tonic seizure, tonic clonic seizure and atonic seizure, and for prevention and treatment of Status Epilepticus (SE).

Neuroinflammatory disorders are conditions in which inflammation affects the central nervous system (the brain, spinal cord, and/or optic nerves). Neuroinflammatory disorders include, but are not limited to, multiple sclerosis (MS), neuromyelitis optica (NMO), anti-myelin oligodendrocyte glycoprotein antibody disorder (MOG), autoimmune encephalitis, transverse myelitis, optic neuritis, and neurosarcoidosis.

Cognitive disorders as any disorder that significantly impairs the cognitive functions of an individual to the point where normal functioning in society is impossible without treatment. Psychiatric disorders are disorders that affect your mood, thinking and behaviour. Cognitive and psychiatric disorders often overlap. Cognitive and/or psychiatric disorders include, but are not limited to, major depression, dysthymia, mania, bipolar disorder (such as bipolar disorder type I, bipolar disorder type II), cyclothymic disorder, rapid cycling, ultradian cycling, mania, hypomania, schizophrenia, schizophreniform disorders, schizoaffective disorders, personality disorders, attention disorders (with or without hyperactive behaviour), delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorder due to a general medical condition, substance-induced psychotic disorders or a psychotic disorder not otherwise specified, anxiety disorders such as generalized anxiety disorder, panic disorders, post- traumatic stress disorder, impulse control disorders, phobic disorders, dissociative states and moreover in smoke, drug addiction and alcoholism. In particular, bipolar disorders, psychosis, anxiety and addiction.

Neuropathic pain is nerve pain that can happen if your nervous system malfunctions or gets damaged. Neuropathic pain syndromes include, but are not limited to, diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; neuralgia, such as postherpetic neuralgia and trigeminal neuralgia, Morton’s neuralgia, causalgia; and pain resulting from physical trauma, amputation, phantom limb, cancer, toxins or chronic inflammatory conditions; central pain such as the one observed in thalamic syndromes, mixed central and peripheral forms of pain such as complex regional pain syndromes (CRPS) also called reflex sympathetic dystrophies.

Chronic pain is long standing pain that persists beyond the usual recovery period or occurs along with a chronic health condition. Chronic pain includes, but is not limited to, chronic pain caused by inflammation or an inflammatory-related condition, ostheoarthritis, rheumatoid arthritis, acute injury or trauma, upper back pain or lower back pain (resulting from systematic, regional or primary spine disease such as radiculopathy), bone pain (due to osteoarthritis, osteoporosis, bone metastasis or unknown reasons), pelvic pain, spinal cord injury-associated pain, cardiac chest pain, non-cardiac chest pain, central poststroke pain, myofascial pain, sickle cell pain, cancer pain, Fabry’s disease, AIDS pain, geriatric pain or pain caused by headache, temporomandibular joint syndrome, gout, fibrosis or thoracic outlet syndromes. In particular rheumatoid arthritis and osteoarthritis.

Acute pain is sudden or urgent pain caused by injury, surgery, illness, trauma, or painful medical procedures and generally lasts from a few minutes to less than six months, and often lessens or stops as healing occurs. Acute pain may be caused by acute injury, illness, sport-medicine injuries, carpal tunnel syndrome, burns, musculoskeletal sprains and strains, musculotendinous strain, cervicobrachial pain 008806333

47 syndromes, dyspepsis, gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis or surgery (such as open heart or bypass surgery), post-operative pain, kidney stone pain, gallbladder pain, gallstone pain, obstetric pain or dental pain.

A headache is pain or discomfort in the head or face. Headaches include, but are not limited to, migraine, tension type headache, transformed migraine or evolutive headache, cluster headache, as well as secondary headache disorders, such as the ones derived from infections, metabolic disorders or other systemic illnesses and other acute headaches, paroxysmal hemicrania and the like, resulting from a worsening of the above mentioned primary and secondary headaches.

Inflammatory processes of the musculoskeletal system of which the following is a list of examples but it is not comprehensive of all target disorders: arthritic conditions such as alkylosing spondylitis, cervical arthritis, fibromyalgia, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, rheumatic disease; disorders affecting skin and related tissues: eczema, psoriasis, dermatitis and inflammatory conditions such as sunburn; disorders of the respiratory system: asthma, allergic rhinitis and respiratory distress syndrome, lung disorders in which inflammation is involved such as asthma and bronchitis; chronic obstructive pulmonary disease; disorders of the immune and endocrinological systems: periarthritis nodosa, thyroiditis, aplastic anaemia, scleroderma, myasthenia gravis, multiple sclerosis and other demyelinizating disorders, encephalomyelitis, sarcoidosis, nephritic syndrome, Bechet’s syndrome, polymyositis, gingivitis.

Gastrointestinal (Gl) tract disorders affect your gastrointestinal tract, from mouth to anus. Gastrointestinal tract disorders include, but are not limited to, inflammatory bowel disorders including but not limited to ulcerative colitis, Crohn’s disease, ileitis, proctitis, celiac disease, enteropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and post ileonatal anastomosis, and irritable bowel syndrome including any disorders associated with abdominal pain and/or abdominal discomfort such as pylorospasm, nervous indigestion, spastic colon, spastic colitis, spastic bowel, intestinal neurosis, functional colitis, mucous colitis, laxative colitis and functional dyspepsia; but also for treatment of atrophic gastritis, gastritis varialoforme, ulcerative colitis, peptic ulceration, pyrosis, and other damage to the Gl tract, for example, by Helicobacter pylori, gastroesophageal reflux disease, gastroparesis, such as diabetic gastroparesis; and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD); emesis, diarrhoea, and visceral inflammation.

Genitourinary disorders are conditions that affect the genitourinary system, which includes the urinary and reproductive systems. Genitourinary tract disorders include, but are not limited to, overactive bladder, prostatitis (chronic bacterial and chronic non-bacterial prostatitis), prostadynia, interstitial cystitis, urinary incontinence and benign prostatic hyperplasia, annexities, pelvic inflammation, bartholinities and vaginitis. In particular, overactive bladder and urinary incontinence.

Ophthalmic diseases affect the eye. Ophthalmic diseases include, but are not limited to, retinitis, retinopathies, uveitis and acute injury to the eye tissue, or glaucoma, and conjunctivitis. It also includes age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME). 008806333

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Chronic Obstructive Pulmonary Disease (COPD) is a common lung disease causing restricted airflow and breathing problems. It is sometimes called emphysema or chronic bronchitis. In people with COPD, the lungs can get damaged or clogged with phlegm.

Cardiovascular diseases include, but are not limited to, cardiac arrhythmia, cardiac infarction or angina pectoris, hypertension, cardiac ischemia, cerebral ischemia.

Endocrine disorders are diseases results from the improper function of the endocrine system, which includes the glands that secrete hormones. The pathophysiology of the disorder involves excessive or hypersecretory or otherwise inappropriate cellular secretion of an endogenous substance (such as catecholamine, a hormone or a growth factor). Endocrine disorders include, but are not limited to, acromegaly or diabetes insipidus.

Liver diseases affect the liver. Liver diseases include., but are not limited to, inflammatory liver diseases, for example chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, liver fibrosis, non-alcoholic steatohepatitis and liver transplant rejection.

Eating disorders are a range of mental conditions in which there is a persistent disturbance of eating behaviour, usually accompanied by the impairment of physical or mental health. Eating disorders include, but are not limited to, anorexia nervosa including the subtypes restricting type and binge-eating/purging type; bulimia nervosa including the subtypes purging type and non-purging type; obesity; compulsive eating disorders; binge eating disorder; and eating disorder not otherwise specified.

Autoimmunity diseases are where the immune system attacks the body's cells instead of protecting them. Allergic diseases are where the immune system recognizes an allergen (such as food or pollen) as dangerous and responds in a similar manner as it would when trying to kill a virus or bacteria.

Autoimmune and allergic diseases include, but are not limited to peripheral inflammatory disorders, rheumatoid arthritis, ostheoarthritis, psoriasis, allergic or contact dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, bronchitis, glomerulonephritis, irritable bowel syndrome, fatty liver disease, liver fibrosis, skin injury, lung emphysema, muscular dystrophy, fibrosis, atherosclerosis, burn injury, Crohn’s Disease, ulcerative colitis, age-related macular degeneration (AMD), growth and metastasis of malignant cells, Sjegren’s syndrome, myoblastic leukaemia, diabetes, osteoporosis, ischemic heart disease, and Amyotrophic Lateral Sclerosis (ALS).

Methods to diagnose and identify the above conditions are well known in the art.

According to the invention, one or more of the compounds, or pharmaceutically acceptable salts or hydrates thereof (e.g. in the form of an appropriate pharmaceutical composition), may be administered to an individual in need thereof in a therapeutically effective amount.

As used herein, “a therapeutically effective amount” refers to an amount that is capable of reducing the symptoms of a given neurovascular condition or pathology in the eye, and preferably which is capable of partly or wholly normalizing physiological responses in a subject with the condition or pathology. Reduction of symptoms or normalization of physiological responses can be determined using methods known in the art and can vary with a given condition or pathology. The effective amount will be 008806333

49 determined by the skilled person taking into account such factors as potency of the drug, age and constitution of the patient, body weight, pharmacokinetic profile of the drug, and in general the drug will be prescribed for each patient or group of patients.

The effective amount of the compound can be at least about 0.001 mg/kg body weight/day, such as at least about 0.01 mg/kg body weight/day, at least about 0.1 mg/body weight/day, and at least about 1 mg /kg body weight/day. On the other hand, the effective amount of the compound can be at most about 100 mg/kg body weight/day, such as at most about 80 mg/kg body weight/day and at most about 50 mg/kg body weight/day.

In some embodiments, the compound is administered to the patient once or twice daily, that is sometimes referred to as QD (quaque die) or BID (bis in die), respectively. In some embodiments, the compound is administered to the patient four times daily, that is sometimes referred to as QID (quaterin die).

The subject or patient to be treated may be any animal or human. The subject or patient is preferably mammalian, more preferably human. The subject or patient may be a non-human mammal, but is more preferably human. The subject or patient may be male or female.

***

The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range 008806333

50 is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example +/- 10%.

Examples

ABBREVIATIONS

CDI: carbonyl diimidazole

EDC or EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

HATU: O-(7-azabenzotriazol-1-yl)-A/,A/,A/',A/'-tetramethyluronium hexafluorophosphate

HBTU: 2-(1/7-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate

HOBt: 1-hydroxybenztriazole

T3P: propylphosphonic anhydride

PyBOP: benzotriazole-1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate

FDPP: pentafluorophenyl diphenylphosphinate

TCFH: chloro(dimethylamino)-A/,A/-dimethylmethaniminium hexafluorophosphate

COMU: 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)] uronium hexafluorophosphate

DABCO: 1 ,4-diazabicyclo[2.2.2]octane

DCMT: 2,4-dichloro-6-methoxy-1 ,3,5-triazine

THF: tetrahydrofuran

2-MeTHF: 2-methyl tetrahydrofuran

DMF: A/,A/-dimethylformamide

DMA: A/,A/-dimethylacetamide

NMP: A/-methyl-2-pyrrolidinone

DCM: dichloromethane

TBDMS or TBS: te/Y-butyldimethyl silyl

Mes or Ms: mesyl

Ts: tosyl

Bn: benzyl 008806333

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Tr: trityl tBOC: tert-butoxycarbonyl

Fmoc: fluorenylmethoxycarbonyl

THP: tetra hydro pyranyl

MTBE: methyl tert-butyl ether

Stereochemical notation

The notation R* or S* in the IUPAC name of the compound means an enantiomerically pure compound without determination of absolute configuration. That is, a compound with R* in its IUPAC name may be R or S at its stereocenter; and a compound with S* in its IUPAC name may be R or S at its stereocenter.

For compounds with two stereocenters:

• a compound with R*,R* in its IUPAC name may be R,R R,S; S,R or S,S (that is, R*,R* does not provide relative configuration R,R or S,S over R,S and S,R).

• a compound with R*,S* in its IUPAC name may be R,R R,S; S,R or S,S (that is, R*,S* does not provide relative configuration R,S or S,R over R,R and S,S).

• a compound with S*,R* in its IUPAC name may be R,R; R,S; S,R or S,S (that is, S*,R* does not provide relative configuration S,R or R,S over R,R and S,S).

• a compound with S*,S* in its IUPAC name may be R,R; R,S; S,R or S,S (that is, S*,S* does not provide relative configuration S,S or R,R over R,S and S,R).

If the stereochemistry in the IUPAC name of the compounds disclosed herein is either denoted (R) or (S) (that is, without the * notation), the stereochemistry is absolute and has been determined (such as by X- ray or by its synthesis) as depicted in the chemical name.

Similarly, for the chemical structures, the solid wedged and hashed wedged bonds in the structures of the compounds without an (R) or (S) annotation at the stereocenter(s) mean enantiomerically and/or diastereomerically pure compound without the determination of the absolute configuration, and have the corresponding R* or S* descriptor in the IUPAC name.

For chemical structures that have the solid wedged and hashed wedged bonds with an (R) or (S) annotation at the stereocenter(s), these are pure stereoisomers where the absolute configuration has been defined and confirmed by X-ray or by its synthesis, as depicted in the structure.

GENERAL SYNTHETIC PROCEDURES

Starting materials, solvents, and reagents are commercially available and used as purchased unless otherwise stated. 008806333

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General scheme target compounds

The compounds disclosed herein may be synthesized in the manner as shown in General Scheme 1 .

General Scheme 1 wherein W, X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined for formula (I); LG is a leaving group, for example halo (e.g., Cl), OH, OR [where R may be, e.g., an alkyl and the like, such that -C(=O)LG is a mixed anhydride, ester, or an “activated” ester], and the like; and P¹, P², and P³ are protecting groups (that is, a reversibly formed derivative of an existing functional group in a molecule). P¹ may be, for example, an acyl or carbamate protecting group when not H. P² is defined further below. For P³, such protecting groups are well known in the art, for example P³ may be Bn, Boc, Fmoc, THP, Tr, Ts, Ms, or a silyl group like TBDMS, TBS, and the like. 008806333

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Step A: acylation or amidation

Step A is an acylation (or amidation) reaction.

Compound (a) may be an acid chloride (where LG is Cl) and standard acylation conditions known in the art may be used to affect the reaction between compound (a) and one of amine compounds (b), (c), or (d), for example Schotten Bauman conditions.

Alternatively, compound (a) may be an ester (for example, where LG is O(alkyl), such as OMe or OEt) and the amine compounds (b), (c), or (d) may be reacted under microwave conditions.

Additionally, the acylation/amidation may use common peptide coupling conditions using activated esters, often generated in situ, by reacting an acid (where LG is OH) with activating agents (for example, CDI, EDC, EDCI, HATU, HOBt, T3P, PyBOP, FDPP, TCFH, COMU, DABCO/DCMT), base, and a non-protic solvent (for example, THF, 2-MeTHF, DMF, DMA, NMP, DCM, and the like).

See, for example, Developments in peptide and amide synthesis F. Albericio Current Opinion in Chemical Biology 2004, 8:211-221 ; E. Valeur, M. Bradley Chem. Soc. Rev. 2009, 38, 606; and El-Faham and F. Albericio Chem Rev. 2011 , 111 , 6557.

Step B: ketone reduction reaction

Step B is a ketone reduction reaction. The conditions for a ketone reduction are well-known in the art and may use reducing agents, such as sodium borohydride and lithium aluminum hydride.

Step C: transforming OH into a leaving group followed by nucleophilic substitution

Step C is a transformation of the OH adjacent to the XYZ ring into a leaving group (for example, halo, mesylate, tosylate, and the like), followed by nucleophilic substitution with a reagent to replace the original OH group with R⁵ and/or R⁶. When the leaving group is halo, the OH adjacent to the XYZ ring may be transformed using thionyl chloride or DAST. Typically, a temperature range of 0°C - 70°C and a time of 10 minutes to 24 hours is required to affect the reaction.

Step D: aryl-aryl coupling reaction

Step D is an aryl-aryl coupling reaction. The conditions for aryl-aryl coupling are well-known in the art.

For example, Suzuki-Miyaura coupling may be used. In a Suzuki-Miyaura coupling reaction, the coupling reaction is between an aryl (Ar) / heteroaryl (HetAr) halide (such as I, Br, or Cl) or triflate (OTf) - sometimes known as the donor coupling partner, and a boronic acid or boronic acid ester - sometimes known as the acceptor coupling partner. The aryl (Ar) / heteroaryl (HetAr) halide or triflate may be compound (g) or, alternatively, the compound providing the R³ moiety (for example, R³-l/Br/CI/OTf where R³ is HetAr). The boronic acid or boronic acid ester may be compound (h) or, alternatively, the compound providing the R³ moiety (for example, R³-B(OP¹)2 where R³ is HetAr). The boronic acid is where (OP²)2 is (OH)2, whereas the boronic ester is where (OP¹)2 may be, for example, - OC(Me)2C(Me)2O- or -[O(alkyl)]2 where alkyl may be Me, Et, and the like. The transition metal catalyst is usually a palladium catalyst, for example Pd(OAc)2, Pd(dppf)Cl2, and the like. Sometimes, a phosphine is added as a ligand to facilitate the reaction, for example PPhs, P(ABu)3, XPhos, SPhos, Xantphos, and the 008806333

54 like. The solvent for such reactions is typically aromatic non-protic solvents, for example toluene. However, other solvents such as DMF, DMA, dioxane, THF, DMSO, 2-MeTHF, water, and combinations thereof are also used. A weak base is also added to facilitate the reaction, for example sodium carbonate, potassium carbonate, NaOH, K3PO4, NaOMe, NaOEt, CS2CO3, pyridine, or a trialkylamine. The reaction is usually conducted at room temperature up to 120°C. See, for example, Miyaura N., Yanagi, T. Suzuki A. Syn. Comm. 1981 , 11 , 513.

Step E: Alkyl anion addition on ketones

Step E is an alkyl anion addition on a ketone yielding a tertiary alcohol. An alkyl anion is typically an organometallic reagent, preferably a Grignard magnesium reagent. Reactions are performed in non- protic solvents, typically ethers such as diethyl ether, THF, 2-MeTHF, and the like. The reaction is usually conducted at -20°C to room temperature.

General scheme biarylcarboxylic acid (ester) intermediates

Where compound (a) (from General Scheme 1) is an intermediate ester compound (a'), such that LG is OP³ where P³ is a protecting group (for example, alkyl such as Me or Et), and R³ is a heteroaryl group

(HetAr), the ester compound (a') may be synthesized in the manner as shown in General Scheme 2.

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General Scheme 2

A l/Br/CI/OTf-R³ where R³ = HetAr

TM catalysis (e.g. Suzuki-Miyaura)

B

Buchwald-Hartwig or Cu-cata lysed c known-in-the-art

5-6 membered ring synthesis

(m) wherein W, R¹, R², R³, and R⁴ are as defined for formula (I); FG is a functional group as defined further below with respect to the specific reactions; and P² and P³ are protecting groups (that is, a reversibly formed derivative of an existing functional group in a molecule) as defined further below.

Steps A and A': transition metal (TM) catalysed coupling reaction

Steps A and A' are transition metal catalysed coupling reactions, for example a Suzuki-Miyaura coupling reaction and the like. In a Suzuki-Miyaura coupling reaction, the coupling reaction is between a heteroaryl (HetAr) halide (such as I, Br, or Cl) or tritiate (OTf) - sometimes known as the donor coupling partner, and a boronic acid or boronic acid ester - sometimes known as the acceptor coupling partner.

The boronic acid is where (OP²)2 is (OH)2, whereas the boronic ester is where (OP²)2 may be, for example, -OC(Me)2C(Me)2O- or -[O(alkyl)]2 where alkyl may be Me, Et, and the like. The transition metal catalyst is usually a palladium catalyst, for example Pd(OAc)2, Pd(dppf)Cl2, and the like. Sometimes, a phosphine is added as a ligand to facilitate the reaction, for example PPhs, P(f-Bu)3, XPhos, SPhos, Xantphos, and the like. The solvent for such reactions is typically aromatic non-protic solvents, for example toluene. However, other solvents such as DMF, DMA, dioxane, THF, DMSO, 2-MeTHF, water, and combinations thereof are also used. A weak base is also added to facilitate the reaction, for example 008806333

56 sodium carbonate, potassium carbonate, NaOH, K3PO4, NaOMe, NaOEt, CS2CO3, pyridine, or a trialkylamine. The reaction is usually conducted at room temperature up to 120°C. See, for example, Miyaura N., Yanagi, T. Suzuki A. Syn. Comm. 1981 , 11 , 513.

In Step A, the boronic acid or boronic acid ester is the compound (i), and the HetAr halide or tritiate is the compound providing the R³ moiety. In Step A', the donor and acceptor coupling partners are switched - the boronic acid or boronic acid ester is the compound providing the R³ moiety, and the HetAr halide or tritiate is the compound (j).

Step B: aryl-aryl coupling reaction - Buchwald-Hartwig or a copper-catalysed coupling

Alternatively, step B is an aryl-aryl coupling reaction, for example Buchwald-Hartwig or a copper- catalysed coupling reaction.

In a Buchwald-Hartwig reaction, the coupling reaction is between a heteroaryl (HetAr) with a reactive (nucleophilic) NH group (for example, optionally substituted pyrrole, imidazole, or triazole) and an aryl (Ar) / heteroaryl (HetAr) halide (such as I, Br, or Cl) or tritiate (OTf). Compound (k) is usually the aryl (Ar) / heteroaryl (HetAr) halide or tritiate, where FG is the halide or tritiate functional group. The compound providing the R³ moiety is usually the heteroaryl with a reactive (nucleophilic) NH group. The transition metal catalyst is usually a palladium catalyst, for example Pd(OAc)2, Pd(dppf)Cl2, and the like. Sometimes, a phosphine is added as a ligand to facilitate the reaction, for example PPhs or P(f-Bu)3, or the more preferred BINAP, XPhos, SPhos, XanthPhos, RuPhos, or the first, second, third, and fourth generation ligands as described in B. T. Ingoglia, Wagen, C. C., and Buchwald, S. L. “Biaryl monophosphine ligands in palladium-catalyzed C-N coupling: An updated User's guide”, Tetrahedron, 2019, 75(32), 4199-4211 . A weak base is also added to facilitate the reaction, for example sodium carbonate, potassium carbonate, NaOH, K3PO4, NaOMe, NaOEt, KOtBu, pyridine, or a trialkylamine. Typical solvents for the reaction may be toluene, DMF, DMA, dioxane, THF, DMSO, 2-MeTHF, water, and combinations thereof. The reaction is usually conducted at room temperature up to 120°C.

