N-cyanopyrrolidines with activity as inhibitors of the USP30

Abstract

The present invention provides compounds of formula (I) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: (a) X1 is CR4a and X2 is N, or (b) X1 is N and X2 is CR4b; X3, X4 and X5 are each independently selected from N, CR4c, CR4d and CR4e; R1 is selected from hydrogen, (C1-C4)alkyl, (C1-C4)fluoroalkyl, CH2O(C1-C4)alkyl, CH2N((C1-C4)alkyl)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl; wherein the pyrazolyl and triazolyl rings are optionally substituted by one to three methyl groups; R2 is selected from hydrogen, (C1-C4)alkyl, cyclopropyl and (C1-C4)fluoroalkyl; R3 is selected from hydrogen, halo, (C1-C4)alkyl, cyclopropyl and (C1-C4)alkoxy; R4a, R4b, R4c, R4d and R4e are each independently selected from hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, CN, hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy and (C1-C6)alkoxy(C1-C6)alkyl; ring A is selected from: (i) phenyl; (ii) a 5 to 6-membered monocyclic heteroaryl ring comprising one to four heteroatoms, each independently selected from N, O and S; and (iii) a 9 to 10-membered bicyclic heteroaryl ring comprising 1 to 4 heteroatoms, each independently selected from N, O and S; ring A is either unsubstituted or substituted by one to five substituents selected from R5, R6, R7, R8 and R9; and R5, R6, R7, R8 and R9 are each independently selected from halo, CN, hydroxy, NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, hydroxy(C2-C6)alkoxy, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, halo(C3-C6)cycloalkoxy, hydroxy(C3-C6)cycloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxy(C3-C6)cycloalkyl, (C1-C6)alkoxy(C3-C6)cycloalkoxy, (C3-C6)cycloalkoxy(C1-C6)alkyl, (C3-C6)cycloalkoxy(C1-C6)alkoxy, oxetanyl, oxetanyloxy, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C3-C6)cycloalkyl, N((C3-C6)cycloalkyl)2, N((C1-C6)alkyl)((C3-C6)cycloalkyl)), C(O)NH(C1-C6)alkyl, C(O)N((C1-C6)alkyl)2, NHC(O)(C1-C6)alkyl, N(C1-C6)alkyl)C(O)(C1-C6)alkyl), C(O)(C1-C6)alkyl, C(O)O(C1-C6)alkyl, P052-WO CO2H, CONH2, SO2NH(C1-C6)alkyl and SO2N((C1-C6)alkyl)2. The compounds have activity as inhibitors of the deubiquitylating enzyme ubiquitin C-terminal hydrolase 30, also known as ubiquitin specific peptidase 30 (USP30), uses thereof, processes for the preparation thereof and composition containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas, including cancer and conditions involving mitochondrial dysfunction.

Description

[0001] N-CYANOPYRROLIDINES WITH ACTIVITY AS INHIBITORS OF THE USP30

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a class of N-cyanopyrrolidines with activity as inhibitors of the deubiquitylating enzyme ubiquitin C-terminal hydrolase 30, also known as ubiquitin specific peptidase 30 (USP30), uses thereof, processes for the preparation thereof and composition containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas, including cancer and conditions involving mitochondrial dysfunction.

[0004] All documents cited or relied upon below are expressly incorporated herein by reference.

[0005] BACKGROUND OF THE INVENTION

[0006] Ubiquitin is a small protein consisting of 76 amino acids that is important for the regulation of protein function in the cell. Ubiquitylation and deubiquitylation are enzymatically mediated processes by which ubiquitin is covalently bound or cleaved from a target protein by deubiquitylating enzymes (DUBs), of which there are approximately 100 DUBs in human cells, divided into sub-families based on sequence homology. The USP family are characterised by their common Cys and His boxes which contain Cys and His residues critical for their DUB activities. The ubiquitylation and deubiquitylation processes have been implicated in the regulation of many cellular functions including cell cycle progression, apoptosis, modification of cell surface receptors, regulation of DNA transcription and DNA repair. Thus, the ubiquitin system has been implicated in the pathogenesis of numerous disease states including inflammation, viral infection, metabolic dysfunction, CNS disorders, and oncogenesis.

[0007] Ubiquitin is a master regulator of mitochondrial dynamics. Mitochondria are dynamic organelles whose biogenesis, fusion and fission events are regulated by the post-translational regulation via ubiquitylation of many key factors such as mitofusins. In humans, USP30 is a 517 amino acid protein which is found in the mitochondrial outer membrane (Nakamura et al, 2008, Mol Biol 19:1903-11). It is the sole deubiquitylating enzyme bearing a mitochondrial addressing signal and has been shown to deubiquitylate a number of mitochondrial proteins. It has been demonstrated that USP30 opposes parkin-mediated mitophagy and that reduction of USP30 activity can rescue parkin-mediated defects in mitophagy (Bingol et al, 2015, Nature 510:370-5; Gersch et al, 2017, Nat Struct Mol Biol 24(11): 920-930; Cunningham et al, 2015, Nat Cell Biol 17(2): 160-169). USP30 inactivation can also increase mitochondrial protein import, potentially through ubiquitylation of TOM proteins (Jacoupy et al, 2019, Sci Rep 9(1): 11829). A small proportion of USP30 has been localized to peroxisomes, which are generated through fusion of mitochondrial and ER vesicles, with USP30 potentially antagonizing the Pex2 / pexophagy pathway (Riccio et al, 2019, J Cell Biol 218(3): 798-807). The E3 Ub ligase March5 and the deubiquitinase USP30 associate with the translocase and regulate mitochondrial import, and while March5 opposes mitochondrial import and directs degradation of substrates, USP30 deubiquitinates substrates to promote their import (Phu et al, 2020, Molecular Cell 77, 1107-1123).Mitochondrial dysfunction can be defined as diminished mitochondrial content (mitophagy or mitochondrial biogenesis), as a decrease in mitochondrial activity and oxidative phosphorylation, but also as modulation of reactive oxygen species (ROS) generation. Hence a role for mitochondrial dysfunctions in a very large number of aging processes and pathologies.

[0008] For example, Parkinson’s disease (PD) affects around 10 million people worldwide (Parkinson’s Disease Foundation) and is characterised by the loss of dopaminergic neurons in the substantia nigra. The exact mechanisms underlying PD are unclear; however mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of both familial and sporadic disease, as well as in toxin-induced Parkinsonism. Parkin is one of a number of proteins that have been implicated with early onset PD. While most PD cases are linked to defects in alpha-synuclein, 10% of Parkinson’s cases are linked to specific genetic defects, one of which is in the ubiquitin E3 ligase parkin. Parkin and the protein kinase PTEN-induced putative kinase 1 (PINK1) collaborate to ubiquitylate mitochondrial membrane proteins of damaged mitochondria resulting in mitophagy. Dysregulation of mitophagy results in increased oxidative stress, which has been described as a characteristic of PD. Inhibition of USP30 could therefore be a potential strategy for the treatment of PD. For example, PD patients with parkin mutations leading to reduced activity could be therapeutically compensated by inhibition of USP30.

[0009] It has been reported that depletion of USP30 enhances mitophagic clearance of mitochondria and also enhances parkin-induced cell death. USP30 has also been shown to regulate BAX / BAK-dependent apoptosis independently of parkin overexpression. Depletion of USP30 sensitises cancer cells to BH-3 mimetics such as ABT-737, without the need for parkin overexpression. Thus, an anti-apoptotic role has been demonstrated for USP30 and USP30 is therefore a potential target for anti -cancer therapy. The ubiquitin-proteasome system has gained interest as a target for the treatment of cancer following the approval of the proteasome inhibitor bortezomib (Velcade®) for the treatment of multiple myeloma. Extended treatment with bortezomib is limited by its associated toxicity and drug resistance. However, therapeutic strategies that target specific aspects of the ubiquitin-proteasome pathway upstream of the proteasome, such as DUBs, are predicted to be better tolerated (Bedford et al, 2011, Nature Rev 10:29-46).

[0010] Fibrotic diseases, including renal, hepatic and pulmonary fibrosis, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrosis is considered to be the result of acute or chronic stress on the tissue or organ, characterized by extracellular matrix deposition, reduction of vascular / tubule / duct / airway patency and impairment of function ultimately resulting in organ failure. Many fibrotic conditions are promoted by lifestyle or environmental factors; however, a proportion of fibrotic conditions can be initiated through genetic triggers or indeed are considered idiopathic (i.e., without a known cause). Certain fibrotic disease, such as idiopathic pulmonary fibrosis (IPF), canbe treated with non-specific kinase inhibitor (nintedanib) or drugs without a well-characterized mechanism of action (pirfenidone). Other treatments for organ fibrosis, such as kidney or liver fibrosis, alleviate pressure on the organ itself (e.g., beta blockers for cirrhosis, angiotensin receptor blockers for chronic kidney disease). Attention to lifestyle factors, such as glucose and diet control, may also influence the course and severity of disease.

[0011] Mitochondrial dysfunction has been implicated in a number of fibrotic diseases, with oxidative stress downstream of dysfunction being the key pathogenic mediator, alongside decreased ATP production. In preclinical models, disruption of the mitophagy pathway (through mutation or knockout of either parkin or PINK1) exacerbates lung fibrosis and kidney fibrosis, with evidence of increased oxidative stress.

[0012] Kurita et al, 2017, Respiratory Research 18:114, discloses that accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodelling in IPF. Recent findings are said to show participation of autophagy / mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis, and that mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. Kurita’s results suggested that pirfenidone induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms for IPF treatment.

[0013] Williams et al, 2015, Pharmacol Res. December; 102: 264-269, discuss the role of PINK 1 -Parkin-mediated autophagy in protecting against alcohol and acetaminophen-induced liver injury by removing damaged mitochondria via mitophagy. It is suggested that pharmacological stabilization of USP8 or inactivation of USP15 and USP30 may be potential therapeutic targets for upregulating Parkin-induced mitophagy and in turn protect against drug-induced liver injury. However, it is noted that the DUBs are regulated both transcriptionally and post-translationally, which may make drug development for targeting these specific enzymes challenging, and in addition, phosphorylated ubiquitin was shown to be resistant to DUBs. The authors conclude that upregulating PINK1 stabilization or kinase activity may be a more effective target than inhibiting DUBs.

[0014] Williams et al, 2015, Biomolecules 5, 2619-2642, and Williams et al, 2015, Am J Physiol Gastrointest Liver Physiol 309: G324–G340, review mechanisms involved in regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease. Luciani et al, 2020, Nat. Commun. 11, 970, reports deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders, including methylmalonic acidemia (MMA). MMA is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl-coenzyme A mutase (MMUT). MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK 1 / Parkin-mediated mitophagy,causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. A link is suggested between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and potential therapeutic perspectives for MMA is provided.

[0015] Kluge et al, Bioorganic & Medicinal Chemistry Letters, 2018, 28 2655-2659, reports that selective inhibitors of USP30 accelerate mitophagy.

[0016] Series of derivatives of N-cyano-substituted heterocycles are disclosed as deubiquitylating enzyme inhibitors in PCT applications WO 2016 / 046530 (US 15 / 513125, US 15 / 894025, US 16 / 448066), WO 2016 / 156816 (US 15 / 558632, US 16 / 297937, US 16 / 419558, US 16 / 419747, US 16 / 788446), WO 2017 / 009650 (US 15 / 738900), WO 2017 / 093718 (US 15 / 776149), WO 2017 / 103614 (US 15 / 781615), WO 2017 / 149313 (US 16 / 078518), WO 2017 / 109488 (US 16 / 060299), WO 2017 / 141036 (US 16 / 070936), WO 2017 / 163078 (US 16 / 087515), WO 2017 / 158381 (US 16 / 080229), WO 2017 / 158388 (US 16 / 080506), WO 2018 / 065768 (US 16 / 336685), WO 2018 / 060742 (US 16 / 336202), WO 2018 / 060689 (US 16 / 334836), WO 2018 / 060691 (US 16 / 336363), WO 2018 / 220355 (US 16 / 615040), WO 2018 / 234775 (US 16 / 615709), WO 2020 / 212350, WO 2020 / 212351, WO 2021 / 043870 (US 17 / 639015), WO 2021 / 204856 (US 17 / 914414), WO 2021 / 239863 (US 17 / 927053), WO 2021 / 245186 (US 18 / 007641), WO 2021 / 249909 (US 18 / 008352), WO 2022 / 084479 and WO 2023 / 099561, each of which are expressly incorporated herein by reference. PCT application WO 2019 / 171042 (US 16 / 977019), which is expressly incorporated herein by reference, discloses the use of N-cyanopyrrolidines as inhibitors of USP30 for the treatment of fibrotic diseases.

[0017] Falgueyret et al, 2001, J. Med. Chem. 44, 94-104, and PCT application WO 01 / 77073 refer to cyanopyrrolidines as inhibitors of Cathepsins K and L, with potential utility in treating osteoporosis and other bone-resorption related conditions. PCT application WO 2015 / 179190 refers to N-acylethanolamine hydrolysing acid amidase inhibitors, with potential utility in treating ulcerative colitis and Crohn’s disease. PCT application WO 2013 / 030218 refers to quinazolin-4-one compounds as inhibitors of ubiquitin specific proteases, such as USP7, with potential utility in treating cancer, neurodegenerative diseases, inflammatory disorders, and viral infections. PCT applications WO 2015 / 017502 and WO 2016 / 019237 refer to inhibitors of Bruton’s tyrosine kinase with potential utility in treating disease such as autoimmune disease, inflammatory disease, and cancer. PCT applications WO 2009 / 026197, WO 2009 / 129365, WO 2009 / 129370, and WO 2009 / 129371, refer to cyanopyrrolidines as inhibitors of Cathepsin C with potential utility in treating COPD. United States patent application US 2008 / 0300268 refers to polyaromatic compounds as inhibitors of tyrosine kinase receptor PDGFR. PCT applications WO 2019 / 222468, WO 2019 / 071073, WO 2020 / 036940 and WO 2020 / 072964, Rusilowicz- Jones et al, 2020, bioRxiv 2020.04.16.044206 (20 April 2020), and Tsefou et al, bioRxiv 2021.02.02.429344 (2 February 2021), refer to cyanamide-containing compoundsas USP30 inhibitors. Yue et al, 2014, Cell Research, 24, 482-496, refers to a diterpenoid derivative 15-oxospiramilactone as a USP30 inhibitor that induced mitochondrial fusion.

[0018] PCT application WO 2015 / 183987 refers to pharmaceutical compositions comprising deubiquitinase inhibitors and human serum albumin in methods of treating cancer, fibrosis, an autoimmune disease or condition, an inflammatory disease or condition, a neurodegenerative disease or condition or an infection. It is noted that deubiquitinases, including UCHL5 / UCH37, USP4, USP9X, USP11 and USP15, are said to have been implicated in the regulation of the TGF-beta signalling pathway, the disruption of which gives rise to neurodegenerative and fibrotic diseases, autoimmune dysfunction, and cancer.