Alternatively, step B may be a copper-catalysed coupling, such as an Ullmann reaction or a Chan-Lam reaction. A copper(l) or copper(ll) catalyst may be used in conjunction with a ligand, such as Cu(OAc)2, CuCI₂, Cui, or CuBr with a phosphine ligand such as PPhs or P(f-Bu)3. A weak base is also added to facilitate the reaction, for example sodium carbonate, potassium carbonate, NaOH, K3PO4, NaOMe, NaOEt, pyridine, or a trialkylamine. The reaction may be conducted at room temperature up to 120°C.

Step C: heterocyclic ring synthesis

In other cases, step C may be used to synthesise the intermediate ester compound (a') via known heterocyclic ring syntheses as described in Comprehensive Heterocyclic chemistry, 1984 edits Alan R. Katritzky and Charles W. Rees. These 5-6 membered heterocyclic ring syntheses are well known in the art and is dependent on the desired R³ group. For example, where R³ is pyrimidinyl, a ketone compound (containing the FG functional group -C(=O)CHRCH2R) may be coupled with urea compound (containing the FG functional group -C(=NH)NH2 or salt thereof). Where R³ is pyrazolyl, a hydrazine compound (containing the FG functional group -NHNH2) may be coupled with an a,p-unsaturated aldehyde 008806333

57 compound (containing the FG functional group -CR=CRC(=O)R); or alternatively a hydrazone compound (containing the FG functional group -C(=NNRTs)) is coupled with an alkyne compound (containing the FG functional group -C=CH). Where R³ is a triazolyl, an azide compound (containing the FG functional group -N3) may be coupled with an alkyne compound (containing the FG functional group -C=CH), such as the Huisgen azide-alkyne 1 ,3-dipolar cycloaddition or Copper- or Ruthenium-Catalysed Azide-Alkyne Cycloaddition (CuAAC or RuAAC respectively). Where R³ is pyridinyl, an aldehyde (containing the FG functional group -CHO) may be coupled with a 1 ,3-diketone (containing the FG functional group - C(=O)CH2C(=O)OR) in the presence of ammonia (NH3), such as the Hantzsch dihydropyridine (pyridine) synthesis; or alternatively an enamine compound (containing a -C(NH2)=CR(EWG) where the EWG (electron withdrawing group) may be an ester -C(= 0)0 R) is coupled with a ethynylketone compound (containing the FG functional group -C(=O)C=CH), such as the Bohlmann-Rahtz pyridine synthesis. Where R³ is imidazolyl, an aldehyde (containing the FG functional group -CHO) may be coupled with a 1 ,2-diketone (containing the FG functional group -C(=O)C(=O)R) in the presence of ammonia (NH3), such as the Debus-Radziszewski imidazole synthesis; or alternatively an aldimine compound (containing the FG functional group -CH(=NR)) may be coupled with an isocyanide (containing the FG functional group - CH(Ts)NC), such as the Van Lausen imidazole synthesis. Where R³ is oxazolyl, an aldehyde (containing the FG functional group -CHO) may be coupled with an isocyanide (containing the FG functional group - CH(Ts)NC), such as the Van Lausen oxazole synthesis. Where R³ is isoxazolyl, an a,p-unsaturated aldehyde (containing the FG functional group -CR=CRC(=O)R) may be coupled with A/-hydroxyl-4- toluenesulfonamide (TsNHOH). Thus, the functional groups FG may be, for example, amine, azide, cyanide, isocyanide, aldehyde, a,p-unsaturated aldehyde, aldimine, ketone, diketone, carboxylic acid, carboxylic ester, oxime, enamine, hydrazine, hydrazone, and the like known in the art.

Generic scheme off>-amino alcohols and fi-amino ketones intermediates

Intermediate derivatives (b') and (c') of compounds (b) and (c) from General Scheme 1 and intermediate derivatives (v) and (y) of compound (d) from General Scheme 1 may be synthesised in the manner as shown in General Scheme 3.

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General Scheme 3

Method A wherein X, Y, Z, and R⁷ are as defined for formula (I), and R in Methods D and E are alkyl as defined further below. Methods A, B, and C are alternative methods to produce intermediate derivatives (b') and (c'). The products of Methods D and E, that is compounds (v) and (y), may be used in place of intermediate compound (d) (when P¹ in compound (d) is H) in General Scheme 1.

Step A: cyanohydrin synthesis

The first step of Method A is step A, a cyanohydrin synthesis, producing cyanohydrin compound (o). The cyanohydrin synthesis uses a cyanide anion reagent, such as HCN, KCN, NaCN, NaHSOs/KCN, 008806333

59

TMSCN/Znh, and the like. This cyanide anion reagent reacts with aldehyde compound (n) to product rhe cyanohydrin compound (o). The solvent is typically an aqueous or apolar solvent, such as diethylether, THF, DCM, or toluene. When TMSCN is used, the reaction temperature is typically from 0°C to 50°C. See, for example, Comprehensive Organic Transformations, R.C. Larock VCH Publisher, Inc. (1989); and Lewis acid catalysed enantioselective cyanohydrin synthesis see M. North, D.L. Usanov and C. Young Chem. Rev. 2008, 108, 12, 5146-5226.

Step B: cyanide reduction

The second step of Method A is step B, a cyanide reduction. The reduction of the cyanide may be affected with hydrogen gas (1 atm. to 5 atm.) using catalysts such as palladium on charcoal (Pd/C), Pt/C, rhodium chloride, Raney-Nickel, or lithium aluminium hydride. The solvent is typically MeOH, EtOH, /- PrOH, THF, diethyl ether, or toluene.

The resulting intermediate compound (c') may they be protected with a suitable protecting group known in the art to form compound (c) in General Scheme 1 . Alternatively, resulting intermediate compound (c') may be oxidized using known methods in the art to the ketone compound (b) in General Scheme 1.

Step C: Henry reaction

The first step of Method B is step C, a Henry reaction, producing nitro compound (p) (also known as a Henry adduct). A Henry reaction is a nitroalkyl addition (such as MeNO2) to an aldehyde compound (n) under basic conditions (using bases such as alkali metals, alkoxides, or non-ionic amines e.g. DBU) and a suitable solvent.

Step D: nitro reduction

The second step of Method B is step D, a nitro reduction. All conditions mentioned in step B may be used to affect the nitro reduction. Additionally, metals (such as zinc, tin, and iron) in the presence of an acid (such as hydrochloric acid or sulfuric acid) at temperatures between 0°C and 100°C in solvents such as DMF, DMA, or DCM may also be used. Lithium aluminium hydride is also commonly used for the reduction of Henry adducts such as nitro compound (p).

Step E: oxazole carboxylic acid ester synthesis

The first step of Method C is step E, an oxazole carboxylic acid ester synthesis, producing oxazole compound (r). The synthesis uses aryl carboxylic acid compound (q) with ethyl 2-isocyanoacetate to form the oxazole compound (r).

Step F: acid hydrolysis of oxazoles into aminoketones

The second step of Method C is step F, acid hydrolysis of the oxazole compound (r) to produce aminoketone compound (b'), typically as a salt of the acid, such as the hydrochloride salt when using 008806333

60 hydrochloric acid in the acid hydrolysis. Water is present to facilitate the acid hydrolysis reaction and conditions are well-known in the art.

Step G: alkyl nitrile aldol condensation

The first step of Method D is step G, aldol-type condensation with an alkyl formate (HC(=O)OR where R is alkyl). The reaction is conducted in the presence of a base such as NaH, NaOtBu, KtOBu, K2CO3, alkali metals, alkoxides, or non-ionic amines (e.g. DBU) and a suitable solvent to yield intermediate compound (t).

When an aldehyde (RCH(=O) where R is alkyl) is used (instead of the alkyl formate), a base such as NaH, NaOtBu, KtOBu, K2CO3, alkali metals, alkoxides, or non-ionic amines e.g. DBU) may be used with a suitable solvent to obtain intermediate compound (u) directly, instead of compound (t).

Step H: reduction of enol

The second step of Method D is step H, a reduction of the enol intermediate compound (t). This reaction can be achieved via a borohydride reduction, for example using NaBHsCN, in protic solvents.

Step I: cyanide reduction

The third step of Method D is step I, a cyanide reduction. The reduction of the cyanide may be affected with hydrogen gas (1 atm. to 5 atm.) using catalysts such as palladium on charcoal (Pd/C), Pt/C, rhodium chloride, Raney-Nickel, or lithium aluminium hydride. The solvent is typically MeOH, EtOH, /-PrOH, THF, diethyl ether, or toluene.

Step J: nitro alkyl Knoevenagel condensation

The first step of Method E is step J, a Knoevenagel condensation with intermediate compound (n) and nitromethane (MeNO2) in the presence of a base such as NaH, NaOtBu, KtOBu, K2CO3, alkoxides, or non-ionic amines (e.g. DBU) and a suitable solvent to yield intermediate compound (w).

Step K: Michael addition of a carbanion

The second step of method E is Step K, which is a carbanion addition on a nitro alkenyl (w). An alkyl anion is typically an organometallic reagent, preferably a Grignard magnesium reagent. Reactions are performed in non-protic solvents, typically ethers such as diethyl ether, THF, 2-MeTHF and the like. The reaction may be conducted at -20°C to room temperature.

Step L: nitro reduction

The third step of method E is Step L, a nitro reduction. All conditions mentioned in step L may be used to affect the nitro reduction. Additionally, metals (such as zinc, tin, and iron) in the presence of an acid (such as hydrochloric acid or sulfuric acid) at temperatures between 0°C and 100°C in solvents such as DMF, DMA, or DCM may also be used. Lithium aluminium hydride is also commonly used for the reduction of nitro compound (x). 008806333

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ANALYTICAL METHODS

¹H, ¹⁹F, and ¹³C NMR were performed on a Bruker, AVANCE III HD 400MHz. LC-MS was performed on a Shimadzu, LCMS-2020+LC-20AB. HPLC was performed on a Shimadzu, LC-20AB. SFC was performed on a SHIMADZU LC-30ADsf.

Analytical LC methods

LC-MS (method A):

Liquid chromatography-mass spectrometry-mass (LC-MS) data (sample analyzed for purity and identity) was obtained with a Shimadzu model-LC-20AB system using a Shimadzu model LC-MS-2020 mass spectrometer utilizing ES-API ionization fitted with a phenomenex (HALO C18, 5pm particle size, 3.0x30mm dimensions) reverse-phase column at 50 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.0375% trifluoroacetic acid in water and 0.01875% trifluoroacetic acid in MeCN. A constant gradient from 100% aqueous to 40% aqueous/60% organic mobile phase over the course of 1 minute was utilized. The flow rate was constant at 1 .5mL/min.

HPLC (method B):

High Performance Liquid Chromatography (HPLC) data were obtained with a Shimadzu model-LC-20AB system using a PDA detector (220nm&215nm&254nm) with a phenomenex (Kinetex C18 LC Column, 5pm particle size, 4.6x50mm dimensions) reverse-phase column at 50 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.0375% trifluoroacetic acid in water and 0.01875% trifluoroacetic acid in MeCN. A constant gradient from 90% aqueous/10% organic to 20% aqueous/80% organic mobile phase over the course of 6 minutes was utilized. The flow rate was constant at 1 .5 mL/min.

SFC (method C):

Column: Chiralcel OJ-3 50x4.6mm I.D., 3pm Mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

SFC (method D):

SFC method: Column: Chiralpak IG-3 50x4.6mm LD., 3pm, Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 20% to 60%; Flow rate: 3mL/min; Detector: PDA, Column Temp: 35°C; Back Pressure: 100 Bar.

LC-MS (method E):

Liquid chromatography-mass spectrometry-mass (LC-MS) data (sample analyzed for purity and identity) was obtained with a Shimadzu model-LC-20AB system using a Shimadzu model LCMS-2020 mass spectrometer utilizing ES-API ionization fitted with a phenomenex (Kinetex EVO C18 2.1X30mm,5pm) reverse-phase column at 50 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.0375% trifluoroacetic acid in water and 0.025% NH3 H2O in MeCN. A constant gradient from 95% 008806333

62 aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 1 minute was utilized.

The flow rate was constant at 1 .5mL/min.

HPLC (method F):

High Performance Liquid Chromatography (HPLC) data were obtained with a Shimadzu model-LC-20AB system using a PDA detector (220nm&215nm&254nm) with a phenomenex (Kinetex C18 LC Column, 5pm particle size, 4.6x50mm dimensions) reverse-phase column at 50 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.025% NH3 H2O in water and 0.025% NH3 H2O in MeCN. A constant gradient from 90% aqueous/10% organic to 20% aqueous/80% organic mobile phase over the course of 6 minutes was utilized. The flow rate was constant at 1 .5mL/min.

SFC (method G):

SFC method: Column: Chiralpak AD-3 50x4.6mm LD., 3pm Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

LC-MS (method H):

Liquid chromatography-mass spectrometry-mass (LC-MS) data (sample analyzed for purity and identity) was obtained with a Shimadzu model-LC-20AB system using a Shimadzu model LCMS-2020 mass spectrometer utilizing ES-API ionization fitted with a phenomenex (HALO C¹⁸, 5pm particle size, 3.0x30mm dimensions) reverse-phase column at 50 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.0375% trifluoroacetic acid in water and 0.01875% trifluoroacetic acid in MeCN. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 1 minute was utilized. The flow rate was constant at 1 .5mL/min.

SFC (method I):

SFC method: Column: Chiralcel OJ-3 50x4.6mm I.D., 3pm, Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

SFC (method J):

SFC method: Column: Chiralpak I F-3 50x4.6mm LD., 3pm Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: 40% IPA+ACN (0.05% DEA) in CO2; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

LC-MS (method K):

HPLC measurement was performed using a VANQUISH FLEX module comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40° C), a diode-array detector DAD and a column as specified in the respective methods below. The MS detector (ISQ Thermo Scientific) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 700 in 0.2 008806333

63 second. The capillary needle voltage was 3 kV in positive and 2 kV in negative ionization mode and the source temperature was maintained at 250°C. Nitrogen was used as the nebulizer gas.

In addition to general procedure: Reversed phase UHPLC was carried out on a Luna Omega-C18 column Phenomenex (3 pm, 50 x 2.1 mm) with a flow rate of 0.600 ml/min. Two mobile phases were used, mobile phase A: water (LC-MS grade) 0,1 % FA; mobile phase B: acetonitrile (LiChrosolv for LC-MS Merck), and they were employed to run a gradient conditions from 15 % B for 0.2 minutes, from 15 % to 95 % in 1.6 minutes, 95 % B for 0.60 minutes and 15 % B in 0.10 minutes and hold these conditions for 1 .05 minutes in order to re-equilibrate the column (Total Run Time 3.55 minutes). An injection volume of 0.8 pL was used. Data acquisition was performed with Chromeleon 7.

SFC (method L):

SFC method: Column: Chiralpak IK-3 50x4.6mm I.D., 3pm; Mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); Gradient elution: 40% IPA (0.05% DEA) in CO2; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35°C;Back Pressure: 100 Bar.

Preparative HPLC (method M):

HPLC system WATERS Quaternary Gradient Mobile 2535 equipped with WATERS UVA/isible Detector 2489 set to a dual-wavelength UV detection. Two mobile phases were used, mobile phase A: water 0,05 % FA; mobile phase B: acetonitrile 0.05 FA, and they were employed to run a gradient conditions from 30 % B for 2 minutes, from 30 % to 60 % in 7 minutes, from 60 % to 95 % in 2 minutes, 95 % B for 1 minute and 30 % B in 3 minutes and hold these conditions for 5 minutes in order to re-equilibrate the column (Total Run Time 15 minutes). The purifications were achieved on a Luna Phenomenex Column C18 5 pm 19 x 150. An injection volume between 100 and 500 mL was used, and the flow was 15 ml/ min.

SFC (method N):

SFC method: Column: Chiralpak AY-3 50x4.6mm I.D., 3pm Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

SFC (method O):

SFC method: Column: Chiralpak IG-3 50x4.6mm LD., 3pm Mobile phase: Phase A for CO2, and Phase B: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

SFC (method P):

SFC method: Column: Chiralpak IC-3 50x4.6mm LD., 3pm Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3mLZ min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar. 008806333

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SFC (method Q):

SFC method: Column: Chiralcel OD-3 50x4.6mm I.D, 3|jm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: B in A from 5% to 40%; Flow rate: 3mL/min; Detector: DAD;

Column Temp: 35°C; Back Pressure: 100 Bar. Chiral purity was analysed by analytical chiral SFC methods (C, D, G, I, J, L, N, O, P and Q) and was >98%.

INTERMEDIATE SYNTHESES

TABLE 1: Table of Intermediates 008806333

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66 008806333

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2-nitro-1-(1,3-thiazol-5-yl)ethan-1-ol (1-1)

To a solution of 5-thiazolecarboxaldehyde (5.00 g, 44.2 mmol, 1.00 eq) and CH3NO2 (27.0 g, 442 mmol, 23.9 mL, 10.0 eq) in MeOH (50 mL) was added K2CO3 (6.11 g, 44.2 mmol, 1 .00 eq). The mixture was stirred at -10 °C for 1 .5 hrs. The residue was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/1 , Rf=0.4). Compound 1-1 (3.20 g, 18.4 mmol, 41 .6% yield) was obtained as a white solid. LC-MS (method A): RT: 0.41 1 min, m/z 175.0; 1H-NMR (400 MHz, CDCh): 6 8.75 (d, J = 5.2 Hz, 1 H), 7.77 (d, J = 5.2 Hz, 1 H), 6.10 (s, 1 H), 5.74-5.71 (m, 1 H), 4.74-4.51 (m, 2H).

The following intermediates were prepared analogously to the synthesis outlined for intermediate 1-1.

Analysis was done by LC-MS (method A), unless otherwise noted. 2-amino-1-(1,3-thiazol-5-yl)ethan-1-ol (1-2)

A mixture of compound 1-1 (3.2 g, 18.3 mmol, 1.00 eq) in MeOH (30.0 mL) was degassed and purged with N2(50.0 psi) for 3 times, and 10% Pd/C (800 mg) was added, then degassed and purged with H2 008806333

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(50.0 psi) for 3 times, the mixture was stirred at 25 °C for 12 hrs under H2 (50.0 psi) atmosphere.

Evaporate the solution on a water bath under reduced pressure using a rotary evaporator. Without purification, compound I-2 (2.50 g, 17.3 mmol, 94.4% yield) was obtained as a yellow solid. LC-MS (method A): RT: 0.091 min, m/z 145.0; ¹H-NMR (400 MHz, CDCb): 6 8.97 (d, J = 3.2 Hz, 1 H), 7.85 (d, J =6.0 Hz, 1 H), 5.31-5.26 (m, 0.5H), 4.97-4.86 (m, 0.5H), 3.38 (s, 1 H), 3.13-3.07 (m, 1 H), 2.89-2.88 (m, 1 H).

The following intermediates were prepared analogously to the synthesis outlined for intermediate I-2.

Analysis was done by LC-MS (method A), unless otherwise noted. methyl 5-(5-fluoropyrimidin-2-yl)-2-methylbenzoate (1-3)

To a mixture of compound methyl 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) benzoate (5.00 g, 18.1 mmol, 1 .00 eq) and 2-chloro-5-fluoropyrimidine (2.40 g, 18.1 mmol, 2.24 mL, 1.00 eq) in dioxane (50.0 mL) was added a solution of K2CO3 (5.00 g, 36.2 mmol, 2.00 eq) in H2O (10.0 mL) , then the mixture was purged with N2 for 3 times, then Pd(dppf)Cl2 (662 mg, 905 pmol, 0.05 eq) was added, the mixture was stirred at 90 °C for 3 hrs. The reaction mixture was concentrated to remove dioxane and diluted with H2O (80.0 mL) and extract it with EtOAc (100 mL x 2), dry the combined organic layers over Na2SO4, filter and concentrate it under reduced pressure to give a residue. The residue was slurried with MTBE (50.0 mL) to obtain compound I-3 (3.00 g, 12.1 mmol, 67.3% yield) as an off-white solid. LC-MS (method A): RT: 0.907 min, m/z 247.0; ¹H-NMR (400MHz, DMSO-cfe): 6 8.98 (s, 2H), 8.82 (d, J = 1 .2 Hz, 1 H), 8.39 (dd, J = 1.2, 7.6 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 3.88 (s, 3H), 2.59 (s, 3H).

5-(5-fluoropyrimidin-2-yl)-2-methylbenzoic acid (1-4)

To a solution of compound 1-3 (1 .50 g, 6.09 mmol, 1 .00 eq) in THF (15 mL) was added a solution of LiOH.H2O (383 mg, 9.14 mmol, 1 .50 eq) in H2O (5 mL), then the mixture was stirred at 25 °C for 12 hrs. Then LiOH.H2O (3834 mg, 9.14 mmol, 1 .50 eq) was added and the mixture was stirred at 45 °C for 3 hrs. The reaction was concentrated to remove most of THF and diluted with H2O (20 mL), then adjusted with 1 M HCI to pH = 3 and extract it with EtOAc (30 mL x 2), the combined organic layers was dried over Na2SO4, filter and concentrate it under reduced pressure to give compound I-4 (1 .35 g, 5.81 mmol, 95.4% yield) as a yellow solid. LC-MS (method A): RT: 0.822 min, m/z 233.0; ¹H-NMR (400MHz, CDCh): 6 9.28 - 9.09 (m, 1 H), 8.74 (s, 2H), 8.55 - 8.32 (m, 1 H), 7.48 - 7.37 (m, 1 H), 2.75 (s, 3H). 008806333

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5-(5-fluoropyrimidin-2-yl)-2-fluorobenzoic acid (1-18)

To a solution of 4-fluoro-3-carboxylphenylboronic acid (1 .0 g, 5.44 mmol, 1 .00 eq) and CS2CO3 (2.66 g, 8.16 mmol, 1 .50 eq) in DMF (4 mL) and H2O (2 mL) purged with N2 for 3 times, then was added 2-chloro- 5-fluoropyrimidine (900 mg, 6.80 mmol, 839 pL, 1.25 eq) and Pd(PPhs)4 (125.65 mg, 108.74 pmol, 0.02 eq). The mixture was stirred at 110 °C for 3hr under N2 atmosphere. The reaction mixture was quenched by addition H2O 10 mL, and then basified with NaOH 3M (10 mL) until pH=12, and extracted with DCM (10 mL x 3). The aqueous phase was acidified by 1 M HCI until pH=1 , the precipitate was filtered, washed with water, and dried under vacuum. Compound 1-18 (1.50 g, crude) was obtained as a gray solid LC-MS (method A): RT: 0.568 min, m/z = 237.2; HPLC (method B): RT: 1.795 min, 84.3% purity.