[0019] PCT application WO 2006 / 067165 refers to a method for treating fibrotic diseases using indolinone kinase inhibitors. PCT application WO 2007 / 119214 refers to a method for treating early-stage pulmonary fibrosis using an endothelin receptor antagonist. PCT application WO 2012 / 170290 refers to a method for treating fibrotic diseases using THC acids. PCT application WO 2018 / 213150 refers to sulfonamide USP30 inhibitors with potential utility in the treatment of conditions involving mitochondrial defects. Larson-Casey et al, 2016, Immunity 44, 582-596, concerns macrophage Aktl kinase-mediated mitophagy, apoptosis resistance and pulmonary fibrosis. Tang et al, 2015, Kidney Diseases 1, 71-79, reviews the potential role of mitophagy in renal pathophysiology.

[0020] There exists a need for safe, alternative, and / or improved methods and compositions for the treatment or prevention of cancer and conditions involving mitochondrial dysfunction, and the various symptoms and conditions associated therewith. While not wishing to be bound by any theory or mechanism, it is believed that the compounds of the present invention act to inhibit the enzyme USP30, which in turn upregulates Parkin-induced mitophagy.

[0021] Acute Kidney Injury (AKI) is defined as an abrupt decrease in kidney function occurring over 7 days or less, with severity of injury staged based on increased serum creatinine (SCr) and decreased urine output as described in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. AKI occurs in about 13.3 million people per year, 85% of whom live in the developing world, and it is thought to contribute to about 1.7 million deaths every year (Mehta et al, 2015, Lancet 385(9987): 2616-2643). AKI more than likely results in permanent kidney damage (i.e., chronic kidney disease; CKD) and may also result in damage to non-renal organs. AKI is a significant public health concern particularly when considering the absolute number of patients developing incident CKD, progressive CKD, end-stage renal disease and cardiovascular events. AKI has been found to be prevalent in patients hospitalised by COVID-19 and is strongly associated with hospital mortality, with mitochondrial damage and dysfunction reported as a potential pathophysiological mechanism and therapeutic target (Kellum et al, Nephrol Dial Transplant (2020) 35: 1652–1662).AKI and CKD are viewed as a continuum on the same disease spectrum (Chawla et al, 2017, Nat Rev Nephrol 13(4): 241-257). Patients undergoing coronary artery bypass graft (CABG) are at high risk for kidney injury. There is an obvious unmet medical need in the development of medicinal products for the treatment and / or prevention of AKI.

[0022] The kidney is a site of high metabolic demand, with high mitophagy rates demonstrated in vivo (McWilliams et al, 2018, Cell Metab 27(2): 439-449 e435). Renal Proximal Tubule Epithelial Cells (RPTECs), a cell type with significant ATP requirement for solute / ion exchange, are rich in mitochondria and are the primary effector cells of Acute Kidney Injury (AKI) in the kidney. Mitochondrial dysfunction has been implicated in AKI / CKD mechanisms, both through multiple lines of evidence from preclinical AKI and CKD models and through data demonstrating abnormal mitochondrial phenotypes in patient biopsies (Emma et al, 2016, Nat Rev Nephrol 12(5): 267-280; Eirin et al, 2017, Handb Exp Pharmacol 240: 229-250). Furthermore, Primary mitochondrial disease often manifests in renal symptoms, such as focal segmental glomerulosclerosis (Kawakami et al, 2015, J Am Soc Nephrol 26(5): 1040-1052) in patients with MELAS / MIDD, and primary tubular pathologies in patients with Coenzyme Q deficiencies. Mutations in mtDNA can cause maternally inherited tubulointerstitial disease (Connor et al, 2017, PLoS Genet 13(3): e1006620).

[0023] Regarding mitochondrial quality control in renal injury (Tang et al, 2018, Autophagy 14(5): 880-897) demonstrated that renal injury was exacerbated following ischemic AKI in both PINK1 KO and PARK2 KO mice, suggesting that PINKl / PARKIN-mediated mitophagy plays a protective role following IRI in the kidney. In addition, parkin / PINKl mitophagy protects against cisplatin induced kidney injury (Wang et al, 2018, Cell Death Dis 9(11): 1113). Limited models of CKD are available for mitophagy investigation, supportive evidence for mitochondrial quality control in fibrosis comes from studies on fibrotic lung conditions such as COPD and IPF. Parkin knockout animals show exacerbated lung fibrosis in response to bleomycin (Kobayashi et al, 2016, J Immunol, 197:504-516). Similarly, airway epithelial cells from parkin knockout (KO) animals show exacerbated fibrotic and senescent responses to cigarette smoke (Araya et al, 2019, Autophagy 15(3): 510-526).

[0024] Preclinical models are available to study potential novel therapeutics, through their ability to model fibrosis pathology (e.g., collagen deposition) consistent with the human condition. Preclinical models can be toxin-mediated (e.g., bleomycin for lung and skin fibrosis), surgical (e.g., ischemia / reperfiision injury model and unilateral ureter obstruction model for acute tubulointerstitial fibrosis), and genetic (e.g., diabetic (db / db) mice for diabetic nephropathy). For example, both examples previously given for indicated IPF treatments (nintedanib and pirfenidone) show efficacy in the bleomycin lung fibrosis model.

[0025] Leigh syndrome is a rare inherited neurometabolic disorder that affects the central nervous system. This progressive disorder begins in infants between the ages of three months and two years. Rarely, it occursin teenagers and adults. Leigh syndrome can be caused by mutations in nuclear DNA encoding for mitochondrial proteins, mutations in mitochondrial DNA (maternally inherited Leigh syndrome -MILS), or by deficiencies of an enzyme called pyruvate dehydrogenase located on the short arm of the X Chromosome (X-linked Leigh syndrome). Symptoms of Leigh syndrome usually progress rapidly. The earliest signs may be poor sucking ability, and the loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. As the disorder progresses, symptoms may also include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function. In maternally inherited Leigh syndrome (MILS), genetic mutations in mitochondrial DNA (at a high proportion of >90%) interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements. Genetic mutations in mitochondrial DNA result in a chronic lack of energy in these cells, which in turn affects the central nervous system and causes progressive degeneration of motor functions. When the genetic mutations in mitochondrial DNA that causes MILS are less abundant (less than 90%), the condition is known as neuropathy ataxia and retinitis pigmentosa (NARP). There is also a form of Leigh’s disease (called X-linked Leigh's disease) which is the result of mutations in a gene that produces another group of substances that are important for cell metabolism. A further variant of Leigh syndrome exists which is called French-Canadian variant, characterized by mutations in a gene called LRPPRC. Similar neurological symptoms are expressed as those for Leigh syndrome, although Liver Steatosis is commonly also observed in the French-Canadian variant.

[0026] Muscular dystrophies are characterized by specific abnormalities (e.g., variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from the patients. Approximately thirty different genetic conditions make up the muscular dystrophies. Duchenne Muscular Dystrophy (DMD) is classified as a dystrophinopathy, one of a spectrum of muscle diseases, each caused by alterations in the dystrophin gene. The clinical hallmarks of DMD include weakness and wasting of various voluntary muscles of the body. In most advanced stages of the disease, the heart and gut muscles will be affected, with cardiomyopathy and subsequent heart failure being a primary cause of mortality.

[0027] Reid, et al, “The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy.” Life 2021, 11, 648, reports that mitochondrial dysfunction is one of the first characteristics that can be seen in dystrophic muscle before the overt breakdown of muscle, suggesting that it could be a significant contributor to the pathology of the disease rather than a later consequence of muscle necrosis. In healthy tissue, these damaged mitochondria are marked for mitophagy, however, it has been shown that mitophagy is significantly impaired in DMD.