5-(5-fluoropyrimidin-2-yl)-2-chlorobenzoic acid (1-19)

Compound 1-19 was synthesized using the method described for compound 1-18 starting from 4-chloro-3- carboxylphenylboronic acid (2.5 g, 12.5 mmol, 1.00 eq), and 2-chloro-5-fluoropyrimidine (2.07 g, 15.6 mmol, 1.9 mL, 1.25 eq) yielding 5-(5-fluoropyrimidin-2-yl)-2-chlorobenzoic acid (3 g, 95% yield). LC-MS (method K): RT: 2.2 min, m/z = 253.1 (ESI⁺); 297.1 (ESI- as Formate adduct).

5-(5-fluoropyrimidin-2-yl)-2-(trifluoromethyl)benzoic acid (1-24)

Compound 1-24 was synthesized using the method described from 1-18 starting from 4-trifluoromethyl-3- carboxylphenylboronic acid (1.0 g, 4.27 mmol, 1.00 eq) and 2-chloro-5-fluoropyrimidine (0.708 g, 5.34 mmol, 0.66 mL, 1.25 eq) yielding compound I-24 (0.699 g, 57 % yield). LC-MS (method K): RT: 2.3 min, m/z = 285.2 (ESI ); 331 .1 (ESI- as Formate adduct).

3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)butanenitrile (1-5)

To a mixture of (4-methyl-1 ,3-thiazol-5-yl)acetonitrile (2.0 g, 14.4 mmol, 1 .00 eq) and K2CO3 (3.33 g, 14.4 mmol, 60% purity, 1.00 eq) in EtOH (25 mL) was added compound acetaldehyde (6.38 g, 144 mmol, 8.12 mL, 10.0 eq) at -10 °C, then the mixture was stirred at -10 °C for 1 hr. The reaction mixture was quenched with H2O (20.0 mL) and extracted with DCM (20.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 1/2), confirmed by TLC (Plate 1 , PE : EtOAc = 1 :1 , Rf = 0.42), to get desired compound I-5 (1 .40 g, 7.68 mmol, 53.0% yield) as yellow oil.

LC-MS (method A): RT: 0.417 min, m/z 183.0; ¹H-NMR (400MHz, CDCh): 6 8.73 (d, J = 2.8 Hz, 1 H), 4.18 - 4.07 (m, 2H), 2.47 (d, J = 2.8 Hz, 3H), 1 .38 (dd, J = 2.0, 8.8 Hz, 3H). 008806333

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4-amino-3-(4-methyl-1,3-thiazol-5-yl)butan-2-ol (1-6)

To a solution of Raney-Ni (0.50 g, 5.84 mmol) in MeOH (10.0 mL) and NH3.H2O (3 mL) was added compound I-5 (0.42 g, 2.30 mmol, 1 .00 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi.) at 25 °C for 16 hrs. The reaction mixture was filtered and concentrated the filtrate to give a residue. The residue was purified by prep- HPLC (column: C18 250x50mm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 1 %-10% B over 9 min) to get compound I-6 (0.16 g, 858 pmol, 37.2% yield) as yellow oil. LC-MS (method A): RT: 0.617 min, m/z 187.1 ; ¹H-NMR (400 MHz, CDCI3): 6 8.68 (s, 1 H), 4.30-4.29 (m, 1 H), 3.20-3.13 (m, 3H), 2.44 (s, 3H), 1.10-1.05 (m, 3H).

3-amino-2-(4-methyl- 1 ,3-thiazol-5-yl)propan- 1-ol (I- 12)

Compound 1-12 was synthesized following the procedure described for I-6 (29.3% yield). LC-MS (method A): RT: 0.417 min, m/z 173.0; ¹H-NMR (400MHz, CDCI3): 6 8.62 (s, 1 H), 3.88 (d, J = 6.0 Hz, 2H), 3.59 - 3.49 (m, 1 H), 3.38 - 3.26 (m, 1 H), 3.20 - 3.03 (m, 2H), 2.46 (s, 3H).

(4-methyl-1,3-thiazol-5-yl)methanol (1-7)

To a solution of compound 4-methyl-1 ,3-thiazole-5-carbaldehyde (15.0 g, 118 mmol, 1.00 eq) in THF (150 mL) was added LAH (2.5 M, 23.6 mL, 0.50 eq at 0 °C, then the mixture was stirred at 0 °C for 0.5hr. The reaction was quenched with H2O (2.30 mL), 15% NaOH (2.30 mL), H2O (6.80 mL) at 0 -10°C, then about 50 g Na2SO4 was added to the mixture, filtered and the filtrate was concentrated to give compound I-7 (13.8 g, 106 mmol, 90.5% yield) as yellow oil. ¹H-NMR (400MHz, CDCI3): 6 8.64 (s, 1 H), 4.83 (s, 2H), 2.43 (s, 3H).

5-(chloromethyl)-4-methyl-1,3-thiazole (1-8)

To a solution of compound 1-7 (16.0 g, 123 mmol, 1.00 eq in DCM (150 mL) was added SOCI2 (73.6 g, 619 mmol, 44.9 mL, 5.00 eq) at 0°C, then the mixture was stirred at 25°C for 12 hrs. The reaction was concentrated to give a residue, then dissolved in H2O (100 mL) and adjusted with NaHCOs (sat.) to pH = 8, extracted with DCM (100 mL x 2), the combined organic layers was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to get compound I-8 (15.0 g, 101 mmol, 82.0% yield) as purple oil. LC-MS (method A): RT: 0.443 min.

(4-methyl-1,3-thiazol-5-yl)acetonitrile (1-9)

To a solution of compound 1-8 (15.0 g, 101 mmol, 1.00 eq in DMF (150 mL) was added KCN (8.45 g, 129 mmol, 5.56 mL, 1 .28 eq), then the mixture was stirred at 25 °C for 12 hrs. The reaction mixture was quenched by addition NaHCOs (sat., 150 mL), and extracted with EtOAc (100 mL x3). The combined 008806333

71 organic layers were washed with H2O (200 mL x 2) and brine (200 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 3/1), confirmed by TLC (Plate 1 , PE : EtOAc = 1 : 1 , Rf = 0.47), to get desired compound I-9 (8.70 g, 62.9 mmol, 61 .9% yield) as a yellow solid. LC-MS (method A): RT: 0.243 min, m/z 139.0; ¹H-NMR (400MHz, CDCb): 6 8.69 (s, 1 H), 3.85 (s, 2H), 2.47 (s, 3H).

3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)prop-2-enenitril (1-10)

To a solution of compound I-9 (1.50 g, 10.8 mmol, 1.00 eq) in THF (20.0 mL) was added compound ethyl formate (8.04 g, 108 mmol, 8.73 mL, 10.0 eq), then the mixture was cooled to 0 °C and NaH (521 mg, 13.0 mmol, 60% purity, 1 .20 eq) was added at 0 °C, the reaction mixture was warmed to 25 °C and stirred for 1 hr. The reaction was quenched with H2O (5 mL) at 0°C and adjusted with 1 M HCI to pH = 3, then extract it with EtOAc (20 mL x 2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 1-10 (1 .60 g, 9.63 mmol, 88.6% yield) as yellow oil. LC-MS (method A): RT: 0.471 min, m/z 167.0; ¹H-NMR (400MHz, DMSO-cfe): 6 9.04 - 8.82 (m, 1 H), 7.93 - 7.59 (m, 1 H), 2.46 - 2.36 (m, 3H).

3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propanenitrile (1-11)

To a solution of compound 1-10 (1.40 g, 8.42 mmol, 1.00 eq) in MeOH (20 mL) was added NaBHsCN (1.06 g, 16.8 mmol, 2.00 eq), then HOAc (10 mL) was added at 50 °C, the mixture was stirred at 70 °C for 12 hrs. The reaction mixture was concentrated to remove MeOH, then diluted with H2O (30 mL) and extracted with DCM (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1), confirmed by TLC (Plate 1 , PE :EA = 1 :1 , Rf =0.4), to get desired compound 1-11 (0.900 g, 5.35 mmol, 63.5% yield) as a yellow solid. LC-MS (method A): RT: 0.264 min, m/z 169.0; ¹H-NMR (400MHz, CDCb): 6 8.91 - 8.46 (m, 1 H), 4.35 - 4.16 (m, 1 H), 3.92 - 3.76 (m, 2H), 2.53 - 2.30 (m, 3H).

3-amino-2-(4-methyl- 1 ,3-thiazol-5-yl)propan-1-ol (I- 12)

To a solution of Raney-Ni (0.50 g, 5.84 mmol, 1.96 eq) in MeOH (10 mL) and NH3.H2O (6 mL) was added compound 1-11 (0.50 g, 2.97 mmol, 1.00 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi.) at 25 °C for 16 hrs. The reaction mixture was filtered and concentrated the filtrate to give a residue. The residue was purified by prep- HPLC (column: C18 250x50mm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 1 %-10% B over 9 min) to get desired compound 1-12 (0.150 g, 870 pmol, 29.3% yield) as yellow oil. LC-MS: 008806333

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(method A) RT: 0.417 min, m/z 173.0; ¹H-NMR (400MHz, CDCb): 6 8.62 (s, 1 H), 3.88 (d, J = 6.0 Hz, 2H), 3.59 - 3.49 (m, 1 H), 3.38 - 3.26 (m, 1 H), 3.20 - 3.03 (m, 2H), 2.46 (s, 3H).

Ethyl 5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3-oxazole-4-carboxylate (1-13)

To a solution of compound 4-methyl-1 ,3-thiazole-5-carboxylic acid (13.0 g, 90.8 mmol, 1.00 eq) in THF (130 mL) was added CDI (17. 7 g, 109 mmol, 1 .20 eq) and stirred at 25 °C for 2 hrs. Then a solution of ethyl 2-isocyanoacetate (11 .3 g, 99.9 mmol, 10.9 mL, 1 .10 eq in THF (130 mL) and LiHMDS (1 .0 M, 90.8 mL, 1 .00 eq) was added to the mixture in turn. The resulting mixture was stirred at 25 °C for 12 hrs. The reaction mixture was quenched by water 100 mL and extracted with Ethyl acetate 300 mL (100 mL x3). The combined organic layers were washed with brine 300 mL (150 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 2: 1 , Petroleum ether: Ethyl acetate = 1 : 1 , Rf = 0.40). Compound 1-13 (20.0 g, 83.9 mmol, 92.4% yield) was obtained as a yellow solid. LC-MS (method A): RT: 0.455 min, m/z = 239.0; ¹H-NMR (400 MHz, CDCb): 6 8.86 (s, 1 H), 7.97 (s, 1 H), 4.41 (q, J = 12 Hz, 2H), 2.64 (s, 3H), 1 .40 (t, J = 7.2 Hz, 3H).

2-amino-1-(4-methyl-1,3-thiazol-5-yl)ethan-1-one — hydrogen chloride (1/1) (1-14)

A solution of compound 1-13 (10.0 g, 42.0 mmol, 1.00 eq in HCI (6 M, 250 mL, 35.7 eq was stirred at 100 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with DCM: MeOH = 20: 1 (100 mL) at 25 °C for 30 min. Compound 1-14 (8.00 g, 41.5 mmol, 98.9% yield, HCI). LC-MS (method A): RT: 0.331 min, m/z = 157.0; ¹H-NMR (400 MHz, DMSO-ck): 6 9.32 (s, 1 H), 8.60 (s, 3H), 4.41 (q, J = 5.2 Hz, 2H), 2.71 (s, 3H). tert-Butyl [2-(4-methyl-1 ,3-thiazol-5-yl)-2-oxoethyl]carbamate (1-15)

To a solution of compound 1-14 (8.00 g, 41 .5 mmol, 1 .00 eq, HCI) and BOC2O (9.97 g, 45.7 mmol, 10.5 mL, 1.10 eq in DCM (150 mL) was added TEA (12.6 g, 124.6 mmol, 17.3 mL, 3.00 eq . The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water 100 mL and extracted with ethyl acetate 300 mL (100 mL x 3). The combined organic layers were washed with brine 300 mL (150 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1 : 1 , Petroleum ether: Ethyl acetate = 1 : 1 , Rf = 0.43). Compound 1-15 (5.10 g, 19.9 mmol, 47.9% yield) was obtained as a white solid. LC-MS (method A): RT: 0.505 min, m/z = 257.0; ¹H-NMR (400 MHz, CDCb): 6 8.83 (s, 1 H), 5.42 (s, 1 H), 4.47 (d, J = 4.4 Hz, 2H), 2.82 (s, 3H), 1.48 (s, 9H). 008806333

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To a solution of compound 1-15 (3.00 g, 11.7 mmol, 1.00 eq) in THF (30.0 mL) was added methylmagnesium bromide (3.00 M in diethyl ether, 7.80 mL, 2.00 eq) at 0 - 5°C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was quenched by NH4CI (sat.) 50 mL and extracted with Ethyl acetate 150 mL (50 mL x 3). The combined organic layers were washed with brine 100 mL (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100:1 to 1 :1 , Petroleum ether: Ethyl acetate = 1 :1 , Rf = 0.34). Compound 1-16 (900 mg, 3.30 mmol, 28.2% yield) was obtained as yellow solid. LC-MS (method A): RT: 0.427 min, m/z = 273.1 ; ¹H-NMR (400 MHz, CDCb): 6 8.57 (s, 1 H), 4.98 (s, 1 H), 4.50 (brs, 1 H), 3.60 - 3.54 (m, 1 H), 3.45 - 3.40 (m, 1 H), 2.51 (s, 3H), 1 .62 (s, 3H), 1 .43 (s, 9H).

1-Amino-2-(4-methyl-1,3-thiazol-5-yl)propan-2-ol — hydrogen chloride (1/1) (1-17)

To a solution of compound 1-16 (900 mg, 3.30 mmol, 1.00 eq) in DCM (10.0 mL) was added HCI/dioxane (2 M, 10.0 mL, 6.05 eq). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 1-17 (650 mg, 3.1 1 mmol, 94.3% yield, HCI) was obtained as yellow solid. ¹H-NMR (400 MHz, DMSO-cfe): 6 9.31 (s, 1 H), 8.10 (br s, 3H), 3.22 - 3.04 (m, 2H), 2.47 (s, 3H), 1 .62 (s, 3H).

4-Methyl-5-[(E)-2-nitroethenyl]-1,3-thiazole (1-20)

4-Methyl-1 ,3-thiazole-5-carbaldehyde (4.0 g, 31 .4 mmol 1 .0 eq) was dissolved in acetic acid (50 mL), nitromethane (7.67 g, 125.6 mmol, 8.74 mL, 4 eq) was added, then acetic anhydride (0.641 g, 6.28 mmol, 0.692 mL, 0.2 eq) and ammonium formate (4.34 g, 62.8 mmol, 2.0 eq) were added. The reaction was heated at reflux for 1 hour, then the volatiles were removed by vacuum evaporation. Water was added (40 mL) followed by EtOAc (40 mL). The solid was filtered and dried yielding compound I-20 (3.5 g, 65% yield) as a brown solid. LC-MS (method K): RT: 1.83 min, m/z = 171.1 (ESI⁺); 212.1 (ESI⁺ as Acetonitrile adduct); ¹H-NMR (400 MHz, CDCb): 6 8.83 (s, 1 H), 8.20 (dd, J = 13.3, 0.9 Hz, 1 H), 7.39 (d, J = 13.3 Hz, 1 H), 2.64 (s, 3H).

4-methyl-5-(1-nitropropan-2-yl)-1,3-thiazole (1-21)

Methylmagnesium bromide solution 3M in Et20 (0.352 g, 2.95 mmol, 1 .0 mL, 2.5 eq) was added at 0°C to a stirred solution of compound I-20 (0.200 g, 1.18 mmol, 1 eq) in THF (3 mL) under N2 atmosphere. The solution was stirred at 50°C for 1 .5 h. The mixture was then carefully quenched with NH4CI and extracted with AcOEt (15 mL x 3). The organic phase was then washed with brine (30 mL x 2), dried over Na2SO4 and finally concentrated under vacuum, affording the compound 1-21 (0.150 g, 68% yield) as a yellow oil, 008806333

74 which was used in the next step without purification. LC-MS (method K): RT: 1.91 min, m/z = 187.1 (ESI⁺); 228.1 (ESI⁺ as Acetonitrile adduct).

2-(4-methyl-1,3-thiazol-5-yl)propan-1 -amine (1-22)

Compound 1-21 (0.150 g, 0.80 mmol, 1 .0 eq) was added under N2 atmosphere over 20 min to a stirred solution of Lithium aluminum hydride 1 M in THF (0.076 g, 2.0 mmol, 2.0 mL, 2.5 eq) in THF (2.5 mL) at 0°C. The obtained mixture was then stirred for 2 hrs. Then the mixture was cooled down to 0°C and, under stirring, Et2<D (5 mL), NaOH (2M, 100 pL) and H2O (0.8 mL) were added in order. The mixture was stirred at that temperature for 15min, then Na2SO4 was added, and the stirring was continued for 16 hrs. The solid was filtered off and the solvent was evaporated. The solid was dissolved again in EtOAc (20 mL), washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and finally concentrated under vacuum yielding compound I-22, which was used in the next step without purification. LC-MS (method K): RT: 0.29 min, m/z = 157.1 (ESI⁺); 198.1 (ESI⁺ as Acetonitrile adduct).

2-chloro-N-[2-chloro-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-5-(5-fluoropyrimidin-2-yl)benzamide (1-23)

Thionyl chloride (0.098 g, 0.82 mmol, 0.060 mL, 2.9 eq) was added dropwise to a stirred solution of compound 11 (0.111 g, 0.28 mmol, 1 .0 eq) in DCM (2 0 mL) at rt. After 3 hrs, LC-MS check showed the disappearance of the starting material. The mixture was dried and directly used in the next step without further purification (0.115 g, y=99%). LC-MS (method K): RT: 2.4 min, m/z = 411.1. tert-butyl [(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamate (1-25)

To a solution of compound 1-15 (17.9 g, 69.8 mmol, 1.00 eq) in DCM (200 mL) was added RuCI(p-CYMENE)[(R,R)-Ts-DPEN] (2.22 g, 3.49 mmol, 0.05 eq) and triethylammonium formate (30.2 g, 69.8 mmol, 1 .00 eq), the mixture was stirred at 25 °C for 5 hrs. The residue was diluted with H2O 200 mL and extracted with DCM (200 mL x3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/1 , plate 1 , Petroleum ether/Ethyl acetate = 1 :1 , Rf =0.3). The residue was further separated by SFC column: DAICEL CHIRALPAK IC (250mmx50mm, 10pm); Mobile phase: [CO₂-EtOH (0.1 % NH3H2O)]; B%: 30%, isocratic elution mode. Compound I-25 (13.6 g, 52.6 mmol, 75.38% yield) was obtained as yellow solid. LC-MS (method E) RT: 0.394 min, m/z = 259.0; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.84 (s, 1 H), 6.86 (t, J = 5.6 Hz, 1 H), 5.84 (d, J = 4 Hz, 1 H), 4.93 - 4.89(m, 1 H), 3.14 - 2.97 (m, 2H), 2.30 (s, 3H), 1.34 (s, 9H); SFC (method N): RT: 0.931 min. 008806333

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(1 R)-2-amino-1-(4-methyl-1 ,3-thiazol-5-yl)ethan-1-ol hydrochloric acid salt (1-26)

To a solution of compound 1-25 (13.6 g, 52.6 mmol, 1.00 eq) in DCM (70.0 mL) was added HCI/dioxane (2 M, 106 mL, 4.00 eq), the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was filtered, and the filtrate was concentrated. Compound I-26 (9.20 g, 47.2 mmol, 89.7% yield, HCI) was obtained as yellow solid. LC-MS (method A): RT: 0.105 min, m/z = 159.0; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.00 (s, 1 H), 8.16 (s, 2H), 5.20 - 5.17 (m, 1 H), 3.00 - 2.88 (m, 1 H), 2.36 (s,3H); SFC (method O): RT: 1 .349 min.

N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-ylbenzamide (1-27) and [3-[[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamoyl]-4-methyl-phenyl]boronic acid (1-28)

To a solution of 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) benzoic acid (8.15 g, 31.1 mmol, 1.10 eq) in DMF (50.0 mL) was added HATU (16.1 g, 42.3 mmol, 1.50 eq) DIEA (10.9 g, 84.7 mmol, 14.8 mL, 3.00 eq) and compound I-26 (5.50 g, 28.2 mmol, 1 .00 eq, HCI), the mixture was stirred at 25 °C for 2 hrs. The residue was diluted with H2O 200 mL and extracted with EtOAC (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeCH=100/1 to 10/1 , plate 1 , DCM: MeOH=10:1 , Rfi=0.4, Rf2=0.3). The residue was purified by prep-HPLC column: Welch Ultimate XB-CN 250x50x10pm; mobile phase: [Hexane- EtOH]; gradient: 1 %-35% B over 15 min. Compound I-27 (7.50 g, 18.6 mmol, 65.9% yield) was obtained as yellow gum, and compound I-28 (2.30 g, 7.18 mmol, 25.4% yield) was obtained as yellow gum.

Analytical data of compound I-27: LC-MS (method E): RT: 0.471 min, m/z = 403.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.88 (s, 1 H), 8.39 - 8.38 (m, 1 H), 7.60 - 7.58 (m, 2H), 7.24(d, J = 7.6 Hz, 1 H), 5.97(d, J = 4 Hz, 1 H), 5.10 - 5.07 (m, 1 H), 3.41 (t, J = 5.6 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 1.29 (s, 12H); HPLC (method B): RT: 2.446min, 92.8% purity.

Analytical data of compound I-28: LC-MS (method E): RT: 0.355 min, m/z = 321.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.87 (s, 1 H), 8.25 (t, J = 5.6 Hz, 1 H), 8.04 - 7.98 (m, 1 H), 7.73 - 7.69 (m, 2H), 7.16 (d, J = 7.6 Hz, 1 H), 5.12 - 5.07 (m, 1 H), 3.41 (d, J = 6.4 Hz, 2H), 2.36 - 2.34 (m, 3H), 2.26 - 2.24 (m, 3H); HPLC (method B): RT: 0.964 min, 99.7% purity; SFC (method P): RT: 1.583 min.