[0028] Vila et al, Cell Death and Differentiation (2017) 24, 330-342, identified that active mitochondria are required for the repair of sarcolemmal injury in healthy myofibers, and that proteins facilitatingmitochondrial function, calcium homeostasis, and sarcolemmal stability are significantly altered at disease onset in dystrophin-deficient mdx mice. It was hypothesised that increased calcium overload in dystrophic myofibers and mitochondria causes mitochondrial dysfunction, which in turn diminishes the repair ability of the dystrophic myofibers and results in their death and, therefore, enhanced autophagy may aid to clear these mitochondria.

[0029] Luan et al, Science Translational Medicine (2021) 13, 1-12, demonstrated that animal DMD models and DMD patient tissue contain reduced expressions of genes involved in mitophagy which contributes to mitochondrial dysfunction. Administration of Urolithin A, a natural compound able to stimulate mitophagy, increased muscle metabolism and stem cell regenerative ability, resulting in muscle function recovery in the mdx mouse model of DMD. Urolithin A also reduced CD45 positive inflammatory cells in TA muscles, suggesting potential anti-inflammatory mechanisms may contribute to benefit in the mdx mouse model.

[0030] Accordingly, there is a need for compounds that are inhibitors of USP30 for the treatment or prevention of conditions where inhibition of USP30 is indicated. In particular, there exists a need for USP30 inhibitors that have suitable and / or improved properties in order to maximise efficacy against the target disease.

[0031] SUMMARY OF THE INVENTION

[0032] The present invention is directed to a compound of formula (I):

[0033]

[0034] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:

[0035] (a) X1is CR4aand X2is N, or

[0036] (b) X1is N and X2is CR4b;

[0037] X3, X4and X5are each independently selected from N, CR4c, CR4dand CR4e;

[0038] R1is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)fluoroalkyl, CH2O(Ci-C4)alkyl, CH2N((Ci-C4)alkyl)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl; wherein the pyrazolyl and triazolyl rings are optionally substituted by one to three methyl groups;

[0039] R2is selected from hydrogen, (Ci-C4)alkyl, cyclopropyl and (Ci-C4)fluoroalkyl;

[0040] R3is selected from hydrogen, halo, (Ci-C4)alkyl, cyclopropyl and (Ci-C4)alkoxy;

[0041] R4a, R4b, R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, CN, hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy and (C1-C6)alkoxy(C1-C6)alkyl;ring A is selected from:

[0042] (i) phenyl;

[0043] (ii) a 5 to 6-membered monocyclic heteroaryl ring comprising one to four heteroatoms, each independently selected from N, O and S; and

[0044] (iii) a 9 to 10-membered bicyclic heteroaryl ring comprising 1 to 4 heteroatoms, each independently selected from N, O and S;

[0045] ring A is either unsubstituted or substituted by one to five substituents selected from R5, R6, R7, R8and R9; and R5, R6, R7, R8and R9are each independently selected from halo, CN, hydroxy, NH2, (Ci-Cg)alkyl, (Ci-Cg)alkoxy, halo(Ci-Cg)alkyl, halo(Ci-Cg)alkoxy, hydroxy(Ci-Cg)alkyl, hydroxy(C2-C6)alkoxy, (C3-Cg)cycloalkyl, halo(C3-Cg)cycloalkyl, hydroxy(C3-Cg)cycloalkyl, (C3-Cg)cycloalkoxy, halo(C3-Cg)cycloalkoxy, hydroxy(C3-Cg)cycloalkoxy, (Ci-Cg)alkoxy(Ci-Cg)alkyl, (Ci-Cg)alkoxy(Ci-Cg)alkoxy, (Ci-Cg)alkoxy(C3-Cg)cycloalkyl, (Ci-Cg)alkoxy(C3-Cg)cycloalkoxy, (C3-C6)cycloalkoxy(Ci-C6)alkyl, (C3-C6)cycloalkoxy(Ci-C6)alkoxy, oxetanyl, oxetanyloxy, NH(Ci-C6)alkyl, N((Ci-Cg)alkyl)2, NH(C3-C6)cycloalkyl, N((C3-C6)cycloalkyl)2, N((Ci-C6)alkyl)((C3-C6)cycloalkyl)), C(O)NH(Ci-C6)alkyl, C(O)N((Ci-C6)alkyl)2, NHC(O)(Ci-C6)alkyl, N(Ci-C6)alkyl)C(O)(Ci-C6)alkyl), C(O)(Ci-C6)alkyl, C(O)O(Ci-C6)alkyl, CO2H, CONH2, SO2NH(C1-C6)alkyl and SO2N((Ci-Cg)alkyl)2.

[0046] The present invention is also directed to uses of the compounds of formula (I), particularly in the treatment of cancer and conditions involving mitochondrial dysfunction, and to processes for the preparation thereof and pharmaceutical compositions containing said compounds.

[0047] DETAILED DESCRIPTION OF THE INVENTION

[0048] The present invention is directed to USP30 inhibitors. Preferably, the inhibitors have suitable and / or improved properties to maximise efficacy against the target disease. Such properties include, for example, potency, selectivity, physicochemical properties, ADME (absorption, distribution, metabolism, and excretion) properties, including PK (pharmacokinetic) profile, and safety profile. It is generally desirable to maximise the potency of a drug molecule against the target enzyme in relevant assays to lower the effective / efficacious dosage that is to be administered to patients. Compounds of the invention may be tested for USP30 affinity using the in vitro biochemical fluorescence polarization (FP) assay described herein.

[0049] USP30 is a transmembrane protein located in the outer membrane of mitochondria, which are energyproducing organelles present inside cells. Therefore, being able to demonstrate cellular activity in vitro is advantageous, as this is one of the components that may indicate a greater ability to engage the target in its physiological setting, i.e., where the USP30 inhibitor compound is able to penetrate cells. The USP30 cellular western blot (WB) assay aims to test the activity of compounds against USP30 in cells using an irreversible activity probe to monitor USP30 activity. Analogously to the cellular western blotassay, target engagement assessment (ex vivo) may be carried out in either brain or kidney tissue samples from compound-dosed animals.

[0050] To extend target binding knowledge to downstream pharmacodynamics, assessment of TOM20 (an outer mitochondrial membrane protein) ubiquitylation may be made.

[0051] In general, it is important for a drug to be as selective as possible for its desired target enzyme; additional activities give rise to the possibility of side effects. The exact physiological role of many DUBs has yet to be fully determined, however, irrespective of whatever role these DUBs may or may not play, it is a sound medicinal chemistry precept to ensure that any drug has selectivity over related mechanistic targets of unknown physiological function. Representative examples of DUB enzymes for which the compounds of the present invention may be screened against are UCHL1, UCHL3, UCHL5, Y0D1, SENP2, SENP6, TRABID, BAP1, Cezanne, MINDY2 / FAM63B, OTUD1, OTUD3, OTUD5, OTUD6A, OTUD6B, OTUB1 / UBCH5B, OTUB2, CYLD, VCPIP, AMSH-LP, JOSD1, JOSD2, USP1 / UAF1, USP2, USP4, USP5, USP6, USP7, USP8, USP9x, USP10, USP11, USP12 / UAF1, USP13, USP14, USP15, USP16, USP19, USP20, USP21, USP22, USP24, USP25, USP28, USP32, USP34, USP35, USP36, USP45, USP46 / UAF1, USP47 and USP48. Suitably, compounds of the invention have good selectivity for USP30 over one or more of these DUB enzymes.

[0052] Aside from selectivity over other DUB enzymes, it is important for a drug to have low affinity for other targets, and pharmacological profiling may be performed against panels of targets to assess the potential for, and to minimise, potential off-target effects. Examples of targets for which the compounds of the present invention may be screened against are those of the industry standard Eurofins-Cerep SafetyScreen44 panel, which includes 44 targets as a representative selection of GPCR receptors, transporters, ion channels, nuclear receptors, and kinase and non-kinase enzymes. Additionally, examples of a particular enzyme class for which the compounds of the present invention may be screened against are the cathepsins (e.g., cathepsins A, B, C, H, K, L, S, V and Z).