2-chloro-N-(3-methoxypropyl)pyrimidin-4-amine (1-29)

To a solution of compound 2,4-dichloropyrimidine (1 .00 g, 6.71 mmol, 1 .00 eq) and compound 3- methoxypropylamine (598 mg, 6.71 mmol, 686 pL, 1 .00 eq) in DMF (5.00 mL) was added DIEA (1 .74 g, 13.4 mmol, 2.34 mL, 2.00 eq), the mixture was stirred at 60 °C for 2 hrs. The mixture was filtered and concentrated under reduced pressure to get the residue. The mixture was purified by Prep-HPLC 008806333

76 column: Waters Xbridge C18 150x50mmx10|jm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 13%-43% B over 10 min. Compound I-29 (900 mg, 4.46 mmol, 66.4% yield) was obtained as colorless oil. LC-MS (method E): RT: 0.416 min, m/z = 202.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 7.91 - 7.86 (m, 2H), 8.42 (d, J = 6.0 Hz, 1 H), 3.38 -3.35 (m, 2H), 3.30 -3.27 (m, 2H), 3.23 (s, 3H), 1 .76 -1 .70 (m, 2H).

P2X7 COMPOUNDS

TABLE 2: Table of Compounds 008806333

11 008806333

78 008806333

79 008806333

80 008806333

81 008806333

82 008806333

83 008806333

84 008806333

85 008806333

86 008806333

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N-[2-hydroxy-2-(1,3-thiazol-5-yl)ethyl]-4-(5-fluoro-2-pyrimidinyl)-2-methylbenzamide (1)

To a solution of compound I-4 (354 mg, 1.53 mmol, 1.10 eq), HATU (1.05 g, 2.77 mmol, 2.00 eq) and DIEA (717 mg, 5.55 mmol, 966 pL, 4.00 eq) in DMF (5.00 mL) was cooled to 0 °C, compound I-2 (200 mg, 1 .39 mmol, 1 .00 eq) was added. The mixture was stirred at 25 °C for 2 hrs. Evaporate the solution on a water bath under reduced pressure using a rotary evaporator. The crude was purified by Pre-HPLC (FA): column: Phenomenex luna C18 150x25mmx 10pm; mobile phase: [water (FA)-ACN]; gradients 8%-48% B over 10 min. Compound 1 (100 mg, 271 pmol, 19.5% yield, 97.2% purity) was obtained as a white solid. LC-MS (method A): RT: 0.454 min, m/z = 359.0; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.01 (s, 1 H), 8.98 (s, 2H), 8.54 (t, J =5.6 Hz, 1 H), 8.28 - 8.24 (m, 2H), 7.80 (s, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 6.06 (d, J = 4.8 Hz, 1 H), 5.15 - 5.10 (m, 1 H), 3.58-3.47 (m, 2H), 2.32 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 -140.15; HPLC (method B): RT: 1.667 min, 97.2% purity. 008806333

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N-[2-hydroxy-2-(1-methyl-5-pyrazolyl)ethyl]-4-(5-fluoro-2-pyrimidinyl)-2-methylbenzamide (2)

To a solution of compound I-4 (430 mg, 1.85 mmol, 1.00 eq) and 2-amino-1-(1-methyl-1 /7-pyrazol-5- yl)ethan-1-ol (287 mg, 2.04 mmol, 1.10 eq) in DMF (5.00 mL) was added HATU (1 .06 g, 2.78 mmol, 1 .50 eq) and DIEA (478 mg, 3.70 mmol, 645 pL, 2.00 eq), the mixture was stirred at 25 °C for 0.5 hrs. The mixture was filtered and concentrated under reduced pressure to get the residue. The mixture was purified by Prep-HPLC, column: Phenomenex luna C18 150x25mmx 10pm; mobile phase: [water (FA)- ACN]; gradient: 20%-40% B over 10 min. Compound 2 (400 mg, 1.12 mmol, 60.4% yield, 99.5% HPLC purity method B) was obtained as yellow solid. LC-MS (method A): RT: 0.461 min, m/z = 356.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.99 (s, 2H), 8.51 - 8.48 (m, 1 H), 8.27 - 8.24 (m, 2H), 7.39 - 7.32 (m, 2H), 8.25 (d, J = 2.0 Hz, 1 H), 5.67 (d, J = 5.6 Hz, 1 H), 4.92 - 4.90 (m, 1 H), 3.86 (s, 3H), 3.68 - 3.65 (m,1 H), 3.50 - 3.48 (m, 1 H), 2.33 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 -140.154.

N-[3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)butyl]-4-(5-fluoro-2-pyrimidinyl)-2-methylbenzamide (3)

To a solution of compound I-4 (0.45 g, 1.94 mmol, 1.00 eq) in DMF (15.0 mL) was added HATU (1.11 g, 2.91 mmol, 1 .50 eq) and DIEA (500 mg, 3.88 mmol, 675 pL, 2.00 eq), the mixture was stirred at 25.0 °C for 15 mins, then compound I-6 (1 .35 g, 5.81 mmol, 3.00 eq) was added, the reaction was stirred at 25°C for 45 mins. The reaction was diluted with H2O (15 mL), then extract it with EtOAc (15 mL x 2), washed the combined organic layers with brine (30 mL x 2), dried over Na2SO4, filter and concentrate it under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150x25mm 10pm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradients 9%-49% B over 10 min) to get compound 3 (0.42 g, 1.05 mmol, 54.1 % yield, 100% purity) as white solid. LC-MS (method A): RT: 0.809 min, m/z = 401.2.

N-[(2R*,3R*)-3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)butyl]-4-(5-fluoro-2-pyrimidinyl)-2- methylbenzamide (3a),

N-[(2S*,3S*)-3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)butyl]-4-(5-fluoro-2-pyrimidinyl)-2- methylbenzamide (3b),

N-[(2S*,3R*)-3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)butyl]-4-(5-fluoro-2-pyrimidinyl)-2- methylbenzamide (3c), and N-[(2R*,3S*)-3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)butyl]-4-(5-fluoro-2-pyrimidinyl)-2- methylbenzamide (3d)

The racemate 3 (0.42 g, 1.05 mmol, 54.1 % yield, 100% purity) was purified by prep-SFC (column: DAICEL CHIRALCEL OJ-H(250mmx30mm, 5pm);mobile phase: [CO₂-MeOH(0.1 %NH₃H₂O)]; B%:20%, isocratic elution mode), then concentrated to give a residue and re-purified by prep-SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10pm);mobile phase: [CO2-i-PrOH(0.1 %NH₃H₂O)];B%:35%, isocratic elution mode) to get compound 3a (90.0 mg, 224.74 pmol, 21 .43% yield) and compound 3b 008806333

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(90.0 mg, 224 pmol, 21 .4% yield) was obtained as yellow solid. Compound 3c (43.0 mg, 106.73 pmol, 10% yield, 99.4% purity) was obtained as off-white solid. Compound 3d (49 mg, 122.36 pmol, 11 % yield, 100% purity) was obtained as off-white solid.

Analytical data of compound 3a: LC-MS (method A): RT: 0.742 min, m/z = 401.2; ¹H-NMR (400 MHz, CDCb): 6 8.76 (s, 1 H), 8.66 (s, 2H), 8.44 - 8.32 (m, 2H), 7.38 (d, J = 7.6 Hz, 1 H), 6.41 - 6.21 (m, 1 H), 4.33 - 4.21 (m, 1 H), 4.21 - 4.07 (m, 1 H), 3.86 - 3.68 (m, 1 H), 3.37 - 3.22 (m, 2H), 2.54 (s, 3H), 2.49 (s, 3H), 1.08 (d, J = 6.4 Hz, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -139.88; HPLC (method B): RT: 1.651 min, 98% purity; SFC (method D): RT: 1.323 min.

Analytical data of compound 3b: LC-MS (method A): RT: 0.737 min, m/z = 401 .1 ; ¹H-NMR (400 MHz, CDCb): 6 8.76 (s, 1 H), 8.66 (s, 2H), 8.42 - 8.29 (m, 2H), 7.38 (d, J = 7.6 Hz, 1 H), 6.41 - 6.20 (m, 1 H), 4.32 - 4.21 (m, 1 H), 4.20 - 4.03 (m, 1 H), 3.91 - 3.57 (m, 1 H), 3.36 - 3.21 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 1.08 (d, J = 6.4 Hz, 1 H); ¹⁹F-NMR (376 MHz, CDCb): 6 -139.88; HPLC (method B): RT: 1.652 min, 98% purity; SFC (method D): RT: 1.445 min.

Analytical data of compound 3c: LC-MS (method A): RT: 0.752 min, m/z = 401.2; ¹H-NMR (400 MHz, CDCb): 6 8.77 - 8.59 (m, 3H), 8.45 (s, 1 H), 8.41 - 8.33 (m, 1 H), 7.39 (d, J = 8.4 Hz,1 H), 6.21 (t, J = 6.8 Hz, 1 H), 4.83 - 4.66 (m, 1 H), 4.43 - 4.30 (m, 1 H), 3.99 - 3.85 (m, 1 H), 3.50 (s, 1 H), 3.52 - 3.47 (m, 1 H), 3.40 - 3.29 (m, 1 H), 3.29 - 3.22 (m, 1 H), 2.56 (s, 3H), 2.50 (s, 3H), 1 .16 (d, J = 6.0 Hz,1 H); ¹⁹F-NMR (376 MHz, CDCb): 6 -139.96; HPLC (method B): RT: 1.747 min, 99% purity; SFC (method C): RT: 1.847 min.

Analytical data of compound 3d: LC-MS (method A): RT: 0.752 min, m/z = 401.2; ¹H-NMR (400 MHz, CDCb): 6 8.83 - 8.59 (m, 3H), 8.45 (s, 1 H), 8.37 (d, J = 7.6 Hz,1 H), 7.39 (d, J = 8.0 Hz,1 H), 6.33 - 6.13 (m, 1 H), 4.86 - 4.60 (m, 1 H), 4.48 - 4.26 (m, 1 H), 3.99 - 3.87 (m, 1 H), 3.41 - 3.30 (m, 1 H), 3.28 - 3.20 (m, 1 H), 2.56 (s, 3H), 2.51 (s, 3H), 1.17 (d, J = 6.0 Hz,1 H); ¹⁹F-NMR (376 MHz, CDCb): 6 -139.95; HPLC (method B): RT: 1.744 min, 100% purity; SFC (method C): RT: 1.973 min.

N-[2-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)ethyl]-4-(5-fluoro-2-pyrimidinyl)-2-methylbenzamide (4)

To a mixture of compound I-32 (140 mg, 884 pmol, 1.0 eq) and compound I-4 (205 mg, 884 pmol, 1.0 eq) in DMF (4.00 mL) was added DIEA (228 mg, 1 .77 mmol, 308 pL, 2.00 eq) and HATU (504 mg, 1 .33 mmol, 1 .50 eq), then the mixture was stirred at 25 °C for 1 .5 hrs. Filter the reaction mixture and the filtrate was purified by prep-HPLC ((column: Waters X bridge C18150x50mmx 10 pm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradients 7%-47% B over 9 min) to get compound 4 (213 mg, 341 pmol, 38.5% yield, 59.6% purity) as a white powder. LC-MS (method A): RT: 0.738 min, m/z = 373.2; SFC (method C): RT (Peak 1): 1 .904 min, RT (Peak 2): 2.420 min; HPLC (method B): RT: 1 .404 min, 99.05% purity. 008806333

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N-[(S*)-2-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)ethyl]-4-(5-fluoro-2-pyrimidinyl)-2-methylbenzamide

(4a), and N-[(R*)-2-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)ethyl]-4-(5-fluoro-2-pyrimidinyl)-2- methylbenzamide (4b)

The racemate 4 (213 mg, 572 pmol, 1.00 eq) was purified by SFC separation (column: DAICEL CHIRALCEL OJ (250mmx30mm, 10 pm); mobile phase: [CO2-i-PrOH (0.1 %NH3H2O)]; B%:35%, isocratic elution mode). Compound 4a (100 mg, 197 pmol, 23.6% yield, 73.6% purity) was obtained as a white solid, compound 4b (91 .0 mg, 244pmol, 29.2% yield) was obtained as a white solid.

Analytical data of compound 4a: LC-MS (method A): RT: 0.738 min, m/z = 373.2; ¹H-NMR (400MHz, DMSO-cfe): 6 8.99 (s, 2H), 8.51 (t, J = 5.6 Hz, 1 H), 8.34 - 8.18 (m, 2H), 7.50 (s, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 5.96 (d, J = 4.8 Hz, 1 H), 5.15 - 4.93 (m, 1 H), 3.64 - 3.44 (m, 2H), 2.62 (s, 3H), 2.33 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -140.14; HPLC (method B): RT: 1.909min, 96.15% purity; SFC (method D): RT: 2.415 min.

Analytical data of compound 4b: LC-MS (method A): RT: 0.742 min, m/z = 373.2; ¹H-NMR (400MHz, DMSO-cfe): 6 8.98 (s, 2H), 8.50 (t, J = 5.2 Hz, 1 H), 8.34 - 8.18 (m, 2H), 7.49 (s, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 5.96 (brs, 1 H), 5.15 - 4.93 (m, 1 H), 3.64 - 3.44 (m, 2H), 2.61 (s, 3H), 2.33 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -140.11 ; HPLC (method B): RT: 1.681 min, 99.80% purity; SFC (method D): RT: 1.928 min.

5-(5-fluoropyrimidin-2-yl)-N-[3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2-methylbenzamide (5)

Compound 5 was synthesized using the method described for compound 4 starting from 1-12 (140 mg; 812 pmol) and I-4 (188mg; 812 pmol). LC-MS (method A): RT: 0.792 min; SFC (method D): RT (Peak 1): 2.266 min, RT (Peak 2): 2.599 min.

5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2- methylbenzamide (5a), and 5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-3-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2- methylbenzamide (5b)

Compound 5 (170 mg, 439 pmol, 1.00 eq) was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 pm);mobile phase: [CO2-EtOH (0.1 % NH3H2O)]; B%:45%, isocratic elution mode) to obtain 5a (80.0 mg, 206 pmol, 46.9% yield, 99.8% purity) as a white solid, and 5b (80.0 mg, 207 pmol, 47.0% yield, 100% purity) as a white solid.

Analytical data of compound 5a: LC-MS (method A): RT: 0.639 min, RT: 0.641 min, m/z = 387.3; ¹H-NMR (400MHz, CDCb): 6 8.84 - 8.61 (m, 3H), 8.43 (s, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 6.37 - 6.17 (m, 1 H), 4.28 - 4.00 (m, 1 H), 3.95 - 3.79 (m, 2H), 3.78 - 3.65 (m, 2H), 3.54 - 3.40 008806333

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(m, 1 H), 2.56 (s, 3H), 2.49 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -139.89; HPLC (method B): RT: 1.606 min, 99.82% purity; SFC (method D): RT: 2.253 min.

Analytical data of compound 5b: LC-MS (method A): RT: 0.641 min, m/z = 387.3; ¹H-NMR (400MHz, CDCb): 6 8.72 (s, 1 H), 8.66 (s, 2H), 8.43 (d, J = 1 .6 Hz, 1 H), 8.39 (dd, J = 1.6, 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 6.34 - 6.25 (m, 1 H), 4.35 - 4.02 (m, 1 H), 3.98 - 3.88 (m, 1 H), 3.86 - 3.78 (m, 1 H), 3.77 - 3.67 (m, 2H), 3.55 - 3.44 (m, 1 H), 2.56 (s, 3H), 2.51 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -139.86; HPLC (method B): RT: 1.608 min, 100% purity; SFC (method D): RT: 2.574 min.

5-(5-fluoropyrimidin-2-yl)-N-[2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2-methylbenzamide (6)

Compound 6 was synthesized using the method described for compound 4 starting from 1-17 (668 mg; 1550 pmol) and I-4 (300 mg; 1290 pmol). LC-MS: (method A): RT: 0.461 min, m/z = 387.2.

5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2- methylbenzamide (6a), and 5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2- methylbenzamide (6b)

Compound 6 (250 mg, 647 mmol, 50.1 % yield) was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 pm);mobile phase: [CO2-EtOH (0.1 % NH3H2O)]; B%:50%, isocratic elution mode) to get 6a (103.28 mg, 264 pmol, 40.9% yield, 98.9% purity; Rt = 0.979min) and 6b (115.75 mg, 287 pmol, 44.4% yield, 95.9% purity; Rt = 1 .705 min) both as off-white solid.

Analytical data of compound 6a: LC-MS (method E): RT: 0.829 min, m/z = 387.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.99 (s, 2H), 8.76 (s, 1 H), 8.38 (t, J = 6.0 Hz, 1 H), 8.25 - 8.22 (m, 2H), 7.37 (d, J = 8.0 Hz, 1 H), 5.94 (s, 1 H), 3.72 - 3.61 (m, 2H), 2.49 (s, 3H), 2.27 (s, 3H), 1 .58 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 -140.18; HPLC (method F): RT: 2.689 min, 98.9% purity; SFC (method G): RT: 0.979 min.

Analytical data of compound 6b: LC-MS (method E): RT: 0.837 min, m/z = 387.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.99 (s, 2H), 8.76 (s, 1 H), 8.39 (t, J = 6.0 Hz, 1 H), 8.26 - 8.22 (m, 2H), 7.37 (d, J = 8.0 Hz, 1 H), 5.95 (s, 1 H), 3.74 - 3.60 (m, 2H), 2.49 (s, 3H), 2.27 (s, 3H), 1 .58 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 5 -140.17; HPLC (method F): RT: 2.720 min, 95.9% purity; SFC (method G): RT: 1.705 min.

5-(5-fluoropyrimidin-2-yl)-N-[2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide (7)

Compound 7 was synthesized using the method described for compound 4 starting from I-33 (120 mg, 758 pmol) and I-4 (176 mg, 758 pmol). LC-MS (method H): RT: 0.458 min, m/z = 373.2. 008806333

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5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide a), and 5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (7b)

The racemate 7 was purified by SFC (condition: column: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 pm); mobile phase: [CO2 - EtOH (0.1 % NH3H2O)]; B%: 45%, isocratic elution mode). The peak 1 was purified by prep-HPLC (neutral condition; column: Waters Xbridge 150 x 25 mm x 5 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 18% - 38% B over 10 mins). Compound 7a (63.54 mg, 163 pmol, 32.1 % yield, 96.0% purity) was obtained as white solid. Compound 7b (82.12 mg, 220 pmol, 43.2% yield, 100% purity) was obtained as white solid.

Analytical data of compound 7a: LC-MS (method H): RT: 0.505 min, m/z = 373.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.99 (s, 2H), 8.89 (s, 1 H), 8.54 - 8.52 (m, 1 H), 8.31 - 8.22 (m, 2H), 7.38 (d, J = 8.0 Hz, 1 H), 6.00 (br s, 1 H), 5.12 (s, 1 H), 3.45 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.32 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 -140.14; HPLC (method B): RT: 1.579 min, 96.0% purity; SFC (method I): RT: 1.485 min.

Analytical data of compound 7b: LC-MS (method H): RT: 0.504 min, m/z = 373.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.98 (s, 2H), 8.88 (s, 1 H), 8.54 - 8.52 (m, 1 H), 8.33 - 8.20 (m, 2H), 7.38 (d, J = 8.0 Hz, 1 H), 6.01 (d, J = 3.2 Hz, 1 H), 5.19 - 5.00 (m, 1 H), 3.45 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 5 -140.15; HPLC (method B): RT: 1.584 min, 100% purity; SFC (method I): RT: 2.059 min.

2-fluoro-5-(5-fluoropyrimidin-2-yl)-N-[2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (8)

Compound 8 was synthesized using the method described for compound 4 starting from I-33 (300 mg, 1.90 mmol, 1.00 eq) and 1-18 (671. mg, 2.84 mmol, 1.50 eq). LC-MS (method H): RT: 0.841 min, m/z = 377.1.

2-fluoro-5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (8a), and 2-fluoro-5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-2-hydroxy-2-(4-methyl-1,3-thiazol-5- yl)ethyl]benzamide (8b)

The racemate 8 was purified by SFC (column: DAICEL CHIRALPAK IF (250mmx30mm,10pm); mobile phase: [CO2-ACN/i-PrOH (0.1 % NH3H2O)]; B%:50%, isocratic elution mode). Compound 8a (75.0 mg, 188 pmol, 17.7% yield) was obtained as a white solid. Compound 8b (65.0 mg, 162 pmol, 15.2% yield) was obtained as a white solid.

Analytical data of compound 8a: LC-MS (method H): RT: 0.503 min, m/z = 377.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.01 (s, 2H), 8.88 (s, 1 H), 8.62 - 8.51 (m, 2H), 8.48 - 8.40 (m, 1 H), 7.44 (t, J = 9.6 Hz, 1 H), 008806333

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6.04 (d, J = 3.6 Hz, 1 H), 5.15 (d, J = 3.2 Hz, 1 H), 3.51 - 3.42 (m, 2H), 2.36 (s, 3H); ¹⁹F-NMR (400 MHz, DMSO-cfe): 6 -111 .59, -139.73; HPLC (method B): RT: 1 .306 min, 98.5% purity; SFC (method J): RT: 0.959 min.

Analytical data of compound 8b: LC-MS (method H): RT: 0.503 min, m/z = 377.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.01 (s, 2H), 8.88 (s, 1 H), 8.61 - 8.49 (m, 2H), 8.48 - 8.40 (m, 1 H), 7.45 (t, J = 8.8 Hz, 1 H), 6.04 (d, J = 4.0 Hz, 1 H), 5.15 (dd, Ji = 6.4 Hz, J₂ = 10.4 Hz, 1 H), 3.51 - 3.39 (m, 2H), 2.36 (s, 3H); ¹⁹F- NMR (400 MHz, DMSO-cfe): 6 -111 .58, -139.74; HPLC (method B): RT: 1.294 min, 99.7% purity; SFC (method J): RT: 1.252 min.

2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[2-(4-methyl-1,3-thiazol-5-yl)propyl]benzamide (9)

Compound 9 was synthesized using the method described for compound 4 starting from compound I-22 (125 mg, 0.8 mmol, 1 .0 eq) and 1-19 (220 mg, 0.88 mmol, 1.0 eq). LC-MS (method K): RT: 2.2 min, m/z = 391.1.

2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-2-(4-methyl-1,3-thiazol-5-yl)propyl]benzamide (9a), and 2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-2-(4-methyl-1,3-thiazol-5-yl)propyl]benzamide (9b)

The racemate 9 was purified using a WATERS Quaternary Gradient Mobile 2535 equipped with WATERS UV/Visible Detector 2489 (dual-wavelength used 254 and 260 nm), in order to collect both enantiomers with enough purity. Normal phase HPLC analytical was carried out on a Lux AMY-Coat Phenomenex column (5 pm, 21 .2 x 150 mm) with a flow rate of 13 ml/min. Two mobile phases were used, mobile phase A: N-Hexane (Chromasolv for HPLC Sigma-Aldrich); mobile phase B: Ethanol (Chromasolv for HPLC Sigma-Aldrich), and they were employed to perform an isocratic run with 20 % B. Back Pressure: 450 PSI. Compound 9a at 24.6 minutes (11 .9 mg, 30 pmol, 40% yield) was obtained as a white solid. Compound 9b at 26.9 minutes (12.0 mg, 31 pmol, 40% yield) was obtained as a white solid.