[0053] There is also a need for compounds that have favourable pharmacokinetic properties such that they are suitable for oral administration. An orally administered drug should have good bioavailability; that is an ability to readily cross the gastrointestinal (GI) tract and not be subject to extensive metabolism as it passes from the GI tract into the systemic circulation. Once a drug is in the systemic circulation the rate of metabolism is also important in determining the time of residence of the drug in the body. Thus, it is clearly favourable for drug molecules to have the properties of being readily able to cross the GI tract and being only slowly metabolised in the body. The Caco-2 assay is a widely accepted model for predicting the ability of a given molecule to cross the GI tract. The majority of metabolism of drug molecules generally occurs in the liver, and in vitro assays using whole cell hepatocytes (animal or human) are widely accepted methods for measuring the susceptibility of a given molecule towardsmetabolism in the liver. Such assays aim to predict in vivo clearance from the hepatocyte calculated clearance value.

[0054] Compounds which have good Caco-2 flux and are stable towards hepatocytes are predicted to have good oral bioavailability (good absorption across the GI tract and minimal extraction of compound as it passes through the liver) and a long residence time in the body that is sufficient for the drug to be efficacious.

[0055] The solubility of a compound is an important factor in achieving a desired concentration of drug in systemic circulation for the anticipated pharmacological response. Low aqueous solubility is a problem encountered with formulation development of new chemical entities and to be absorbed a drug must be present in the form of solution at the site of absorption. The kinetic solubility of a compound may be measured using a turbidimetric solubility assay, the data from which may also be used in conjunction with Caco-2 permeability data to predict dose dependent human intestinal absorption.

[0056] Other parameters that may be measured using standard assays that are indicative of a compound’s exposure profile include, for example plasma stability (half-life measurement), blood AUC, Cmax, Cmin and Tmax values.

[0057] The treatment of CNS disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease, requires drug molecules to target the brain, which requires adequate penetration of the blood brain barrier. There is, therefore, a need for USP30 inhibitors that possess effective blood brain penetration properties and provide suitable residence time in the brain to be efficacious. The probability that a compound can cross the blood brain barrier may be measured by an in vitro flux assay utilizing a MDR1-MDCK cell monolayer (Madin-Darby Canine Kidney cells transfected with MDR-1 resulting in overexpression of the human efflux transporter P-glycoprotein). Additionally, exposure and / or target engagement may also be measured directly in brain and blood using in vivo animal models.

[0058] There is also a need for compounds that have a favourable safety profile, which may be measured by a variety of standard in vitro and in vivo methods. A cell toxicity counter-screen may be used to assay the anti-proliferative / cytotoxic effect in a particular cell line (e.g., HCT116) by fluorometric detection of rezasurin (alamarBlue™) to resofurin in response to mitochondrial activity.

[0059] Toxicology and safety studies may also be conducted to identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Regulatory requirements generally require studies to be conducted in at least two laboratory animal species, one rodent (rat or mouse) and one nonrodent (rabbit, dog, non-human primate, or other suitable species). The bacterial reverse mutation assay (Ames Test) may be used to evaluate the mutagenic properties of compounds of the invention, commonly by using the bacterial strain Salmonella typhimurium, which is mutant for the biosynthesis of the amino acid histidine.The micronucleus assay may be used to determine if a compound is genotoxic by evaluating the presence of micronuclei. Micronuclei may contain chromosome fragments produced from DNA breakage (clastogens) or whole chromosomes produced by disruption of the mitotic apparatus (aneugens).

[0060] The hERG assay provides valuable information about the possible binding of test compounds to the hERG potassium channel and potential QT prolongation on echocardiogram. Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia (Torsades de Pointes). Typically, assay data may be generated from an automated patch-clamp assay platform.

[0061] According to a first aspect, the present invention provides a compound of formula (I):

[0062]

[0063] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:

[0064] (a) X1is CR4aand X2is N, or

[0065] (b) X1is N and X2is CR4b;

[0066] X3, X4and X5are each independently selected from N, CR4c, CR4dand CR4e;

[0067] R1is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)fluoroalkyl, CH2O(Ci-C4)alkyl, CH2N((Ci-C4)alkyl)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl; wherein the pyrazolyl and triazolyl rings are optionally substituted by one to three methyl groups;

[0068] R2is selected from hydrogen, (Ci-C4)alkyl, cyclopropyl and (Ci-C4)fluoroalkyl;

[0069] R3is selected from hydrogen, halo, (Ci-C4)alkyl, cyclopropyl and (Ci-C4)alkoxy;

[0070] R4a, R4b, R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, CN, hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy and (C1-C6)alkoxy(C1-C6)alkyl;

[0071] ring A is selected from:

[0072] (i) phenyl;

[0073] (ii) a 5 to 6-membered monocyclic heteroaryl ring comprising one to four heteroatoms, each independently selected from N, O and S; and

[0074] (iii) a 9 to 10-membered bicyclic heteroaryl ring comprising 1 to 4 heteroatoms, each independently selected from N, O and S;

[0075] ring A is either unsubstituted or substituted by one to five substituents selected from R5, R6, R7, R8and R9; and R5, R6, R7, R8and R9are each independently selected from halo, CN, hydroxy, NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl,hydroxy(C2-C6)alkoxy, (C3-Cg)cycloalkyl, halo(C3-Cg)cycloalkyl, hydroxy(C3-Cg)cycloalkyl, (C3-Cg)cycloalkoxy, halo(C3-Cg)cycloalkoxy, hydroxy(C3-Cg)cycloalkoxy, (Ci-Cg)alkoxy(Ci-Cg)alkyl, (Ci-Cg)alkoxy(Ci-Cg)alkoxy, (Ci-Cg)alkoxy(C3-Cg)cycloalkyl, (Ci-Cg)alkoxy(C3-Cg)cycloalkoxy, (C3-Cg)cycloalkoxy(Ci-Cg)alkyl, (C3-Cg)cycloalkoxy(Ci-Cg)alkoxy, oxetanyl, oxetanyloxy, NH(Ci-C6)alkyl, N((Ci-C6)alkyl)2, NH(C3-C6)cycloalkyl, N((C3-C6)cycloalkyl)2, N((Ci-Cg)alkyl)((C3-C6)cycloalkyl)), C(O)NH(Ci-C6)alkyl, C(O)N((Ci-C6)alkyl)2, NHC(O)(Ci-C6)alkyl, N(C1-C6)alkyl)C(O)(C1-C6)alkyl), C(O)(Ci-C6)alkyl, C(O)O(Ci-C6)alkyl, CO2H, CONH2, SO2NH(C1-C6)alkyl and SO2N((C1-C6)alkyl)2.

[0076] Unless otherwise indicated, alkyl and alkoxy groups may be straight or branched and contain one to six carbon atoms, and more typically, one to four carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isobutoxy and n-butoxy. Examples of alkoxyalkyl include methoxymethyl, methoxyethoxy and ethoxymethoxy.

[0077] Unless otherwise indicated, cycloalkyl and cycloalkoxy (O-cycloalkyl) groups contain three to six carbon atoms, and more typically, three to four carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of cycloalkoxy include cyclopropoxy and cyclobutoxy.

[0078] Halo means fluoro, chloro, bromo or iodo, suitably, fluoro or chloro. Haloalkyl and haloalkoxy groups may contain one or more halo substituents. Examples are fluoromethyl, difluoromethyl, trifluoromethyl and trifluoromethoxy.

[0079] Monocyclic heteroaryl rings are aromatic. Examples of heteroaryl groups include furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. The N-linked triazolyl ring may be 1,2,3-triazolyl or 1,2,4-triazolyl, suitably 1,2, 3 -triazol- 1-yl, and most suitably 1 H- 1,2,3-triazol-l-yl.

[0080] Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from more than one alternative, the selected groups may be the same or different. The term ‘independently’ means that where more than one substituent is selected from more than one possible substituent, those substituents may be the same or different.

[0081] In preferred embodiments of the compound of formula (I), at least one of X3, X4and X5is selected from CR4c, CR4dand CR4e.

[0082] In more preferred embodiments, the compound of formula (I) is selected from formulae (I)(i), (I)(ii), (I)(iii), (I)(iv), (I)(v), (I)(vi) and (I)(vii):(I)(ii)

[0083] (I)(iii) (I)(iv) R4cR4cR4b

[0084] (I)(vi)

[0085]

[0086] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0087] In preferred embodiments of each compound of formula (I), ring A is selected from:

[0088] (i) phenyl;

[0089] (ii) a 5 to 6-membered monocyclic heteroaryl ring selected from furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl; and

[0090] (iii) a 9 to 10-membered bicyclic heteroaryl ring selected from indazolyl, indolyl, indolinyl, indolizinyl, isoindolyl, isoindolinyl, purinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, dihydropyrrolopyridinyl, oxazolopyridinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzothiazinyl, dihydrobenzoxazinyl, dihydroquinazolinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.More suitably, ring A is selected from phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl. Yet more suitably, ring A is selected from phenyl, imidazolyl, pyrazolyl and pyridinyl. Most suitably, ring A is selected from phenyl, IH-pyrazol- 1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and pyrimidinyl.

[0091] In preferred embodiments of each compound of formula (I), the present invention is directed to a compound of formula (I) selected from formulae (I)(A), (I)(B), (I)(C), (I)(D), (I)(E) and (I)(F), which correspond to ring A being phenyl (A), pyridin-2-yl (B), pyridin-3-yl (C), pyridin-4-yl (D), pyrimidin-4-yl (E) and IH-pyrazol-l-yl (F):

[0092]

[0093] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0094] In one embodiment, the compound of formula (I) is selected from formulae (I)(A)(i), (I)(B)(i), (I)(C)(i), (I)(D)(i), (I)(E)(i) and (I)(F)(i):

[0095]

[0096] (I)(B)(i)(I)(D)(i)

[0097]

[0098] (I)(F)(i) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0099] In another embodiment, the compound of formula (I) is selected from formulae (I)(A)(ii), (I)(B)(ii), (I)(C)(ii), (I)(D)(ii), (I)(E)(n) and (I)(F)(n):

[0100] (I)(A)(ii) (I)(B)(ii)

[0101] (I)(D)(n)

[0102]

[0103] (I)(F)(ii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.In another embodiment, the compound of formula (I) is selected from formulae (I)(A)(iii), (I)(B)(iii), (I)(C)(hi), (I)(D)(iii), (I)(E)(m) and (I)(F)(iii):

[0104]

[0105] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0106] In another embodiment, the compound of formula (I) is selected from formulae (I)(A)(iv), (I)(B)(iv), (I)(C)(iv), (I)(D)(iv), (I)(E)(iv) and (I)(F)(iv):

[0107] (I)(B)(iv)

[0108]

[0109] (I)(D)(iv)

[0110]

[0111] (I)(F)(iv) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0112] In another embodiment, the compound of formula (I) is selected from formulae (I)(A)(v), (I)(B)(v), (I)(C)(v), (I)(D)(v), (I)(E)(v) and (I)(F)(v):

[0113] R4c

[0114] (I)(A)(v) (I)(B)(v)

[0115] (I)(D)(v)

[0116]

[0117] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0118] In another embodiment, the compound of formula (I) is selected from formulae (I)(A)(vi), (I)(B)(vi), (I)(C)(vi), (I)(D)(vi), (I)(E)(vi) and (I)(F)(vi):(I)(A)(vi)

[0119] (I)(C)(vi) (I)(D)(vi)

[0120]

[0121] (I)(F)(vi) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0122] In another embodiment, the compound of formula (I) is selected from formulae (I)(A)(vii), (I)(B)(vii), (I)(C)(vh), (I)(D)(vii), (I)(E)(vii) and (I)(F)(vii):

[0123] (I)(B)(vn)

[0124]

[0125]

[0126] (I)(E)(vii) (I)(F)(vii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0127] The compounds of formula (I) may contain up to four chiral centres at the carbon atoms of the pyrrolidine ring, for example where R1, R2or R3are other than hydrogen. The designation of the absolute configuration (R) and (. S') for stereoisomers in accordance with IUPAC nomenclature is dependent on the nature of the substituents and application of the sequence-rule procedure. Included within the scope of the present invention are all stereoisomers of the compounds of formula (I) and combinations thereof.

[0128] In respect of the chiral centres of the pyrrolidine ring substituted by the N-attached bicyclic ring and R1groups, where R1is other than hydrogen, the compound of formula (I) may exist in any of the following configurations:

[0129]

[0130] Thus, in preferred embodiments where R1is other than hydrogen, and R2and R3are each hydrogen, the compound of formula (I) may exist in any of the following configurations:

[0131]

[0132] and most suitably exists as a stereoisomer having the absolute configuration of formula (aa):

[0133]

[0134] (aa).In respect of the chiral centres of the pyrrolidine ring substituted by the N-attached bicyclic ring and R2groups, where R2is other than hydrogen, the compounds of formula (I) may exist in any of the following configurations:

[0135]

[0136] and suitably exist as a stereoisomer having the absolute configuration of formula (b):

[0137]

[0138] (b).

[0139] Thus, in preferred embodiments where R2is other than hydrogen, and R1and R3are each hydrogen, the compounds of formula (I) may exist in any of the following configurations:

[0140]

[0141] and most suitably exist as a stereoisomer having the absolute configuration of formula (bb):

[0142]

[0143] (bb).

[0144] Where the compound of formula (I) is a single stereoisomer, it suitably exists with a stereoisomeric excess of at least 60%, more suitably at least 80%, yet more suitably at least 90%, and most suitably at least 95%, for example 96%, 97%, 98%, 99%, or 100%.

[0145] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume ofpropan-2-ol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. The present invention includes all crystal forms of the compounds of formula (I) including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, " Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).

[0146] In one embodiment, the compound of formula (I) is suitably of formula (I)(a):

[0147]

[0148] (I)(a)

[0149] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0150] In one embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA), (I)(aB), (I)(aC), (I)(aD), (I)(aE) and (I)(aF):

[0151] (I)(aB)

[0152] (I)(aC) (I)(aD)

[0153]

[0154] (I)(aE) (I)(aF) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0155] In one embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(i), (I)(aB)(i), (I)(aC)(i), (I)(aD)(i), (I)(aE)(i) and (I)(aF)(i):R4c

[0156]

[0157] (I)(aF)(i) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0158] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(ii), (I)(aB)(ii), (I)(aC)(ii), (I)(aD)(ii), (I)(aE)(ii) and (I)(aF)(ii):

[0159]

[0160]

[0161] (I)(aF)(ii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0162] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(iii), (I)(aB)(iii), (I)(aC)(iii), (I)(aD)(iii), (I)(aE)(iii) and (I)(aF)(iii):

[0163]

[0164] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0165] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(iv), (I)(aB)(iv), (I)(aC)(iv), (I)(aD)(iv), (I)(aE)(iv) and (I)(aF)(iv):

[0166]