Analytical data of compound 9a: LC-MS (method K): RT: 2.29 min, m/z = 391 .1 ; ¹H-NMR (400 MHz, CDCb): 6 8.66 (d, J = 9.6 Hz, 3H), 8.59 (d, J = 2.2 Hz, 1 H), 8.35 (dd, J = 8.4, 2.2 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 6.27 (NH), 3.85 (ddd, J = 13.2, 7.0, 6.0 Hz, 1 H), 3.64 - 3.51 (m, 1 H), 3.40 (ddd, J = 13.5, 8.3, 5.3 Hz, 1 H), 2.47 (s, 3H), 1 .40 (d, J = 6.8 Hz, 3H).

Analytical data of compound 9b: LC-MS (method K): RT: 2.29 min, m/z = 391 .1 ; ¹H-NMR (400 MHz, CDCb): 6 8.66 (d, J = 9.6 Hz, 3H), 8.59 (d, J = 2.2 Hz, 1 H), 8.35 (dd, J = 8.4, 2.2 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 6.27 (NH), 3.85 (ddd, J = 13.2, 7.0, 6.0 Hz, 1 H), 3.64 - 3.51 (m, 1 H), 3.40 (ddd, J = 13.5, 8.3, 5.3 Hz, 1 H), 2.47 (s, 3H), 1 .40 (d, J = 6.8 Hz, 3H). 008806333

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2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[2-(4-methyl-1,3-thiazol-5-yl)-2-oxoethyl]benzamide (10)

To a solution of compound 1-19 (1.00 g, 3.97 mmol, 1 eq) in DMF (10.0 mL) was added HATU (1.81 g, 4.77 mmol, 1 .2 eq) and DIEA (2.05 g, 15.90 mmol, 2.77 mL, 4 eq) at 20 °C and stirred for 1 h. Then compound 1-14 (842.19 mg, 4.37 mmol, 1.1 eq) was added to the mixture at 20°C and stirred for another 2 hrs. The mixture was filtered, the filter cake was collected and concentrated under reduced pressure to give a residue. The residue was triturated with EtOAc (5.00 mL) at 20 °C for 2 hrs. Compound 10 (900 mg, 2.23 mmol, 56.21 % yield, 97% purity) was obtained as a white solid. LC-MS (method H): RT: 0.789 min, m/z = 391.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.26 (s, 1 H), 9.10 (t, J = 5.6 Hz, 1 H), 9.04 (s, 2H), 8.50 (d, J = 2.0 Hz, 1 H), 8.38 (dd, J = 2.4 Hz, 8.8 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 4.63 (d, J = 4.6 Hz, 2H) 2.75 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 -138.98; HPLC (method B): RT: 2.467 min, 97.3% purity.

2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (11)

Method 1

Compound 10 (0.040g, 0.10 mmol, 1.0 eq) was dissolved in EtOH (2.5 mL) and sodium borohydride (0.004g, 0.11 mmol, 1.1 eq) was added. The solution was left under magnetic stirring at RT for 30 min. Then, the solvent was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage Isolera- SNAP 20 g) eluting with 70% to 100% EtOAc/DCM to obtain compound 11 (0.039 g, 95% yield).

Method 2

To a solution of compound 1-19 (1.58 g, 6.26 mmol, 1.5 eq) in DMF (22.0 mL) was added HATU (2.38 g, 6.26 mmol, 1.50 eq) and DIEA (1.62 g, 12.5 mmol, 2.18 mL, 3.00 eq), then I-33 (1 .10 g, 4.17 mmol, 1 .00 eq) was added into the mixture. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition H2O 100 mL, and then diluted with EtOAc 10.0 mL and extracted with EtOAc 200 mL (50.0 mL x 4). The combined organic layers were washed with aqueous NaCI (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250x70mm, 10 pm); mobile phase: [water (TFA)- ACN]; gradient: 20%-50% B over 20 min). Compound 11 (1.60 g, 4.07 mmol, 97.6% yield) was obtained as a yellow oil.

LC-MS (method A): RT: 0.612 min, m/z = 393.1 ; LC-MS (method K): RT: 2.0 min, m/z = 393.1 ; ¹H-NMR (600 MHz, CDCI3): 6 8.72 - 8.65 (m, 4H), 8.41 (dd, J = 8.5, 2.3 Hz, 1 H), 7.53 (dt, J = 8.4, 1 .3 Hz, 1 H), 6.72 (NH), 5.35 (m, 1 H), 3.98 - 3.90 (m, 1 H), 3.70 - 3.62 (m, 1 H), 2.50 (s, 3H). 008806333

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2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2S)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide

(11a), and 2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5- yl)ethyl]benzamide (11b)

The racemate 11 (3 g) was separated by SFC separation (condition: column: DAICEL CHIRALPAK IK (250mmx30mm, 10pm); mobile phase: [CO2-i-PrOH (0.1%NH3H2O)]; B%:40%, isocratic elution mode). Compound 11a (1.10 g, 2.77 mmol, 36.2% yield, 98.8% purity) was obtained as a white solid, compound 11b (1.05 g, 2.57 mmol, 33.6% yield, 96.0% purity) was obtained as a white solid.

Analytical data of compound 11a: LC-MS (method H): RT: 0.420 min, m/z = 393.0; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.03 (s, 2H), 8.89 (s, 1 H), 8.73 (t, J = 6.0 Hz, 1 H), 8.37 - 8.28 (m, 2H), 7.69 - 7.58 (m, 1 H), 6.03 (d, J = 4.2 Hz, 1 H), 5.16 - 5.08 (m, 1 H), 3.45 (q, J = 6.0 Hz, 2H), 2.39 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 139.08; HPLC (method B): RT: 1 .282 min, 98.8% purity; SFC (method L): RT: 0.752 min; OR: [a]20 D +16.869 (c 0.5620, DMSO).

Analytical data of compound 11 b: LC-MS (method H): RT: 0.424 min, m/z = 393.0; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.03 (s, 2H), 8.89 (s, 1 H), 8.73 (s, 1 H), 8.39 - 8.28 (m, 2H), 7.64 (d, J = 8.6 Hz, 1 H), 6.03 (d, J = 4.2 Hz, 1 H), 5.12 (d, J = 4.2 Hz, 1 H), 3.51 - 3.39 (m, 2H), 2.39 (s, 3H); ¹³C NMR (100 MHz, DMSO-cfe): <5 166.6, 158.8 (d, J C-F = 5.7 Hz), 157.4 (d, J C-F = 260.9 Hz), 151.9, 148.3, 146.5, 146.2, 137.5, 135.7, 135.4, 133.0, 130.8, 130.0, 128.0; ¹⁹F-NMR (376 MHz, DMSO-cfe): 5 139.07; HPLC (method B): RT: 1 .277 min, 96.0% purity; SFC (method L): RT: 0.980 min; OR: [a]20 D -16.808 (c 0.4714, DMSO).

2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[2-methoxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (12)

Sodium methoxide (0.030 g, 0.56 mmol, 2.0 eq) was added to a stirred solution of compound I-23 (0.115 g, 0.28 mmol, 1.0 eq) in MeOH (5 mL). The suspension was then stirred at rt overnight. The solvent was evaporated then the crude was dissolved in DCM (15 mL), washed with brine (3x15mL), dried over anhydrous Na2SO4 and finally concentrated under vacuum. The crude mixture was then purified by preparative HPLC on a Luna Phenomenex Column C18 5 pm 19 x 150 mm (gradient from 70:30 to 25:75 H2O/ACN in 15min), with the desired product that was collected at 11 min and resulted in a colorless glassy solid (68% yield). LC-MS (method K): RT: 2.3 min, m/z = 407.2; ¹H-NMR (600 MHz, CDCI3): 6 8.73 (d, J = 1 .9 Hz, 1 H), 8.70 - 8.63 (br s, 3H) 3H), 8.40 (dt, J = 8.5, 2.3 Hz, 1 H), 7.53 (NH), 6.65 (t, J = 6.0 Hz, 1 H), 4.80 (ddd, J = 8.5, 4.4, 1 .8 Hz, 1 H), 3.99 - 3.91 (m, 1 H), 3.60 - 3.53 (m, 1 H), 3.32 (s, 3H), 2.53 (s, 3H). 008806333

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2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-2-methoxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (12a), and 2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-2-methoxy-2-(4-methyl-1,3-thiazol-5- yl)ethyl]benzamide (12b)

The racemate 12 was separated in its enantiomers using a WATERS Quaternary Gradient Mobile 2535 equipped with WATERS UVA/isible Detector 2489 (dual-wavelength used 254 and 260 nm), in order to collect both enantiomers with sufficient purity. Normal phase HPLC analytical was carried out on a Lux AMY-Coat Phenomenex column (5 pm, 21 .2 x 150 mm) with a flow rate of 13 ml/min. Two mobile phases were used, mobile phase A: N-Hexane (Chromasolv for HPLC Sigma-Aldrich); mobile phase B: IPA (Chromasolv for HPLC Sigma-Aldrich), and they were employed to perform an isocratic run with 50 % B. Back Pressure: 600 PSI. Compound 12a (13.7 mg, 34 pmol, 46% yield) was obtained at RT=21.5 min, and compound 12b (14.0 mg, 34 pmol, 46.6% yield) was obtained at RT=24.0 min.

Analytical data of compound 12a: LC-MS (method K): RT: 2.28 min, m/z = 407.1 ; ¹H-NMR (400 MHz, CDCb): 6 9.02 (s, 1 H), 8.67 (br s, 3H), 8.41 (dd, J = 8.5, 2.2 Hz, 1 H), 7.53 (NH), 6.69 (s, 1 H), 4.84 (dd, J = 7.8, 4.2 Hz, 1 H), 3.93 (ddd, J = 13.8, 7.0, 4.3 Hz, 1 H), 3.62 (ddd, J = 13.4, 7.8, 4.8 Hz, 1 H), 3.37 (s, 3H), 2.64 (s, 3H).

Analytical data of compound 12b: LC-MS (method K): RT: 2.28 min, m/z = 407.1 ; ¹H-NMR (400 MHz, CDCb): 6 9.01 (s, 1 H), 8.67 (br s, 3H), 8.41 (dd, J = 8.5, 2.2 Hz, 1 H), 7.53 (NH), 6.69 (s, 1 H), 4.84 (dd, J = 7.9, 4.2 Hz, 1 H), 3.93 (ddd, J = 13.9, 7.0, 4.3 Hz, 1 H), 3.61 (ddd, J = 13.9, 7.8, 4.7 Hz, 1 H), 3.37 (s, 3H), 2.63 (s, 3H).

2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[2-(2-hydroxymethoxy)-2-(4-methyl-1,3-thiazol-5- yl)ethyl]benzamide (13)

Compound I-23 (0.218 g, 0.53 mmol, 1.0 eq) was suspended in ethylene glycol (5 mL), then the mixture was stirred at 60°C for 16 hrs. After that time the mixture was cooled down to rt, diluted with DCM (200 mL), washed with brine (250 mL x 2), dried over anhydrous Na2SO4 and finally concentrated under vacuum. The crude mixture was then purified by preparative HPLC on a Luna Phenomenex Column C18 5 pm 19 x 150 mm (gradient: H2O/ACN from 70:30 to 5:95 in 10 min, product collected at 7min), affording compound 13 as a colorless glassy solid (0.045 g, y=19%). LC-MS (method K): RT: 2.0 min, m/z = 437.1 ; ¹H-NMR (600 MHz, CDCb): 6 8.73 (s, 1 H), 8.67 (d, J = 4.0 Hz, 3H), 8.40 (dd, J = 8.4, 2.2 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 6.79 (NH), 5.03 - 4.97 (m, 1 H), 3.97 (ddd, J = 13.9, 7.4, 4.2 Hz, 1 H), 3.83 - 3.72 (m, 2H), 3.65 - 3.53 (m, 3H), 2.53 (s, 3H). 008806333

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2-Trifluoromethyl-5-(5-fluoropyrimidin-2-yl)-N-[2-(4-methyl-1,3-thiazol-5-yl)-2-oxoethyl]benzamide

(14)

To a stirring solution of compound I-24 (0,189 g, 0.66 mmol, 1.0 eq) in DCM/DMF (3.5/1 .0 mL) HATU (0.300 g, 0.79 mmol, 1 .2 eq) and TEA (0.160 g, 1 .58 mmol, 0.220 mL, 2.4 eq) were added. The reaction mixture was left under stirring for 10 min. Then, the amine 1-14 (0.150 g, 0.79 mmol, 1 .2 eq) was added and the reaction was left under stirring at room temperature for 16 hrs. The solution was then dried under vacuum, diluted with DCM (20 mL), washed with brine (3x20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash silica gel chromatography (Biotage Isolera-SNAP 20 g) eluting with 5% to 50% AcOEt/DCM to yield compound 14 (0.229 g, yield 82%). LC-MS (method K): RT: 2.3 min, m/z = 425.1 .

2-Trifluoromethyl-5-(5-fluoropyrimidin-2-yl)-N-[2-hydroxy-2-(4-methyl-1,3-thiazol-5- yl)ethyl]benzamide (15)

Compound 14 (0.229 g, 0.54 mmol, 1 .0 eq) was dissolved in EtOH (50 mL) and sodium borohydride (0.023 g, 0.59 mmol, 1 .1 eq) was added. The reaction was left under magnetic stirring at RT. After a few minutes the suspension became a clear solution. After 1 h, the solution was then dried under vacuum, diluted with AcOEt (15 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. Part of the crude mixture (0.064 g) was purified by HPLC (elution gradient H2O/ACN from 70:30 to 5:95 in 15 min, the product was collected at 10.5 min) yielding compound 15 (0.022 g; yield 34%) of colorless glassy solid. LC-MS (method K): RT: 2.1 min, m/z = 427.2; ¹H-NMR (600 MHz, MeOD): 5 8.89 (d, J = 4.1 Hz, 3H), 8.64 (ddt, J = 8.3, 1 .8, 0.9 Hz, 1 H), 8.52 - 8.49 (m, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 5.31 (t, J = 6.4 Hz, 1 H), 3.68 (d, J = 6.4 Hz, 2H), 2.54 (s, 3H).

5-(5-fluoropyrimidin-2-yl)-N-[2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)propyl]-2-chlorobenzamide (16)

A solution of methylmagnesium bromide 3M in diethyl ether (0.77 g, 0.65 mmol, 0.217 mL, 2.5 eq) was added to compound 10 (0.100 g, 0.26 mmol, 1 .0 eq) in THF (5 mL). After 3 h, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by HPLC (method M RT: 8.5 minutes) affording compound 16 (0.056 g, yield 54%). LC-MS (method K): RT: 2.13 min, m/z = 407.1 ; Purity Grade: 95%; ¹H-NMR (600 MHz, MeOD): 5 8.81 (t, J = 1.4 Hz, 2H), 8.74 (dd, J = 6.0, 2.1 Hz, 1 H), 8.41 (dt, J = 8.6, 1 .8 Hz, 1 H), 8.35 (q, J = 3.5 Hz, 1 H), 7.55 (dt, J = 8.5, 1 .6 Hz, 1 H), 3.88 (dd, J = 14.2, 1.8 Hz, 1 H), 3.78 (dt, J = 13.8, 1.4 Hz, 1 H), 2.62 - 2.57 (m, 3H), 1.75 - 1.71 (m, 3H). 008806333

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2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[2-fluoro-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (17)

Compound 11 (0.100 g, 0.25 mmol, 1.0 eq) was dissolved in DCM (5.00 mL) under the flow of N2; then DAST (0.052 g, 0.32 mmol, 0.320 mL, 1 .3 eq) was added dropwise at 0°C. The reaction mixture was slowly warmed up to rt and stirred until the reaction was completed. After 3 hrs, the reaction solution was added to a saturated NaHCOs aqueous solution (4.00 mL) to terminate the reaction and extracted three times with DCM. The organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC (method M; RT:12.2 minutes) affording compound 17 (0.035 g, yield 35%). LC-MS (method K): RT: 2.3 min, m/z = 395.23, 436.06 (ESI⁺ as Acetonitrile adduct); Purity Grade: 92.9%.

2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2S*)-2-fluoro-2-(4-methyl-1,3-thiazol-5-yl)ethyl]benzamide (17a), and 2-chloro-5-(5-fluoropyrimidin-2-yl)-N-[(2R*)-2-fluoro-2-(4-methyl-1,3-thiazol-5- yl)ethyl]benzamide (17b)

The racemate 17 was separated using a WATERS Quaternary Gradient Mobile 2535 equipped with WATERS UVA/isible Detector 2489 (dual-wavelength used 254 and 260 nm), in order to collect both enantiomers with enough purity. Normal phase HPLC analytical was carried out on a Lux AMY-Coat Phenomenex column (5 pm, 21 .2 x 150 mm) with a flow rate of 13 mL/min. Two mobile phases were used, mobile phase A: N-Hexane (Chromasolv for HPLC Sigma-Aldrich); mobile phase B: Isopropanol (Chromasolv for HPLC Sigma-Aldrich), and they were employed to perform an isocratic run with 25 % B. Back Pressure: 700 PSI. Compound 17a was obtained at RT: 23.8 min; and compound 17b was obtained at RT: 28.0 min.

Analytical data of compound 17a: LC-MS (method K): RT: 2.32 min, m/z = 395.1 ; Purity Grade: >95%; ¹H-NMR (400 MHz, CDCI3): 6 8.79 (s, 1 H), 8.73 - 8.63 (m, 3H), 8.42 (dd, J = 8.5, 2.2 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 6.67 (NH), 6.03 (m, J_H,F = 48.1 , J = 8.4, 3.6 Hz, 1 H), 4.15 (dddd, J = 28.7, 14.5, 7.2, 3.6 Hz, 1 H), 3.81 (tdd, J = 14.6, 8.5, 4.9 Hz, 1 H), 2.57 (s, 3H).

Analytical data of compound 17b: LC-MS (method K): RT: 2.32 min, m/z = 395.1 ; Purity Grade: >95%; ¹H-NMR (400 MHz, CDCI3): 6 8.80 (s, 1 H), 8.73 - 8.63 (m, 3H), 8.42 (dd, J = 8.4, 2.2 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 6.66 (NH), 6.04 (m, J_H,F = 48.1 , J= 8.4, 3.6 Hz, 1 H), 4.15 (dddd, J = 28.6, 14.5, 7.2, 3.6 Hz, 1 H), 3.81 (tdd, J = 14.7, 8.4, 5.0 Hz, 1 H), 2.58 (s, 3H).

5-(1-methyl-1H-pyrazol-5-yl)-N-(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (18)

To a solution of I-26 (50 mg, 256.83 pmol, 1 eq, HCI) and 2-methyl-5-(1-methyl-1 /7-pyrazol-5-yl)benzoic acid (61 .09 mg, 282.51 pmol, 1 .1 eq) in pyridine (5 mL) was added EDCI (246.17 mg, 1 .28 mmol, 5 eq). The mixture was stirred at 15°C for 1 hr. The reaction mixture was filtered, and the filtrate was 008806333

99 concentrated. The residue was purified by prep-HPLC (column: Waters xbridge 150x25mm 10 pm; mobile phase: [water (NH4HCO3)-ACN]; gradients 5%-45% B over 10 min). Compound 18 (75 mg, 113.8 pmol, 44.3% yield, 99% purity) was obtained as a yellow gum. LC-MS (method E): RT: 0.400 min, m/z = 357.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.88 (s, 1 H), 8.46 (t, J = 6.0 Hz, 1 H), 7.49 - 7.46 (m, 2H), 7.37 - 7.33 (m, 2H), 6.39 (d, J = 2.0 Hz, 1 H), 6.00 (d, J = 3.2 Hz, 1 H), 5.13 - 5.09 (m, 1 H), 3.84 (s, 3H), 3.43 - 3.41 (m, 2H), 2.35 (s, 3H), 2.31 (s, 3H); HPLC (method B): RT: 1.447 min, 99.2% purity; SFC (method I): RT: 1.284 min.

5-(1H-pyrazol-1-yl)-N-(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-chlorobenzamide (19)

To a solution of I-26 (50.0 mg, 256 pmol, 1 .00 eq, HCI) in pyridine (2.00 mL) was added EDCI (246 mg, 1.28 mmol, 5.00 eq) and 2-chloro-5-(1 /7-pyrazol-1-yl)benzoic acid (57.1 mg, 256 pmol, 1.00 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (150x25mm, 10 pm); mobile phase: [water (TFA)-ACN]; gradient: 6%-36% B over 10 min). Compound 19 (52.7 mg, 164 pmol, 64.0% yield) was obtained as a yellow solid. LC-MS (method E): RT: 0.440 min, m/z = 363.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.95 (s, 1 H), 8.71 (t, J = 11 .6 Hz, 1 H), 8.54 (d, J = 2.4 Hz, 1 H), 7.91 - 7.88 (m, 1 H), 7.87 - 7.86 (m, 1 H), 7.79 (d, J = 1 .6 Hz, 1 H), 7.60 (t, J = 8.4 Hz, 1 H), 6.59 - 6.58 (m, 1 H), 5.11 (t, J = 13.2 Hz, 1 H), 3.46 - 3.42 (m, 2H), 2.39 (s, 3H); HPLC (method B): RT: 1 .431 min, 99.4% purity; SFC (method I): RT: 1.638 min.

5-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N-(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5- yl)propyl]-2-chlorobenzamide (20)

To a solution of I-26 (50 mg, 256.83 pmol, 1 eq, HCI salt) and 2-chloro-5-(3,5-dioxo-4,5-dihydro-1 ,2,4- triazin-2(3/-/)-yl)benzoic acid (75.61 mg, 282.51 pmol, 1.1 eq) in pyridine (5 mL) was added EDCI (246.17 mg, 1 .28 mmol, 5 eq). The mixture was stirred at 15°C for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Waters xbridge 150x25mm 10pm; mobile phase: [water (NH4HCO3)-ACN]; gradient:0%-30% B over 10 min). Compound 20 (51 mg, 88.9 pmol, 34.6% yield, 98% purity) was obtained as a blue gum. LC-MS (method E): RT: 0.370 min, m/z = 408.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.87 (s, 1 H), 8.66 (t, J = 6.0 Hz, 1 H), 7.57 - 7.51 (m, 4H), 5.98 (s, 1 H), 5.08 (t, J = 6.4 Hz, 1 H), 3.42 - 3.40 (m, 2H), 2.36 (s, 3H); HPLC (method B): RT: 1.1 10 min, 98.9 % purity; SFC (method I) : RT: 2.120 min.