[0167] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0168] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(v), (I)(aB)(v), (I)(aC)(v), (I)(aD)(v), (I)(aE)(v) and (I)(aF)(v):

[0169] R4cR4c

[0170] (I)(aB)(v)

[0171]

[0172] (I)(aD)(v)

[0173]

[0174] (I)(aE)(v) (I)(aF)(v) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0175] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(vi), (I)(aB)(vi), (I)(aC)(vi), (I)(aD)(vi), (I)(aE)(vi) and (I)(aF)(vi):

[0176]

[0177] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0178] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(aA)(vii), (I)(aB)(vii), (I)(aC)(vii), (I)(aD)(vii), (I)(aE)(vii) and (I)(aF)(vii):(I)(aC)(vii) (I)(aD)(vii)

[0179]

[0180] (I)(aE)(vii) (I)(aF)(vii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0181] In one embodiment, the compound of formula (I) is suitably of formula (I)(b):

[0182]

[0183] (I)(b)

[0184] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0185] In one embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA), (I)(bB), (I)(bC), (I)(bD), (I)(bE) and (I)(bF):

[0186]

[0187] (I)(bC) (I)(bD)

[0188]

[0189] (I)(bE) (I)(bF) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0190] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA)(i), (I)(bB)(i), (I)(bC)(i), (I)(bD)(i), (I)(bE)(i) and (I)(bF)(i):

[0191]

[0192] (I)(bF)(i) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0193] In another embodiment, formulae (I)(bA)(ii), (I)(bB)(ii), (I)(bC)(ii), (I)(bD)(ii), (I)(bE)(ii) and (I)(bF)(ii):

[0194]

[0195] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0196] 5 In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA)(iii), (I)(bB)(iii), (I)(bC)(iii), (I)(bD)(iii), (I)(bE)(iii) and (I)(bF)(iii):

[0197]

[0198]

[0199] (I)(bE)(iii) (I)(bF)(iii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0200] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA)(iv), (I)(bB)(iv), (I)(bC)(iv), (I)(bD)(iv), (I)(bE)(iv) and (I)(bF)(iv):

[0201] (I)(bA)(iv)

[0202] (I)(bD)(iv)

[0203]

[0204] (I)(bF)(iv) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0205] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA)(v), (I)(bB)(v), (I)(bC)(v), (I)(bD)(v), (I)(bE)(v) and (I)(bF)(v):

[0206] R4cR4c

[0207]

[0208] (I)(bB)(v)R4c

[0209] (I)(bC)(v) (I)(bD)(v)

[0210]

[0211] (I)(bE)(v) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0212] In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA)(vi), (I)(bB)(vi), (I)(bC)(vi), (I)(bD)(vi), (I)(bE)(vi) and (I)(bF)(vi):

[0213] (I)(bD)(vi)

[0214]

[0215] (I)(bF)(vi) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.In another embodiment, the compound of formula (I) is suitably selected from formulae (I)(bA)(vii), (I)(bB)(vii), (I)(bC)(vii), (I)(bD)(vii), (I)(bE)(vii) and (I)(bF)(vii):

[0216] (I)(bC)(vii) (I)(bD)(vii)

[0217]

[0218] (I)(bE)(vii) (I)(bF)(vii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0219] In preferred embodiments of each compound of formulae (I), (I)(a), (I)(aA), (I)(aB), (I)(aC), (I)(aD), (I)(aE), (I)(aF), (I)(b), (I)(bA), (I)(bB), (I)(bC), (I)(bD), (I)(bE) and (I)(bF), and each of the substructures (i) to (vii) thereof, substituents R1, R2, R3, R4a, R4b, R4c, R4d, R4e, R5, R6, R7, R8and R9are as defined below.

[0220] Suitably, R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CEE-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl). More suitably, R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl). Yet more suitably, R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H-1,2,3-triazol-1-yl).

[0221] Suitably, R2is selected from hydrogen, methyl, CF3 and cyclopropyl. More suitably, R2is selected from hydrogen and methyl. Suitably, R3is selected from hydrogen, fluoro, chloro, methyl, cyclopropyl and methoxy. Most suitably, R3is hydrogen.

[0222] Suitably, one of R1, R2and R3is other than hydrogen and the remainder are each hydrogen. In one preferred embodiment, R1is other than hydrogen, and R2and R3are each hydrogen. More suitably, R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl), and R2and R3are each hydrogen. In another preferred embodiment, R2is other than hydrogen, and R1and R3are each hydrogen. More suitably, R2is methyl, and R1and R3are each hydrogen.

[0223] Suitably, R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3. More suitably, R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, methyl and CN. Most suitably, R4ais selected from hydrogen and methyl. Most suitably, R4bis selected from hydrogen and methyl. Most suitably, R4cis selected from hydrogen and CN. Most suitably, R4dand R4eare each hydrogen. Most suitably, only one of R4a, R4b, R4c, R4dand R4eis other than hydrogen.

[0224] Suitably, R5, R6, R7, R8and R9are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy). More suitably, R5, R6, R7, R8and R9are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy. Yet more suitably, R5, R6, R7, R8and R9are each independently selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3. Even more suitably, R5and R7are each independently selected from hydrogen, CN and cyclopropoxy, and are most suitably each hydrogen. Even more suitably, R8is selected from hydrogen, CN and cyclopropoxy, and is most suitably selected from hydrogen and CN. Most suitably, R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3. Most suitably, R9is selected from hydrogen, CN and cyclopropoxy.

[0225] In a preferred embodiment, two of the R5, R6, R7, R8and R9substituents are each hydrogen, and the remaining three substituents are as defined in the embodiments herein. In another preferred embodiment, three of the R5, R6, R7, R8and R9substituents are each hydrogen, and the remaining two substituents are as defined in the embodiments herein. In another preferred embodiment, four of the R5, R6, R7, R8and R9substituents are each hydrogen, and the remaining substituent is as defined herein. In further preferred embodiments, one to four, more suitably one to three, and most suitably, one or two of R5, R7, R8and R9are each hydrogen, and R6is as defined herein. In further preferred embodiments, R5and R7are each hydrogen, and one or two of R8and R9are hydrogen.

[0226] In one particularly preferred embodiment of each compound of formulae (I)(A), (I)(aA) and (I)(bA), and each of the substructures (i) to (vii) thereof:

[0227] R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CFE-N-linked pyrazolyl and CFE-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl);R2is selected from hydrogen, methyl, CF3 and cyclopropyl;

[0228] R3is hydrogen;

[0229] R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3; and

[0230] R5, R6, R7, R8and R9are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy);

[0231] with the proviso that two or three of the R5, R7, R8and R9substituents are each hydrogen.

[0232] In a more particularly preferred embodiment of each compound of formulae (I)( A), (I)(aA) and (I)(bA), and each of the substructures (i) to (vii) thereof:

[0233] R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably lH-l,2,3-triazol-l-yl);

[0234] R2is selected from hydrogen and methyl, and is suitably hydrogen;

[0235] R3is hydrogen;

[0236] one of R4a, R4b, R4c, R4dand R4eis selected from hydrogen, methyl and CN, and the others are each hydrogen; and

[0237] R5, R6, R7, R8and R9are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy;

[0238] with the proviso that two or three of the R5, R7, R8and R9substituents are each hydrogen.