N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methyl-5-(pyrimidin-2-yl)benzamide (21)

To a solution of compound I-27 (100 mg, 248 pmol, 1.00 eq) and 2-chloropyrimidine (42.7 mg, 372 pmol, 1 .50 eq) in dioxane (3.00 mL) and H2O (1 .00 mL) was added Na2COs (39.5 mg, 372 pmol, 1 .50 eq) and Pd(dppf)Cl2 (18.1 mg, 24.8 pmol, 0.100 eq) under N2, the mixture was stirred at 100 °C for 2 hr. The 008806333

100 mixture was filtered and concentrated under reduced pressure to get the residue. The mixture was purified by Prep-HPLC column: Waters Xbridge C18 150x50mmx 10pm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 14%-44% B over 9 min. Compound 21 (61.0 mg, 171 pmol, 68.9% yield, 99.5% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.439 min, m/z = 355.2; ¹H-NMR (400 MHz, DMSO-cfe): <5 8.90 (t, J = 4.8 Hz, 3H), 8.52 (t, J = 5.6 Hz, 1 H), 8.34 - 8.30 (m, 2H), 7.45 (t, J = 4.8 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 6.02 (s, 1 H), 5.13 (t, J = 6.4 Hz, 1 H), 3.45 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H); HPLC (method B): RT: 1.549 min, 99.5% purity; SFC (method I): RT: 2.144 min.

The method as described for compound 21 was used to prepare compounds 22-56 analogously.

5-(5-methylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide

(22)

Compound 22 was synthesized according to the route described for compound 21 with 2-chloro-5- methylpyrimidine and purified with gradient elution: 9%-39% B over 9 min. Compound 22 (35.0 mg, 94.9 pmol, 38.2% yield) was obtained as white solid. LC-MS (method E): RT: 0.773 min, m/z = 369.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.88 (s, 1 H), 8.75 - 8.74 (m, 2H), 8.50(f, J = 6 Hz, 1 H), 8.31 - 8.26 (m, 2H), 7.35 (d, J = 8 Hz, 1 H), 5.98(d, J = 4 Hz, 1 H), 5.14 - 5.10 (m, 1 H), 3.44 t, J = 6 Hz, 2H), 2.49 (s, 3H), 2.38 (s, 6H); HPLC (method B): RT: 1.542min, 99.1 % purity; SFC (method P): RT: 1.204 min.

5-(4-methylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide

(23)

Compound 23 was synthesized according to the route described for compound 21 with 2-chloro-4- methylpyrimidine and purified with gradient elution. Compound 23 (70.0 mg, 189 pmol, 76.4% yield) was obtained as white solid. LC-MS (method E): RT: 0.774 min, m/z = 369.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.89 (s, 1 H), 8.73 (d, J = 4.8 Hz, 1 H), 8.49 (t, J = 6 Hz, 1 H), 8.31 - 8.29 (m, 2H), 7.36 (d, J = 7.6 Hz, 1 H), 7.32 (d, J = 4.8 Hz, 1 H), 5.98 (s, 1 H), 5.12 (t, J = 6.4 Hz, 1 H), 3.48 - 3.41 (m, 2H), 2.55 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H); HPLC (method B): RT: 1.509 min, 98.5% purity; SFC (method Q): RT: 1.690 min.

5-(5-aminopyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide

(24)

Compound 24 was synthesized according to the route described for compound 21 with 5-amino-2- chloropyrimidine and purified with gradient elution gradient: 14%-44% B over 10 min. Compound 24 (60.0 mg, 144 pmol, 58.2% yield, 98.9% purity) was obtained as brown solid. LC-MS (method E): RT: 0.412 min, m/z = 370.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.80 (s, 1 H), 8.44 (t, J = 5.6 Hz, 1 H), 8.20 (s, 2H), 8.15 (s,1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.0 Hz, 1 H), 5.99 (s, 1 H), 5.69 (s, 2H), 5.12 (t, J = 6.4 Hz, 1 H), 3.44 (t, J = 6.0Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H); HPLC (method B): RT: 1.295 min, 98.9% purity; SFC (method I): RT: 2.017 min. 008806333

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5-(4-aminopyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide

(25)

Compound 25 was synthesized according to the route described for compound 21 with 4-amino-2- chloropyrimidine and purified with gradient elution gradient: 10%-40% B over 10 min. Compound 25 (50.0 mg, 134 pmol, 54.1 % yield, 99.4% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.375 min, m/z = 370.2; ¹H-NMR (400 MHz, CDCb): 6 8.66 (s, 1 H), 8.32 - 8.21 (m, 3H), 7.31 (d, J = 8.0 Hz, 1 H), 6.73 (t, J = 4.8Hz, 1 H), 6.32 (d, J = 6.0 Hz, 1 H), 5.29 - 5.26 (m, 1 H), 5.14 (s, 2H), 4.78 (s, 1 H), 3.83 - 3.62 (m, 2H), 2.51 (s, 3H), 2.46 (s, 3H); HPLC (method B): RT: 0.583 min, 99.4% purity; SFC (method Q): RT: 1.933 min.

5-(5-hydroxypyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (26)

Compound 26 was synthesized according to the route described for compound 21 with 2-chloro-5- hydroxypyrimidine and purified with gradient elution: 1 %-30% B over 10 min. Compound 26 (1 1 .0 mg, 105 pmol, 42.4% yield, 97.7% purity) was obtained as white solid. LC-MS (method E): RT: 0.418 min, m/z = 371.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.88 (s, 1 H), 8.46 (t, J = 5.6Hz, 1 H), 8.38 (s, 2H), 8.21 - 8.15 (m, 2H), 7.30 (d, J = 8.0 Hz, 1 H), 5.98 (d, J = 2.0 Hz, 1 H), 5.12 (t, J = 5.2Hz, 1 H), 3.49 - 3.42 (m, 2H), 2.38 (s, 3H), 2.29 (s, 3H); HPLC (method B): RT: 1.512 min, 97.7% purity; SFC (method G): RT: 0.677 min.

5-(4-hydroxypyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (27)

Compound 27 was synthesized according to the route described for compound 21 with 2-chloro-4- hydroxypyrimidine. The residue was purified by prep-HPLC column: Phenomenex luna C18 150x25mmx 10pm; mobile phase: [water (FA)-ACN]; gradient:5%-35% B over 10 min. Compound 27 (17.0 mg, 45.0 pmol, 18.1 % yield, 98.0% purity) was obtained as white solid. LC-MS (method E): RT: 0.421 min, m/z = 371 .1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.88 (s, 1 H), 8.44 - 8.41 (m, 1 H), 8.10 - 8.03 (m, 3H), 7.37 (d, J = 8.0 Hz, 1 H), 6.34 - 6.33 (m, 1 H), 6.01 (d, J = 4.0 Hz, 1 H), 5.12 - 5.08 (m, 1 H), 3.46 - 3.43 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H); HPLC (method B): RT: 0.858 min, 98.0% purity; SFC (method P): RT: 1 .157 min.

5-(5-ethynylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (28)

To a solution of compound I-28 (100 mg, 312 pmol, 1.00 eq) and 2-chloro-5-ethynylpyimidine (51.9 mg, 374 pmol, 1.20 eq) in dioxane (10.0 mL) was added Na2COs (49.6 mg, 468 pmol, 1.50 eq) and 008806333

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Pd(dppf)Cb (22.8 mg, 31.2 pmol, 0.10 eq), the mixture was stirred at 100 °C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC column: Waters Xbridge C18 150x50mmx 10pm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 24%-54% B over 10 min. Compound 28 (20.0 mg, 52.8 pmol, 16.9% yield) was obtained as yellow solid. LC-MS (method E): RT: 0.436 min, m/z = 379.1 ; ¹H-NMR (400 MHz, CDCb): 6 8.86 (s, 2H), 8.68 (s, 1 H), 8.58 - 8.49 (m, 1 H), 8.43 (d, J = 8Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 6.42 - 6.41 (m, 1 H), 5.35 - 5.31 (m, 1 H), 3.95 - 3.89 (m, 2H), 3.70 - 3.64 (m, 1 H), 3.43(s, 1 H), 2.57 (s, 3H), 2.50 (s, 3H); HPLC (method B) : RT: 2.12 min, 95.5 % purity; SFC (method G): RT: 1.799 min.

5-(5-cyanopyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide

(29)

Compound 29 was synthesized according to the route described for compound 21 with 2-chloro-5- cyanopyrimidine and purified with gradient elution:20%-50% B over 10 min. Compound 29 (46.0 mg, 170 pmol, 68.6% yield, 92.5% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.451 min, m/z = 380.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.38 (s, 2H), 8.89 (s, 1 H), 8.58 (t, J = 5.6Hz, 1 H), 8.38 - 8.35 (m, 2H), 7.44 (d, J = 8.0 Hz, 1 H), 5.13 (t, J = 6.4Hz, 1 H), 3.45 (t, J = 6.0Hz, 2H), 2.38 (s, 3H), 2.35 (s, 3H); HPLC (method B): RT: 1.628 min, 92.5% purity; SFC (method Q): RT: 1.869 min.

5-(4-cyanopyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2-methylbenzamide

(30)

Compound 30 was synthesized according to the route described for compound 21 with 2-chloro-4- cyanopyrimidine and purified with gradient elution: 21 %-51 % B over 9 min. Compound 30 (38.0 mg, 178.03 pmol, 71.62% yield, 96.5% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.464 min, m/z = 380.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.23 (d, J = 4.8 Hz, 1 H), 8.89 (s, 1 H), 8.57 (t, J = 5.6Hz, 1 H), 8.32 - 8.32 (s, 2H), 8.06 (d, J = 4.8 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 5.13 (t, J = 6.4Hz, 1 H), 3.46 (t, J = 6.0Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H); HPLC (method B): RT: 1.897 min, 96.5% purity; SFC (method Q): RT: 1 .820 min.

5-(4,5-dimethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (31)

Compound 31 was synthesized according to the route described for compound 21 with 2-chloro-4,5- dimethylpyrimidine and purified with gradient elution: 22%-52% B over 9 min. Compound 30 (36.0 mg, 156 pmol, 62.8% yield, 99.5% purity) was obtained as off-white solid. LC-MS (method E): RT: 0.493 min, m/z = 383.2; ¹H-NMR (400 MHz, CDCb): 6 8.67 (s, 1 H), 8.46 - 8.39 (m, 3H), 7.36 (d, J = 8.0 Hz, 1 H), 6.52 (t, J = 5.2 Hz, 1 H), 5.35 - 5.32 (m, 1 H), 4.22 (d, J = 3.2 Hz, 1 H), 3.94 - 3.88 (m, 1 H), 3.69 - 3.63 (m, 1 H), 008806333

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2.55 (s, 6H), 2.49 (s, 3H), 2.30 (s, 3H); HPLC (method B): RT: 1 .917 min, 99.5% purity; SFC (method G): RT: 0.907 min.

5-(4,6-dimethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (32)

Compound 32 was synthesized according to the route described for compound 21 with 2-chloro-4,6- dimethylpyrimidine and purified with gradient elution: 22%-52% B over 9 min. Compound 32 (41 .0 mg, 149 pmol, 60.0% yield, 95.1% purity) was obtained as white solid LC-MS (method E): RT: 0.488 min, m/z = 383.2; ¹H-NMR (400 MHz, CDCb): 6 8.68 (s, 1 H), 8.49 - 8.43 (m, 2H), 7.36 (d, J = 8.0 Hz, 1 H), 6.95 (s, 1 H), 6.50 (s, 1 H), 5.36 - 5.34 (m, 1 H), 4.15 - 4.14 (m, 1 H), 3.94 - 3.89 (m, 1 H), 3.71 - 3.66 (m, 1 H), 2.56 - 2.50 (m, 12H); HPLC (method B): RT: 1.852 min, 95.1 % purity; SFC (method I): RT: 1.669 min.

5-(5-methoxypyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (33)

Compound 33 was synthesized according to the route described for compound 21 with 2-chloro-5- meth oxy pyrimidine and purified with gradient elution: 19%-49% B over 9 min. Compound 33 (74.0 mg, 174 pmol, 46.7% yield, 95.7% purity) was obtained as white solid. LC-MS (method E): RT: 0.484 min, m/z = 385.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.89 (s, 1 H), 8.64 (s, 2H), 8.49 (t, J = 6.0 Hz, 1 H), 8.25 - 8.21 (m, 2H), 7.34 (d, J = 7.6 Hz, 1 H), 6.00 (s, 1 H), 5.13 (t, J = 6.8 Hz, 1 H), 3.96 (s, 3H), 3.45 (t, J = 6.4 Hz, 2H), 2.38 (s, 3H), 2.31 (s, 3H); HPLC (method B): RT: 1 .814 min, 95.7% purity; SFC (method I): RT: 2.505 min.

5-(4-methoxypyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (34)

Compound 34 was synthesized according to the route described for compound 21 with 2-chloro-4- meth oxy pyrimidine and purified with gradient elution: 22%-52% B over 10 min. Compound 34 (65.0 mg, 128 pmol, 51.6% yield, 98.7% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.451 min, m/z = 385.2; ¹H-NMR (400 MHz, CDCb): 6 8.66 (s, 1 H), 8.47 - 8.46 (m, 2H), 8.41 (dd, Ji = 8.4 Hz, J₂ = 2.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 5.6 Hz, 1 H), 6.51 (t, J = 4.4 Hz, 1 H), 5.35 - 5.33 (m, 1 H), 4.16 (d, J =3.2 Hz, 1 H), 4.10 (s, 3H), 3.95 - 3.89 (m, 1 H), 3.69 - 3.63 (m, 1 H), 2.55 (s, 3H), 2.49 (s, 3H); HPLC (method B): RT: 1.706 min, 98.7% purity; SFC (method Q): RT: 1.593 min. 008806333

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5-(5-hydroxymethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (35)

Compound 35 was synthesized according to the route described for compound 21 with 2-chloro-5- hydroxymethylpyrimidine and purified with gradient elution: 10%-40% B over 9 min. Compound 35 (42.0 mg, 178 pmol, 47.7% yield, 97.8% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.414 min, m/z = 385.2; ¹H-NMR (400 MHz, CDCb): 6 8.78 (s, 2H), 8.68 (s, 1 H), 8.48 - 8.41 (m, 2H), 7.39 (d, J = 8.0 Hz, 1 H), 6.53 - 6.52 (m, 1 H), 5.35 - 5.32 (m, 1 H), 4.80 (s, 2H), 4.1 1 (s, 1 H), 3.94 - 3.89 (m, 1 H), 3.69 - 3.64 (m, 1 H), 2.57 (s, 3H), 2.49 (s, 3H); HPLC (method B): RT: 1 .331 min, 97.8% purity; SFC (method I): RT: 1.837 min.

5-(4-hydroxymethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (36)

Compound 36 was synthesized according to the route described for compound 21 with 2-chloro-4- hydroxymethylpyrimidine and purified with gradient elution: 11 %-41 % B over 9 min. Compound 36 (72.0 mg, 179 pmol, 48.2% yield, 98.8% purity) was obtained as white solid. LC-MS (method E): RT: 0.423 min, m/z = 385.2; ¹H-NMR (400 MHz, CDCb): 6 8.73 (d, J =5.2 Hz, 1 H), 8.69 (s, 1 H), 8.43 - 8.41 (m, 2H), 7.37 (d, J = 8.0 Hz, 1 H), 7.19 (d, J =5.2 Hz, 1 H), 6.48 (s, 1 H), 5.36 - 5.34 (m, 1 H), 4.81 (s, 2H), 4.06 (s, 1 H), 3.92 - 3.85 (m, 1 H), 3.73 - 3.68 (m, 1 H), 2.55 (s, 3H), 2.49 (s, 3H); HPLC (method B): RT: 1.410 min, 98.8% purity; SFC (method I): RT: 1.822 min.

5-(5-cyclopropylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (37)

Compound 37 was synthesized according to the route described for compound 21 with 2-chloro-5- cyclopropylpyrimidine and purified with gradient elution: 25%-55% B over 10 min. Compound 37 (64.0 mg, 125 pmol, 50.3% yield, 98.6% purity) was obtained as pink solid. LC-MS (method E): RT: 0.475 min, m/z = 395.2; ¹H-NMR (400 MHz, CDCb): 6 8.67 (s, 1 H), 8.49 (s, 2H), 8.43 (d, J = 1 .6 Hz, 1 H), 8.35 (dd, Ji = 8.0 Hz, J₂ = 1 .6 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.58 (t, J = 5.6 Hz, 1 H), 5.34 - 5.31 (m, 1 H), 4.31 (d, J = 7.6 Hz, 1 H), 3.93 - 3.87 (m, 1 H), 3.67 - 3.60 (m, 1 H), 2.55 (s, 3H), 2.48 (s, 3H), 1 .92 - 1.88 (m, 1 H), 1.15 - 1.11 (m, 2H), 0.84 - 0.80 (m, 2H); HPLC (method B): RT: 2.126 min, 98.6% purity; SFC (method Q): RT: 1 .804 min.

5-(5-isopropylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (38)

Compound 38 was synthesized according to the route described for compound 21 with 2-chloro-5- isopropylpyrimidine and purified with gradient elution: 29%-59% B over 10 min. Compound 38 (30.0 mg, 100 pmol, 40.4% yield, 99.6% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.491 min, 008806333

105 m/z = 397.2; ¹H-NMR (400 MHz, CDCb): 6 8.68 - 8.64 (m, 3H), 8.46 (s, 1 H), 8.40 - 8.37 (m, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 6.61 - 6.52 (m, 1 H), 5.34 - 5.33 (m, 1 H), 4.38 - 4.15 (m, 1 H), 3.94 - 3.88 (m, 1 H), 3.69 - 3.62 (m, 1 H), 3.02 - 2.95 (m, 1 H), 2.53 (d, J = 26 Hz, 6H), 1 .35 (d, J = 12 Hz, 6H); HPLC (method B): RT: 2.264 min, 99.6% purity; SFC (method P): RT: 0.955 min.

5-(4-difluoromethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (39)

Compound 39 was synthesized according to the route described for compound 21 with 2-chloro-4- difluoromethylpyrimidine and purified with gradient elution: 25%-55% B over 10 min. Compound 39 (53.0 mg, 123 pmol, 49.7% yield, 100% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.473 min, m/z = 405.2; ¹H-NMR (400 MHz, CDCb): 6 9.06 - 8.98 (m, 1 H), 8.69 (s, 1 H), 8.61 - 8.46 (m, 2H), 7.60 - 7.56 (m, 1 H), 7.44 - 7.33 (m, 1 H), 6.78 - 6.50 (m, 1 H), 6.45 - 6.41 (m, 1 H), 5.37 - 5.36 (m, 1 H),

3.96 - 3.88 (m, 2H), 3.73 - 3.67 (m, 1 H), 2.57 (s, 3H), 2.51 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -119.256; HPLC (method B): RT: 2.051 min, 100% purity; SFC (method G): RT: 1.011 min.

5-(5-difluoromethoxypyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (40)

Compound 40 was synthesized according to the route described for compound 21 with 2-chloro-5- difluoromethoxypyrimidine and purified with gradient elution: 25%-55% B over 10 min. Compound 40 (49.0 mg, 118 pmol, 47.5% yield, 99.4% purity) was obtained as pink solid. LC-MS (method B): RT: 0.514 min, m/z = 421.2; ¹H-NMR (400 MHz, CDCb): 6 8.68 - 8.67 (m, 3H), 8.46 - 8.45 (m, 1 H), 8.40 (dd, Ji =8.4 Hz, Ji =2.0 Hz, 1 H), 7.39 (d, J =8.0 Hz, 1 H), 6.81 - 6.43 (m, 2H), 5.37 - 5.33 (m, 1 H), 3.96 - 3.90 (m, 2H), 3.71 - 3.64 (m, 1 H), 2.56 (s, 3H), 2.50 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -81.722; HPLC (method B): RT: 2.109 min, 99.4% purity; SFC (method G): RT: 1.385 min.

5-(5-trifluoromethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (41)

Compound 41 was synthesized according to the route described for compound 21 with 2-chloro-5- trifluoromethylpyrimidine and purified with gradient elution: 31 %-61 % B over 10 min. Compound 41 (49.0 mg, 93.4 pmol, 37.6% yield, 98.6% purity) was obtained as yellow solid. LC-MS (method B): RT: 0.499 min, m/z = 423.1 ; ¹H-NMR (400 MHz, CDCb): 6 9.02 (s, 2H), 8.69 (s, 1 H), 8.55 (d, J =1 .6 Hz, 1 H), 8.49 (dd, Ji =8.0 Hz, Ji =1 .6 Hz, 1 H), 7.42 (d, J =8.0 Hz, 1 H), 6.44 (t, J =1 .2 Hz, 1 H), 5.36 - 5.35 (m, 1 H),

3.97 - 3.91 (m, 1 H), 3.84 (s, 1 H), 3.71 - 3.65 (m, 1 H), 2.58 (s, 3H), 2.51 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -62.260; HPLC (method B): RT: 2.367 min, 98.6% purity; SFC (method G): RT: 1.167 min. 008806333

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5-(5-fluoro-4-methylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (42)

Compound 42 was synthesized according to the route described for compound 21 with 2-bromo5-fluoro-

4-methylpyrimidine and purified with gradient elution: 25%-55% B over 10 min. Compound 42 (63.0 mg, 103 pmol, 41.5% yield, 99.7% purity) was obtained as off-white solid. LC-MS (method E): RT: 0.472 min, m/z = 387.2; ¹H-NMR (400 MHz, CDCb): 6 8.67 (s, 1 H), 8.47 (d, J =2.0 Hz, 1 H), 8.42 (d, J =1 .6 Hz, 1 H), 8.36 (dd, Ji =8.0 Hz, Ji =1 .6 Hz, 1 H), 7.36 (d, J =8.0 Hz, 1 H), 6.48 (t, J =1 .2 Hz, 1 H), 5.35 - 5.32 (m, 1 H), 4.09 (d, J =3.2 Hz, 1 H), 3.95 - 3.89 (m, 1 H), 3.70 - 3.65 (m, 1 H), 2.60 (d, J =3.2 Hz, 3H), 2.54 (s, 3H), 2.49 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -140.587; HPLC (method B): RT: 2.033 min, 99.7% purity; SFC (method I): RT: 2.165 min.

5-[5-fluoro-4-{(2-hydroxyethyl)amino}pyrimidin-2-yl]-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5- yl)ethyl]-2-methylbenzamide (43)

Compound 43 was synthesized according to the route described for compound 21 with 2-chloro-5-fluoro-

4-(2-hydroxyethylamino)pyrimidine and purified with gradient elution: 13%-43% B over 10 min.

Compound 43 (35.0 mg, 68.9 pmol, 27.7% yield, 99.1 % purity) was obtained as white solid. LC-MS (method E): RT: 0.397 min, m/z = 432.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.89 (s, 1 H), 8.45 (t, J =1.6 Hz, 1 H), 8.21 - 8.17 (m, 3H), 7.62 (t, J =5.2 Hz, 1 H), 7.30 (d, J =8.8 Hz, 1 H), 5.12 (d=t, J =6.4 Hz, 1 H), 3.64 - 3.58 (m, 4H), 3.49 - 3.40 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 6 -157.291 ; HPLC (method B): RT: 1.024 min, 99.1 % purity; SFC (method Q): RT: 1.706 min.

5-(5-methylsulfonylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (44)

Compound 44 was synthesized according to the route described for compound 21 with 2-chloro-5- methylsulfonylpyrimidine and purified with gradient elution: 16%-46% B over 10 min. Compound 44 (55.0 mg, 115 pmol, 46.5% yield, 100% purity) was obtained as gray solid. LC-MS (method E): RT: 0.438 min, m/z = 433.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.34 (s, 2H), 8.90 (s, 1 H), 8.59 (t, J =5.6 Hz, 1 H), 8.40 - 8.38 (m, 2H), 7.45 (d, J =8.0 Hz, 1 H), 5.14 (t, J =6.4 Hz, 1 H), 3.48 - 3.46 (m, 2H), 3.44 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H); HPLC (method B): RT: 1.674 min, 100% purity; SFC (method I): RT: 1.976 min.

5-(4-methylsulfonylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (45)

Compound 45 was synthesized according to the route described for compound 21 with 2-chloro-4- methylsulfonylpyrimidine and purified with gradient elution: 13%-43% B over 10 min. Compound 45 (23.0 mg, 33.3 pmol, 13.4% yield, 96.0% purity) was obtained as light yellow solid. LC-MS (method E): 008806333

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RT: 0.452 min, m/z = 433.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.31 (d, J = 5.2 Hz, 1 H), 8.89 (s, 1 H), 8.80 - 8.58 (m, 1 H), 8.40 - 8.35 (m, 2H), 7.99 (d, J = 4.8 Hz, 1 H), 7.44 (d, J =8.4 Hz, 1 H), 6.04 (s, 1 H), 5.14 (t, J =6.8 Hz, 1 H), 3.49 (s, 3H), 3.47 - 3.43 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H); HPLC (method B): RT: 1.538 min, 96.0% purity; SFC (method I): RT: 1.633 min.

5-[4-{(3-methoxypropyl)amino}pyrimidin-2-yl]-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]- 2-methylbenzamide (46)

Compound 46 was synthesized from I-29 and I-27 according to the route described for compound 21 and purified with gradient elution: 20%-50% B over 10 min. Compound 46 (35.0 mg, 105 pmol, 42.3% yield, 93.0% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.414 min, m/z = 442.2; ¹H-NMR (400 MHz, DMSO-cfe): <5 8.88 (s, 1 H), 8.44 (t, J = 6.0 Hz, 1 H), 8.24 - 8.22 (m, 2H), 8.12 (s, 1 H), 7.42 (s, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 6.38 (d, J = 6.0 Hz, 1 H), 5.12 (t, J = 6.4 Hz, 1 H), 3.51 - 3.38 (m, 6H), 3.24 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H), 1.85 - 1.78 (m, 2H). HPLC (method B): RT: 1.188 min, 93.0% purity; SFC (method I): RT: 1.873 min.

5-[4-(N,N-dimethylamino)pyrimidin-2-yl]-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (47)

Compound 46 was synthesized according to the route described for compound 21 with 2-bromo-4- dimethylaminopyrimidine and purified with gradient elution: 22%-52% B over 10 min. Compound 47 (41 .0 mg, 100 pmol, 40.3% yield, 99.6% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.403 min, m/z = 398.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.88 (s, 1 H), 8.46 (t, J = 6.0 Hz, 1 H), 8.28 - 8.25 (m, 3H), 7.31 (d, J = 8.4 Hz, 1 H), 6.60 (d, J = 6.0 Hz, 1 H), 5.13 (t, J = 6.4 Hz, 1 H), 3.50 - 3.38 (m, 2H), 3.14 (s, 6H), 2.37 (s, 3H), 2.30 (s, 3H); HPLC (method B): RT: 1.109 min, 99.6% purity; SFC (method Q): RT: 1.876 min.

Methyl 2-(3-{[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamoyl}-4- methylphenyl)pyrimidine-4-carboxylate (48)

Compound 47 was synthesized according to the route described for compound 21 with methyl 2-bromo- pyrimidine-4-carboxylate and purified with gradient elution: 16%-46% B over 10 min. Compound 48 (78.0 mg, 92.2 pmol, 37.1 % yield, 95.1 % purity) was obtained as brown gum. LC-MS (method E): RT: 0.450 min, m/z = 413.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.17 (d, J = 4.8 Hz, 1 H), 8.89 (s, 1 H), 8.55 (t, J = 5.6 Hz, 1 H), 8.36 - 8.34 (m, 2H), 7.93 (d, J = 4.8 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 1 H), 5.13 (t, J = 6.4 Hz, 1 H), 3.97 (s, 3H), 3.49 - 3.44 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H); HPLC (method B): RT: 1 .698 min, 95.1 % purity; SFC (method G): RT: 1.710 min. 008806333

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Ethyl 5-fluoro-2-(3-{[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamoyl}-4- methylphenyl)pyrimidine-4-carboxylate (49)

Compound 49 was synthesized according to the route described for compound 21 with ethyl 2-chloro-5- fluoropyrimidine-4-carboxylate and purified with gradient elution: 24%-54% B over 10 min. Compound 49 (10.0 mg, 22.2 pmol, 8.93% yield, 98.7% purity) was obtained as white solid. LC-MS (method E): RT: 0.498 min, m/z = 445.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 9.20 (d, J = 2.4 Hz, 1 H), 8.88 (s, 1 H), 8.55 (t, J = 6.0 Hz, 1 H), 8.27 - 8.26 (m, 2H), 7.41 (d, J = 8.8 Hz, 1 H), 6.00 (d, J = 4.0 Hz, 1 H), 5.13 - 5.12 (m, 1 H), 4.50 - 4.45 (m, 2H), 3.48 - 3.44 (m, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 1 .38 (t, J = 6.8 Hz, 2H); ¹⁹F-NMR (376 MHz, DMSO-cfe: 6 -135.226; HPLC (method B): RT: 2.087 min, 98.7% purity; SFC (method I): RT: 1.824 min.

5-[4-(2,2,2-trifluoroethoxy)-pyrimidin-2-yl]-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (50)

Compound 50 was synthesized according to the route described for compound 21 with 2-chloro-4-(2,2,2- trifluoroethoxy)pyrimidine and purified with gradient elution: 32%-62% B over 10 min. Compound 50 (58.0 mg, 108 pmol, 43.6% yield, 98.2% purity) was obtained as gray solid. LC-MS (method E): RT: 0.538 min, m/z = 453.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.88 (s, 1 H), 8.73 (d, J = 5.6 Hz, 1 H), 8.51 (t, J = 6.0 Hz, 1 H), 8.35 (d, Ji = 7.6 Hz, J₂ = 1 .6 Hz, 1 H), 8.30 (d, J = 1 .6 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.06 (d, J = 5.6 Hz, 1 H), 5.29 - 5.22 (m, 2H), 5.13 (t, J = 6.8 Hz, 1 H), 3.50 - 3.40 (m, 2H), 2.38 (s, 3H), 2.33 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-cfe): 5 -72.046; HPLC (method B): RT: 2.311 min, 98.2% purity; SFC (method G): RT: 2.109 min.

5-[4-(3-hydroxypiperidin-1-yl)pyrimidin-2-yl]-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (51)

Compound 51 was synthesized according to the route described for compound 21 with 2-chloro-4-(3- hydroxypiperidin-1-yl)pyrimidine and purified with gradient elution: 19%-49% B over 10 min. Compound 51 (14.6 mg, 32.1 pmol, 25.8% yield, 99.4% purity) was obtained as white solid. LC-MS (method E): RT: 0.439 min, m/z = 454.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.89 (s, 1 H), 8.47 - 8.45 (m, 1 H), 8.25 - 8.21 (m, 3H), 7.32 (d, J = 8.0 Hz, 1 H), 6.78 - 6.75 (m, 1 H), 5.98 - 5.97 (m, 1 H), 5.13 - 5.11 (m, 1 H), 5.01 - 4.98 (m, 1 H), 4.29 - 3.95 (m, 2H), 3.48 - 3.54 (m, 1 H), 3.48 - 3.40 (m, 2H), 3.13 - 3.04 (m, 1 H), 2.37 (s, 3H), 2.30 (s, 3H), 1 .94 - 1 .89 (m, 1 H), 1.81 - 1 .75 (m, 1 H), 1 .50 - 1 .42 (m, 2H); HPLC (method B): RT: 1.029 min, 99.4% purity; SFC (method I): RT: 1.621 min, RT: 1.695 min. 008806333

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5-[5-fluoro-4-(piperidin-1-yl)pyrimidin-2-yl]-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (52)

Compound 52 was synthesized according to the route described for compound 21 with 2-chloro-5-fluoro-

4-(piperidin-1 -yl)pyrimidine and purified with gradient elution: 40%-70% B over 10 min. Compound 52 (3.65 mg, 7.96 pmol, 6.40% yield, 99.3% purity) was obtained as white solid. LC-MS (method E): RT: 0.512 min, m/z = 456.2; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.88 (s, 1 H), 8.47 - 8.44 (m, 1 H), 8.30 (d, J = 6.8 Hz, 1 H), 8.18 - 8.16 (m, 2H), 7.31 (d, J = 8.4 Hz, 1 H), 5.97 (d, J = 4.0 Hz, 1 H), 5.14 - 5.12 (m, 1 H), 3.80 - 3.77 (m, 4H), 3.47 - 3.40 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 1 .65 - 1 .63 (m, 6H); HPLC (method B): RT: 1.882 min, 99.3% purity; SFC (method P): RT: 1.093 min.

Methyl 2-(3-{[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamoyl}-4- methylphenyl)pyrimidine-5-carboxylate (53)

Compound 53 was synthesized according to the route described for compound 21 with methyl 2-bromo- pyrimidine-5-carboxylate and purified with gradient elution: 22%-52% B over 9 min. The residue was purified by prep-HPLC column: Phenomenex luna C18 150x25mmx 10pm; mobile phase: [water(FA)- ACN]; gradient:21 %-51 % B over 10 min yielding compound 53 (18 mg, 0.043 mmol, 22% yield, 99.8% purity) as white solid. LC-MS (method E): RT: 0.447 min, m/z = 413.2; ¹H-NMR (400 MHz, DMSO-cfe): 6 9.31 (s, 2H), 8.89 (s, 1 H), 8.56(f, J = 5.2 Hz, 1 H), 8.40 - 8.37 (m, 2H), 7.43 (d, J = 7.6 Hz, 1 H), 6.00(d, J = 4.4 Hz, 1 H), 5.15 - 5.11 (m, 1 H), 3.93(s, 3H), 3.45 (t, J = 6 Hz, 2H), 2.38 (s, 3H), 2.34 (s, 3H); HPLC: RT: 2.071 min, 99.8% purity; SFC (method I): RT: 2.124 min.

5-(4-trifluoromethylpyrimidin-2-yl)-N-[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]-2- methylbenzamide (54)

Compound 54 was synthesized according to the route described for compound 21 with 2-bromo-4- trifluoromethylpyrimidine and purified with gradient elution: 30%-60% B over 9 min. Compound 54 (50 mg; 0.118 mmol; 47% yield; was obtained as white solid. LC-MS (method E): RT: 0.472 min, m/z = 423.1 ; ¹H-NMR (400 MHz, CDCb): 6 9.04 (d, J = 4.8 Hz, 1 H), 8.69 (s, 1 H), 8.55 (d, J = 1.6 Hz, 1 H), 8.50 (dd, J = 1 .6 Hz, J = 8.0 Hz, 1 H), 7.54 (d, J = 4.8 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 6.43-6.41 (m, 1 H), 5.38- 5.35 (m, 1 H), 3.99-3.93 (m, 3H), 3.71-3.66 (m, 1 H), 2.57 (s, 3H), 2.50 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): <570.019; HPLC (method B): RT: 2.408min, 100 % purity; SFC (method I): RT: 1.304 min.

2-(3-{[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamoyl}-4-methylphenyl)pyrimidine-4- carboxylic acid (55)

Compound 55 was synthesized according to the route described for compound 21 with methyl 2-bromo- pyrimidine-4-carboxylate and purified with gradient elution: 1 %-20% B over 10 min. Compound 55 (63.0 mg, 74.7 pmol, 30.0% yield, 99.2% purity) was obtained as yellow solid. LC-MS (method E): RT: 008806333

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0.422 min, m/z = 399.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 5 8.89 (s, 1 H), 8.79 (d, J = 5.2 Hz, 1 H), 8.64 (t, J = 5.6 Hz, 1 H), 8.36 (d, J = 1 .6 Hz, 1 H), 8.27 (d, Ji = 8.0 Hz, J₂ = 1 .6 Hz, 1 H), 7.51 (d, J = 4.8 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 6.21 (s, 1 H), 5.17 (t, J = 6.8 Hz, 1 H), 3.54 - 3.48 (m, 2H), 2.39 (s, 3H), 2.32 (s, 3H); HPLC (method B): RT: 1.447 min, 99.2% purity; SFC (method G): RT: 1.419 min.

5-fluoro-2-(3-{[(2R)-2-hydroxy-2-(4-methyl-1,3-thiazol-5-yl)ethyl]carbamoyl}-4- methylphenyl)pyrimidine-4-carboxylic acid (56)

Compound 56 was synthesized according to the route described for compound 21 with ethyl 2-chloro-5- fluoropyrimidine-4-carboxylate, and purified with gradient elution: 1%-20% B over 10 min. Compound 56 (10.0 mg, 35.3 pmol, 14.2% yield, 98.2% purity) was obtained as yellow solid. LC-MS (method E): RT: 0.448 min, m/z = 417.1 ; ¹H-NMR (400 MHz, DMSO-cfe): 6 8.88 (s, 1 H), 8.74 (s, 1 H), 8.53 (t, J = 6.0 Hz, 1 H), 8.26 - 8.21 (m, 2H), 7.34 (d, J = 8.0 Hz, 1 H), 6.00 (d, J = 4.0 Hz, 1 H), 5.13 - 5.12 (m, 1 H), 3.49 - 3.42 (m, 2H), 2.37 (s, 3H), 2.31 (s, 3H); ¹⁹F-NMR (376 MHz, CDCb): 6 -142.450; HPLC (method B): RT: 1.367 min, 98.2% purity; SFC (method P): RT: 1.198 min.

BIOLOGICAL EXAMPLES

Extracellular binding of Bz-ATP to P2X7 receptor opens the channel and allows Ca2+ influx into the cells. The P2X7 receptor has been stably transfected into HEK-293 cells which express the genetically encoded Calcium biosensor GCaMP2.1 . When HEK-293/P2X7 cell are stimulated with Bz-ATP, Ca²⁺ enters the cells, complexes with GCaMP2.1 thus leading to an increase of the fluorescence emitted by the biosensor.

HEK-293 cells stably transfected with P2X7 receptor are seeded overnight in growth medium at 20,000 cell/well in 384-well plate. 24 hours later, the medium is removed and replaced with 20 pL/well of Assay buffer (HBSS 1x Gibco cat. 14065; NaHCO₃4.17 mM; Hepes 20 mM, pH 7.4 + Pluronic-68 0.005%).

Then 10 pL/w of tests compounds or reference antagonist A438079 at 3X-concentration are injected with the FLIPR^TETRA (Molecular Devices) and the kinetic response is monitored over a period of five minutes (Exc wavelength 470_495nm, Em wavelength 515-575 nm). A second injection of 15 pL/w of 3x reference activator (Bz-ATP at ECao) is performed at the FLIPR^TETRA and the signal of the emitted fluorescence is recorded for additional three minutes. The effect of the test compounds is reported as percent inhibition vs the reference antagonist at saturating concentration and ICso values are calculated accordingly. 008806333

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TABLE 3: hP2X7 FLIPR IC50 008806333

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References

A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

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Clapp C, Diaz-Lezama N, Adan-Castro E, Ramirez-Hernandez G, Moreno-Carranza B, Sarti AC, Falzoni S, Solini A, Di Virgilio F. Pharmacological blockade of the P2X7 receptor reverses retinal damage in a rat model of type 1 diabetes. Acta Diabetol. 2019 Sep;56(9):1031-1036. doi: 10.1007/s00592-019-01343-4. Epub 2019 Apr 13. PMID: 30982154.

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Kong H, Zhao H, Chen T, Song Y, Cui Y. Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy. Cell Death Dis. 2022 Apr 12;13(4):336. doi: 10.1038/s41419-022-04786-w. PMID: 35410316; PMCID: PMC9001662.

Moriguchi, M., Nakamura, S., Inoue, Y., Nishinaka, A., Nakamura, M., Shima- zawa, M., and Hara, H. (2018). Irreversible photoreceptors and RPE cells dam- age by intravenous sodium iodate in mice is related to macrophage accumulation. Invest. Ophthalmol. Vis. Sci. 59, 3476-3487.

Pavlou S, Augustine J, Cunning R, Harkin K, Stitt AW, Xu H, Chen M. Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7. Int J Mol Sci. 2019 Apr 29;20(9):2101 . doi: 10.3390/ijms20092101 . PMID: 31035433; PMCID: PMC6540042. 008806333

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Sakurai E, Anand A, Ambati BK, van Rooijen N, Ambati J. Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3578-85. doi: 10.1167/iovs.03- 0097. PMID: 12882810.

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Sennlaub F, Auvynet C, Calippe B, Lavalette S, Poupel L, Hu SJ, Dominguez E, Camelo S, Levy O, Guyon E, Saederup N, Charo IF, Rooijen NV, Nandrot E, Bourges JL, Behar-Cohen F, Sahel JA, Guillonneau X, Raoul W, Combadiere C (2013) CCR2(+) monocytes infiltrate atrophic lesions in age- related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. EMBO Mol Med 5:1775-1793. doi:10.1002/emmm.201302692.

Shukla P, Russell MW, Muste JC, Shaia JK, Kumar M, Nowacki AS, Hajj-Ali RA, Singh RP, Talcott KE. Propensity-Matched Analysis of the Risk of Age-Related Macular Degeneration with Systemic Immune- Mediated Inflammatory Disease. Ophthalmol Retina. 2024 Aug;8(8):778-785. doi: 10.1016/j.oret.2024.01 .026. Epub 2024 Feb 4. PMID: 38320691.

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Clauses A

1. A compound of formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

W is CR⁸ or N;

X and Y are independently CR⁹ or N;

R³ is selected from the group consisting of: 008806333

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R⁵ is H or C1-4 alkyl;

R¹⁰ is H, C1- alkyl, C1-4 haloalkyl, -(C1-4 alkylene)OH, or -(C1-4 alkylene)-O-(Ci-4 alkyl);

A is NR¹², S, or O; m is 1 , 2, or 3; and each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alky ny I, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(C3-8 cycloalkyl), -0(Ci-6 haloalkyl), -(C1-6 alkylene)OH, -(C1-4 alkylene)-0-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), amino, -NH(CI-6 alkyl), -N(CI-6 alky 1)2 , -NH(CI-6 alkylene)OH, -NH(CI-6 alkylene)0(Ci-4 alkyl), -(C1-6 alkylene)NH₂, -C(=O)OH, -C(=0)0(Ci-₄ alkyl), -C(=O)NH₂, -C(=O)NH(Ci- 4 alkyl), -C(=0)N(CI-4 alkyl)₂, cyano, -SO₂(Ci-6 alkyl), -SO(Ci-₆ alkyl), -S(Ci-₆ alkyl), -SO₂NH(CI-₆ alkyl), -SO₂N(CI-₆ alkyl)2, -S0NH(CI-6 alkyl), -S0N(CI-6 alkyl)2, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; and

R¹² is selected from the group consisting of H, D, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alky ny I, C1-6 haloalkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-0-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), -(C1-6 alkylene)NH2, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of R¹² is optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

2. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

1 , wherein when Z is S or O, at least one of X or Y is N. 008806333

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3. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 1 , wherein when Z is NR¹⁰, X is not N.

4. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 1 , wherein the moiety: in formula (I) is not furanyl, thiophenyl, or pyrrolyl.

5. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 1 , wherein the moiety: in formula (I) is not furanyl, thiophenyl, pyrrolyl, or imidazolyl.

6. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein W is CR⁸.

7. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein W is CH.

8. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein X is N.

9. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein Y is CR⁹.

10. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein Z is S.

11. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein the moiety: in formula (I) is selected from the group consisting of: 008806333

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12. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 11 , wherein the moiety:

13. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

12, wherein the moiety: in formula (I) is selected from the group consisting of:

14. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

13, wherein the moiety:

15. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl.

16. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

15, wherein R¹ is methyl, fluoro, chloro, or trifluoromethyl.

17. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

16, wherein R¹ is methyl or chloro.

18. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

17, wherein R¹ is methyl. 008806333

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19. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R² is H.

20. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R³ is selected from the group consisting of:

21. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

20, wherein R³ is:

22. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

20 or 21 , wherein R³ is:

23. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 19, wherein R³ is selected from the group consisting of: 008806333

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5 008806333

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24. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 20 to 23, wherein R³ is:

25. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 20 to 24, wherein R³ is:

26. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein m is 1 or 2.

27. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 26, wherein m is 1 .

28. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, amino, -N(CI-6 alkyl)2, -NH(CI-6 alkylene)OH, -NH(CI-6 alkylene)O(Ci-4 008806333

122 alkyl), -C(=O)OH, -C(=O)O(Ci-4 alkyl), cyano, -SO2(Ci-6 alkyl), and 3- to 8-membered heterocycloalkyl; wherein the carbon ring atoms of C3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

29. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 28, wherein each R¹¹ is independently selected from the group consisting of H, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me,

1 -piperidinyl, 3-hydroxypiperidin-1-yl, D, -(CH2)2OH, -CH2CH(CH3)OH, -CH2CHF2, and - CH₂CH(CH3)OH.

30. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁴ is H.

31. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁵ is H.

32. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), -(C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH.

33. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

32, wherein R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, - CH(CH₃)OH, and -OCH2CH2OH.

34. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

33, wherein R⁶ is OH.

35. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁷ is H, C1-4 alkyl, or C1-4 difluoroalkyl.

36. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

35, wherein R⁷ is H or Me.

37. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

36, wherein R⁷ is Me.

38. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁸ is H. 008806333

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39. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁹ is H or CM alkyl.

40. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

39, wherein R⁹ is H or Me.

41. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

40, wherein R⁹ is Me.

42. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 40, wherein R⁹ is H.

43. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R¹⁰ is H or C1-4 alkyl.

44. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

43, wherein R¹⁰ is H or Me.

45. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

44, wherein R¹⁰ is Me.

46. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein A is NR¹².

47. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R¹² is selected from the group consisting of H, C1-6 alkyl, -(0-6 alkylene)OH, -(C1- alkylene)-O-(Ci-4 alkyl), -(0-6 haloalkylene)OH, -(C1- haloalkylene)-O-(Ci-4 alkyl), and -(Ci-6 alkylene)NH2.

48. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

47, wherein R¹² is selected from the group consisting of H, methyl, -(CH2)2OH, -CH2CH(CH3)OH, - CH₂C(CH₃)2OH, -CH₂CH(CH₂CH₃)OH, -CH₂OCH₃, -CH₂CH(CH₃)OCH₃, -CH₂CH(CH₂F)OH, - CH₂CHFCH₂OCH₃, and -(CH₂)₂NH2.

49. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

48, wherein R¹² is H or Me.

50. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein X is N, Y is CR⁹, and Z is S. 008806333

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51. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 50, wherein R⁹ is H.

52. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 50 or 51 , wherein R⁷ is Me.

53. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R³ is: , and m is 1 or 2.

54. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

53, wherein R³ is: , and m is 1 .

55. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any clause 53, wherein R³ is: , m is 1 or 2, and R¹¹ is fluoro.

56. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 53 to 55, wherein R³ is: , m is 1 , and R¹¹ is fluoro.

57. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R¹ is Me, R² is H, and R⁴ is H.

58. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

57, wherein W is CR⁸.

59. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

58, wherein W is CH.

60. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁵ is H and R⁶ is OH. 008806333

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61. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 1 , wherein the compound is a compound in TABLE 2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

62. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable carrier.

63. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, for use as a medicament.

64. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, for use in the prevention and/or treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor.

65. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, for use in the prevention and/or treatment of a condition selected from all forms of age-related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases.

66. Use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, for the manufacture of a medicament for a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor.

67. Use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, for the manufacture of a medicament for a condition selected from all forms of age-related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, neuroinflammatory, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic 008806333

126 diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases.

68. A method of treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor, wherein the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, to a patient in need thereof.

69. A method of treatment of a condition selected from all forms of age-related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, cognitive, neuroinflammatory, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases, wherein the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 61 , or a pharmaceutical composition according to clause 62, to a patient in need thereof.

70. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use according to clause 65, or the use according to clause 67, or the method of treatment according to clause 69, wherein the condition is age-related macular degeneration (AMD).

71. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is early AMD.

72. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is intermediate AMD.

73. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is late AMD. 008806333

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74. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is choroidal neovascular AMD.

75. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is geographic atrophy AMD.

76. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is central geographic atrophy AMD.

77. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is peripheral geographic atrophy AMD.

78. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is exudative AMD.

79. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 70, wherein the age-related macular degeneration (AMD) is non-exudative AMD.

80. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use according to clause 65, or the use according to clause 67, or the method of treatment according to clause 69, wherein the condition is diabetic retinopathy (DR).

81. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 80, wherein the diabetic retinopathy (DR) is early diabetic retinopathy.

82. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 80, wherein the diabetic retinopathy (DR) is non-proliferative diabetic retinopathy (NPDR).

83. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 82, 008806333

128 wherein the non-proliferative diabetic retinopathy (NPDR) is early non-proliferative diabetic retinopathy (NPDR).

84. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 82, wherein the non-proliferative diabetic retinopathy (NPDR) is moderate non-proliferative diabetic retinopathy (NPDR).

85. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 82, wherein the non-proliferative diabetic retinopathy (NPDR) is moderate-severe non-proliferative diabetic retinopathy (NPDR).

86. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 82, wherein the non-proliferative diabetic retinopathy (NPDR) is severe non-proliferative diabetic retinopathy (NPDR).

87. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 80, wherein the diabetic retinopathy (DR) is proliferative diabetic retinopathy (PDR).

88. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 87, wherein the proliferative diabetic retinopathy (PDR) is early proliferative diabetic retinopathy (PDR).

89. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 87, wherein the proliferative diabetic retinopathy (PDR) is moderate proliferative diabetic retinopathy (PDR).

90. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 87, wherein the proliferative diabetic retinopathy (PDR) is moderate-severe proliferative diabetic retinopathy (PDR).

91. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 87, wherein the proliferative diabetic retinopathy (PDR) is severe proliferative diabetic retinopathy (PDR). 008806333

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92. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use according to clause 65, or the use according to clause 67, or the method of treatment according to clause 69, wherein the condition is diabetic macular edema (DME).

93. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 92, wherein the diabetic macular edema (DME) is centre-involved macular edema (DME).

94. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 92, wherein the diabetic macular edema (DME) is peripheral diabetic macular edema (DME).

95. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 92, wherein the diabetic macular edema (DME) is early diabetic macular edema (DME).

96. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 92, wherein the diabetic macular edema (DME) is early centre-involved macular edema (DME).

97. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 92, wherein the diabetic macular edema (DME) is early peripheral diabetic macular edema (DME).

98. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use according to clause 65, or the use according to clause 67, or the method of treatment according to clause 69, wherein the condition is glaucoma.

99. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 98, wherein the glaucoma is glaucoma secondary to ocular hypertension.

100. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 98, wherein the glaucoma is normal tension glaucoma. 008806333

130

101 . The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use according to clause 65, or the use according to clause 67, or the method of treatment according to clause 69, wherein the condition is retinal vein occlusion (RVO).

102. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 101 , wherein the retinal vein occlusion (RVO) is branched vein retinal vein occlusion (RVO).

103. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use, or the use, or the method of treatment according to clause 101 , wherein the retinal vein occlusion (RVO) is central vein retinal vein occlusion (RVO).

104. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition for use according to clause 65, or the use according to clause 67, or the method of treatment according to clause 69, wherein the condition is choroidal neovascular myopia.

008806333

131

Clauses B

1. A compound of formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: W is OR⁸ or N;

X and Y are independently OR⁹ or N;

R¹, R², R⁴, and R⁸ are independently selected from the group consisting of H, D, C1-6 alkyl, halo, and C1-6 haloalky I, and -0(0-6 alkyl);

R³ is selected from the group consisting of:

R⁵ is H or C1-4 alkyl;

A is NR¹², S, or O; m is 1 , 2, or 3; and each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alky ny I, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(C3-8 cycloalkyl), -0(Ci-6 haloalkyl), -(C1-6 alkylene)OH, -(C1-4 alkylene)-0-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), amino, -NH(CI-6 alkyl), -N(CI-6 alky 1)2 , -NH(CI-6 alkylene)OH, -NH(CI-6 008806333

132 alkylene)O(Ci-₄ alkyl), -(C1-6 alkylene)NH₂, -C(=O)OH, -C(=O)O(Ci-₄ alkyl), -C(=O)NH₂, -C(=O)NH(Ci- 4 alkyl), -C(=O)N(CI-4 alkyl)₂, cyano, -SO₂(Ci-₆ alkyl), -SO(Ci-₆ alkyl), -S(Ci-₆ alkyl), -SO₂NH(CI-₆ alkyl), -SO₂N(CI-6 alkyl)₂, -SONH(CI-6 alkyl), -SON(CI-6 alkyl)₂, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; and

R¹² is selected from the group consisting of H, D, C1-6 alkyl, C3-8 cycloalkyl, C₂-6 alkenyl, C₂-6 alky ny I, C1-6 haloalky I, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), -(C1-6 alkylene)NH₂, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of R¹² is optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl.

2. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 1 , wherein W is CR⁸; optionally wherein W is CH.

3. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause

1 or 2, wherein the moiety: in formula (I) is selected from the group consisting of: optionally wherein the moiety optionally wherein the moiety in formula (I) is selected from the group consisting of: optionally wherein the moiety in formula (I) is 008806333

133

4. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl; optionally wherein R¹ is methyl, fluoro, chloro, or trifluoromethyl; optionally wherein R¹ is methyl or chloro; optionally wherein R¹ is methyl; optionally wherein R² is H; optionally wherein R⁴ is H.

5. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R³ is selected from the group consisting of: or wherein R³ is selected from the group consisting of: 008806333

134

5 008806333

135 optionally wherein R³ is:

6. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein m is 1 or 2; optionally wherein m is 1 ; optionally wherein each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, amino, -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-₄ alkyl), -C(=O)OH, -C(=O)O(Ci-4 alkyl), cyano, -SO2(Ci-6 alkyl), and 3- to 8-membered heterocycloalkyl; wherein the carbon ring atoms of C3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; optionally wherein each R¹¹ is independently selected from the group consisting of H, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me, 1 -piperidinyl, 3-hydroxypiperidin-1-yl, D, -(CH2)2OH, -CH2CH(CH3)OH, -CH2CHF2, and - CH₂CH(CH3)OH.

7. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁵ is H; optionally wherein R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), - (C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH; optionally wherein R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, -CH(CH₃)OH, and -OCH2CH2OH; optionally wherein R⁶ is OH. 008806333

136

8. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R⁷ is H, C1-4 alkyl, or C1-4 difluoroalkyl; optionally wherein R⁷ is H or Me; optionally wherein R⁸ is H. optionally wherein R⁹ is H or C1-4 alkyl; optionally wherein R⁹ is H or Me. optionally wherein R¹⁰ is H or C1-4 alkyl; optionally wherein R¹⁰ is H or Me; optionally wherein R¹⁰ is Me.

9. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein A is NR¹².

10. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding clauses, wherein R¹² is selected from the group consisting of H, C1-6 alkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), and -(C1-6 alkylene)NH2; optionally wherein R¹² is selected from the group consisting of H, methyl, -(CH2)2OH, - CH₂CH(CH₃)OH, -CH₂C(CH₃)2OH, -CH₂CH(CH₂CH₃)OH, -CH₂OCH₃, -CH₂CH(CH₃)OCH₃, - CH₂CH(CH₂F)OH, -CH₂CHFCH₂OCH₃, and -(CH₂)2NH₂; optionally wherein R¹² is H or Me.

11. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to clause 1 , wherein the compound is a compound in TABLE 2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 11 , a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable carrier.

13. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 11 , or a pharmaceutical composition according to clause 12, for use as a medicament.

14. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of clauses 1 to 11 , or a pharmaceutical composition according to clause 12, for use in the prevention and/or treatment of a condition selected from all forms of age-related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases. 008806333

137

15. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition for use according to clause 14, wherein the condition is selected from: age-related macular degeneration (AMD), optionally wherein the age-related macular degeneration (AMD) is selected from early AMD, intermediate AMD, late AMD, choroidal neovascular AMD, geographic atrophy AMD, central geographic atrophy AMD, peripheral geographic atrophy AMD, exudative AMD, and non-exudative AMD; diabetic retinopathy (DR), optionally wherein the diabetic retinopathy (DR) is selected from early DR, non-proliferative diabetic retinopathy (NPDR), early non-proliferative diabetic retinopathy (NPDR), moderate non-proliferative diabetic retinopathy (NPDR), moderate-severe non-proliferative diabetic retinopathy (NPDR), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), early proliferative diabetic retinopathy (PDR), moderate proliferative diabetic retinopathy (PDR), moderate-severe proliferative diabetic retinopathy (PDR), and severe proliferative diabetic retinopathy (PDR); diabetic macular edema (DME), optionally wherein the diabetic macular edema (DME) is selected from centre-involved DME, peripheral DME, early DME, early centre-involved DME, and early peripheral DME; glaucoma, optionally wherein the glaucoma is selected from glaucoma secondary to ocular hypertension, and normal tension glaucoma; retinal vein occlusion (RVO), optionally wherein the retinal vein occlusion (RVO) is selected from branched vein RVO and central vein RVO; and choroidal neovascular myopia.

Claims

008806333 138 Claims:

X and Y are independently OR⁹ or N;

R³ is selected from the group consisting of:

R⁵ is H or C1-4 alkyl;

139 alkylene)O(Ci-₄ alkyl), -(C1-6 alkylene)NH₂, -C(=O)OH, -C(=O)O(Ci-₄ alkyl), -C(=O)NH₂, -C(=O)NH(Ci- 4 alkyl), -C(=O)N(CI-4 alkyl)₂, cyano, -SO₂(Ci-₆ alkyl), -SO(Ci-₆ alkyl), -S(Ci-₆ alkyl), -SO₂NH(CI-₆ alkyl), -SO₂N(CI-6 alkyl)₂, -SONH(CI-6 alkyl), -SON(CI-6 alkyl)₂, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl; wherein the carbon ring atoms of C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-io aryl, and 5- to 10-membered heteroaryl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; and

2. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 1 , wherein W is CR⁸; optionally wherein W is CH.

3. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 1 or 2, wherein the moiety: in formula (I) is selected from the group consisting of: optionally wherein the moiety optionally wherein the moiety in formula (I) is selected from the group consisting of: optionally wherein the moiety in formula (I) is 008806333

140

4. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein R¹ is C1-6 alkyl, halo, or C1-6 haloalkyl; optionally wherein R¹ is C1-6 alkyl or halo; optionally wherein R¹ is methyl, fluoro, chloro, or trifluoromethyl; optionally wherein R¹ is methyl, fluoro, or chloro; optionally wherein R¹ is methyl or chloro; optionally wherein R¹ is methyl; optionally wherein R² is H; optionally wherein R⁴ is H.

5. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein R³ is selected from the group consisting of: or wherein R³ is selected from the group consisting of: 008806333

141

5 008806333

142

6. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein m is 1 or 2; optionally wherein m is 1 ; optionally wherein each R¹¹ is independently selected from the group consisting of H, D, OH, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -(C1-6 alkylene)OH, amino, -N(CI-₆ alkyl)₂, -NH(CI-₆ alkylene)OH, -NH(CI-₆ alkylene)O(Ci-₄ alkyl), -C(=O)OH, -C(=O)O(Ci-4 alkyl), cyano, -SO2(Ci-6 alkyl), and 3- to 8-membered heterocycloalkyl; wherein the carbon ring atoms of C3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl of each R¹¹ is independently optionally substituted with a group selected from D, OH, amino, halo, and C1-3 fluoroalkyl; optionally wherein each R¹¹ is independently selected from the group consisting of H, OH, methyl, ethyl, isopropyl, cyclopropyl, -CCH, fluoro, -CF3, -CHF2, -OMe, -OCF3, -OCHF2, -OCH2CF3, -CH2OH, amino, -NMe₂, -NH(CH₂)₂OH, -NH(CH₂)₃OMe, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, cyano, -SO₂Me, 008806333

143

1 -piperidinyl, 3-hydroxypiperidin-1-yl, D, -(CH2)2OH, -CH2CH(CH3)OH, -CH2CHF2, and - CH₂CH(CH₃)OH.

7. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein R⁵ is H; optionally wherein R⁶ is selected from the group consisting of OH, C1-6 alkyl, halo, -O(Ci-6 alkyl), - (C1-6 alkylene)OH, and -O(Ci-6 alkylene)OH; optionally wherein R⁶ is selected from the group consisting of OH, methyl, fluoro, -OMe, -CH2OH, -CH(CH₃)OH, and -OCH2CH2OH; optionally wherein R⁶ is OH.

8. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein R⁷ is H, C1-4 alkyl, or C1-6 haloalkyl; optionally wherein R⁷ is H, C1-4 alkyl, or C1-4 difluoroalkyl; optionally wherein R⁷ is H or C1-4 alkyl; optionally wherein R⁷ is H or Me; optionally wherein R⁸ is H. optionally wherein R⁹ is H or C1-4 alkyl; optionally wherein R⁹ is H or Me. optionally wherein R¹⁰ is H or C1-4 alkyl; optionally wherein R¹⁰ is H or Me; optionally wherein R¹⁰ is Me.

9. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein A is NR¹².

10. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the preceding claims, wherein R¹² is selected from the group consisting of H, C1-6 alkyl, -(C1-6 alkylene)OH, -(C1-4 alkylene)-O-(Ci-4 alkyl), -(C1-6 haloalkylene)OH, -(C1-4 haloalkylene)-O-(Ci-4 alkyl), and -(C1-6 alkylene)NH2; optionally wherein R¹² is selected from the group consisting of H, methyl, -(CH2)2OH, - CH₂CH(CH₃)OH, -CH₂C(CH₃)₂OH, -CH₂CH(CH₂CH₃)OH, -CH₂OCH₃, -CH₂CH(CH₃)OCH₃, - CH₂CH(CH₂F)OH, -CH₂CHFCH₂OCH₃, and -(CH₂)2NH₂; optionally wherein R¹² is H or Me.

11. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim

1 , wherein the compound is: 008806333

144 008806333

145 008806333

146 008806333

147 008806333

148 008806333

149 008806333

150 008806333

151 008806333

152 008806333

153 008806333

154 008806333

155 or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable carrier.

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

14. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , or a pharmaceutical composition according to claim 12, for use in the prevention and/or treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor.

15. A compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , or a pharmaceutical composition according to claim 12, for use in the prevention and/or treatment of a condition selected from all forms of age-related macular degeneration (AMD), 008806333

156 all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, cognitive, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases.

16. The compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition for use according to claim 14 or 15, wherein the condition is selected from: age-related macular degeneration (AMD), optionally wherein the age-related macular degeneration (AMD) is selected from early AMD, intermediate AMD, late AMD, choroidal neovascular AMD, geographic atrophy AMD, central geographic atrophy AMD, peripheral geographic atrophy AMD, exudative AMD, and non-exudative AMD; diabetic retinopathy (DR), optionally wherein the diabetic retinopathy (DR) is selected from early DR, non-proliferative diabetic retinopathy (NPDR), early non-proliferative diabetic retinopathy (NPDR), moderate non-proliferative diabetic retinopathy (NPDR), moderate-severe non-proliferative diabetic retinopathy (NPDR), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), early proliferative diabetic retinopathy (PDR), moderate proliferative diabetic retinopathy (PDR), moderate-severe proliferative diabetic retinopathy (PDR), and severe proliferative diabetic retinopathy (PDR); diabetic macular edema (DME), optionally wherein the diabetic macular edema (DME) is selected from centre-involved DME, peripheral DME, early DME, early centre-involved DME, and early peripheral DME; glaucoma, optionally wherein the glaucoma is selected from glaucoma secondary to ocular hypertension, and normal tension glaucoma; retinal vein occlusion (RVO), optionally wherein the retinal vein occlusion (RVO) is selected from branched vein RVO and central vein RVO; and choroidal neovascular myopia.

17. Use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor.

18. Use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for a condition selected from all forms of age-related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, neuroinflammatory, cognitive, psychiatric disorders, 008806333

157 neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, autoimmune and allergic diseases, cancer and proliferative diseases.

19. The use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or use of a pharmaceutical composition, for the manufacture of a medicament according to claim 17 or 18 for a condition selected from: age-related macular degeneration (AMD), optionally wherein the age-related macular degeneration (AMD) is selected from early AMD, intermediate AMD, late AMD, choroidal neovascular AMD, geographic atrophy AMD, central geographic atrophy AMD, peripheral geographic atrophy AMD, exudative AMD, and non-exudative AMD; diabetic retinopathy (DR), optionally wherein the diabetic retinopathy (DR) is selected from early DR, non-proliferative diabetic retinopathy (NPDR), early non-proliferative diabetic retinopathy (NPDR), moderate non-proliferative diabetic retinopathy (NPDR), moderate-severe non-proliferative diabetic retinopathy (NPDR), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), early proliferative diabetic retinopathy (PDR), moderate proliferative diabetic retinopathy (PDR), moderate-severe proliferative diabetic retinopathy (PDR), and severe proliferative diabetic retinopathy (PDR); diabetic macular edema (DME), optionally wherein the diabetic macular edema (DME) is selected from centre-involved DME, peripheral DME, early DME, early centre-involved DME, and early peripheral DME; glaucoma, optionally wherein the glaucoma is selected from glaucoma secondary to ocular hypertension, and normal tension glaucoma; retinal vein occlusion (RVO), optionally wherein the retinal vein occlusion (RVO) is selected from branched vein RVO and central vein RVO; and choroidal neovascular myopia.

20. A method of treatment of a condition susceptible of being improved or prevented by inhibition of the P2X7 receptor, wherein the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , or a pharmaceutical composition according to claim 12, to a patient in need thereof.

21. A method of treatment of a condition selected from all forms of age-related macular degeneration (AMD), all forms of diabetic retinopathy (DR), all forms of diabetic macular edema (DME), all forms of glaucoma, all forms of retinal vein occlusion (RVO), choroidal neovascular myopia, neurological, neurodegenerative, cognitive, neuroinflammatory, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, inflammatory processes of the musculoskeletal system, gastrointestinal tract disorders, genitourinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, 008806333

158 autoimmune and allergic diseases, cancer and proliferative diseases, wherein the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1 to 11 , or a pharmaceutical composition according to claim 12, to a patient in need thereof.

22. The method of treatment of a condition according to claim 20 or 21 , wherein the condition is selected from: age-related macular degeneration (AMD), optionally wherein the age-related macular degeneration (AMD) is selected from early AMD, intermediate AMD, late AMD, choroidal neovascular AMD, geographic atrophy AMD, central geographic atrophy AMD, peripheral geographic atrophy AMD, exudative AMD, and non-exudative AMD; diabetic retinopathy (DR), optionally wherein the diabetic retinopathy (DR) is selected from early DR, non-proliferative diabetic retinopathy (NPDR), early non-proliferative diabetic retinopathy (NPDR), moderate non-proliferative diabetic retinopathy (NPDR), moderate-severe non-proliferative diabetic retinopathy (NPDR), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), early proliferative diabetic retinopathy (PDR), moderate proliferative diabetic retinopathy (PDR), moderate-severe proliferative diabetic retinopathy (PDR), and severe proliferative diabetic retinopathy (PDR); diabetic macular edema (DME), optionally wherein the diabetic macular edema (DME) is selected from centre-involved DME, peripheral DME, early DME, early centre-involved DME, and early peripheral DME; glaucoma, optionally wherein the glaucoma is selected from glaucoma secondary to ocular hypertension, and normal tension glaucoma; retinal vein occlusion (RVO), optionally wherein the retinal vein occlusion (RVO) is selected from branched vein RVO and central vein RVO; and choroidal neovascular myopia.