[0239] In a yet more particularly preferred embodiment of each compound of formulae (I)(A), (I)(aA) and (I)(bA), and each of the substructures (i) to (vii) thereof:

[0240] R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl);

[0241] when R1is hydrogen, R2is methyl;

[0242] when R1is other than hydrogen, R2is hydrogen;

[0243] R3, R4d, R4e, R5and R7are each hydrogen;

[0244] one of R4a, R4band R4cis selected from hydrogen, methyl and CN, and the others are each hydrogen; R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3;

[0245] R8is selected from hydrogen and CN; and

[0246] R9is selected from hydrogen, CN and cyclopropoxy;

[0247] with the proviso that one or two of R8and R9are hydrogen.In one particularly preferred embodiment of each compound of formulae (I)(B), (I)(aB) and (I)(bB), and each of the substructures (i) to (vii) thereof:

[0248] R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl);

[0249] R2is selected from hydrogen, methyl, CF3 and cyclopropyl;

[0250] R3is hydrogen;

[0251] R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3;

[0252] R5, R6, R7and R8are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy);

[0253] with the proviso that two or three of the R5, R7and R8substituents are each hydrogen.

[0254] In a more particularly preferred embodiment of each compound of formulae (I)(B), (I)(aB) and (I)(bB), and each of the substructures (i) to (vii) thereof:

[0255] R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably lH-l,2,3-triazol-l-yl);

[0256] R2is selected from hydrogen and methyl, and is suitably hydrogen;

[0257] R3is hydrogen;

[0258] one of R4a, R4b, R4c, R4dand R4eis selected from hydrogen, methyl and CN, and the others are each hydrogen;

[0259] R5, R6, R7and R8are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy;

[0260] with the proviso that two or three of the R5, R7and R8substituents are each hydrogen.

[0261] In a yet more particularly preferred embodiment of each compound of formulae (I)(B), (I)(aB) and (I)(bB), and each of the substructures (i) to (vii) thereof:

[0262] R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl);

[0263] when R1is hydrogen, R2is methyl;

[0264] when R1is other than hydrogen, R2is hydrogen;

[0265] R3, R4d, R4e, R5and R7are each hydrogen;

[0266] one of R4a, R4band R4cis selected from hydrogen, methyl and CN, and the others are each hydrogen; R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3; and

[0267] R8is selected from hydrogen and CN; and is suitably hydrogen.In one particularly preferred embodiment of each compound of formulae (I)(C), (I)(aC) and (I)(bC), and each of the substructures (i) to (vii) thereof:

[0268] R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl);

[0269] R2is selected from hydrogen, methyl, CF3 and cyclopropyl;

[0270] R3is hydrogen;

[0271] R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3;

[0272] R5, R6, R7and R9are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy);

[0273] with the proviso that two or three of the R5, R7and R9substituents are each hydrogen.

[0274] In a more particularly preferred embodiment of each compound of formulae (I)(C), (I)(aC) and (I)(bC), and each of the substructures (i) to (vii) thereof:

[0275] R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably lH-l,2,3-triazol-l-yl);

[0276] R2is selected from hydrogen and methyl, and is suitably hydrogen;

[0277] R3is hydrogen;

[0278] one of R4a, R4b, R4c, R4dand R4eis selected from hydrogen, methyl and CN, and the others are each hydrogen;

[0279] R5, R6, R7and R9are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy;

[0280] with the proviso that two or three of the R5, R7and R9substituents are each hydrogen.

[0281] In a yet more particularly preferred embodiment of each compound of formulae (I)(C), (I)(aC) and (I)(bC), and each of the substructures (i) to (vii) thereof:

[0282] R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl);

[0283] when R1is hydrogen, R2is methyl;

[0284] when R1is other than hydrogen, R2is hydrogen;

[0285] R3, R4d, R4e, R5and R7are each hydrogen;

[0286] one of R4a, R4band R4cis selected from hydrogen, methyl and CN, and the others are each hydrogen; R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3; and

[0287] R9is selected from hydrogen, CN and cyclopropoxy; and is suitably hydrogen.In one particularly preferred embodiment of each compound of formulae (I)(D), (I)(aD) and (I)(bD), and each of the substructures (i) to (vii) thereof:

[0288] R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl);

[0289] R2is selected from hydrogen, methyl, CF3 and cyclopropyl;

[0290] R3is hydrogen;

[0291] R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3;

[0292] R5, R6, R8and R9are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy);

[0293] with the proviso that two or three of the R5, R8and R9substituents are each hydrogen.

[0294] In a more particularly preferred embodiment of each compound of formulae (I)(D), (I)(aD) and (I)(bD), and each of the substructures (i) to (vii) thereof:

[0295] R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably lH-l,2,3-triazol-l-yl);

[0296] R2is selected from hydrogen and methyl, and is suitably hydrogen;

[0297] R3is hydrogen;

[0298] one of R4a, R4b, R4c, R4dand R4eis selected from hydrogen, methyl and CN, and the others are each hydrogen;

[0299] R5, R6, R8and R9are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy;

[0300] with the proviso that two or three of the R5, R8and R9substituents are each hydrogen.

[0301] In a yet more particularly preferred embodiment of each compound of formulae (I)(D), (I)(aD) and (I)(bD), and each of the substructures (i) to (vii) thereof:

[0302] R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl);

[0303] when R1is hydrogen, R2is methyl;

[0304] when R1is other than hydrogen, R2is hydrogen;

[0305] R3, R4d, R4e, R5and R8are each hydrogen;

[0306] one of R4a, R4band R4cis selected from hydrogen, methyl and CN, and the others are each hydrogen; R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3; and

[0307] R9is selected from hydrogen, CN and cyclopropoxy; and is suitably hydrogen.In one particularly preferred embodiment of each compound of formulae (I)(E), (I)(aE) and (I)(bE), and each of the substructures (i) to (vii) thereof:

[0308] R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl);

[0309] R2is selected from hydrogen, methyl, CF3 and cyclopropyl;

[0310] R3is hydrogen;

[0311] R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3;

[0312] R5, R6and R8are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy);

[0313] with the proviso that one or two of the R5and R8substituents are each hydrogen.

[0314] In a more particularly preferred embodiment of each compound of formulae (I)(E), (I)(aE) and (I)(bE), and each of the substructures (i) to (vii) thereof:

[0315] R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably lH-l,2,3-triazol-l-yl);

[0316] R2is selected from hydrogen and methyl, and is suitably hydrogen;

[0317] R3is hydrogen;

[0318] one of R4a, R4b, R4c, R4dand R4eis selected from hydrogen, methyl and CN, and the others are each hydrogen;

[0319] R5, R6and R8are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy;

[0320] with the proviso that one or two of the R5and R8substituents are each hydrogen.

[0321] In a yet more particularly preferred embodiment of each compound of formulae (I)(E), (I)(aE) and (I)(bE), and each of the substructures (i) to (vii) thereof:

[0322] R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl);

[0323] when R1is hydrogen, R2is methyl;

[0324] when R1is other than hydrogen, R2is hydrogen;

[0325] R3, R4d, R4eand R8are each hydrogen;

[0326] one of R4a, R4band R4cis selected from hydrogen, methyl and CN, and the others are each hydrogen; R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3; and

[0327] R5is selected from hydrogen, CN and cyclopropoxy, and is suitably hydrogen.In one particularly preferred embodiment of each compound of formulae (I)(F), (I)(aF) and (I)(bF), and each of the substructures (i) to (vii) thereof:

[0328] R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2,3-triazol- 1 -yl);

[0329] R2is selected from hydrogen, methyl, CF3 and cyclopropyl;

[0330] R3is hydrogen;

[0331] R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3 and OCF3;

[0332] R5, R6and R7are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy (suitably oxetan-3-yloxy);

[0333] with the proviso that one or two of the R5and R7substituents are each hydrogen.

[0334] In a more particularly preferred embodiment of each compound of formulae (I)(F), (I)(aF) and (I)(bF), and each of the substructures (i) to (vii) thereof:

[0335] R1is selected from hydrogen, methyl, CH2F, CH2OCH3, CH2OCH2CH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably lH-l,2,3-triazol-l-yl);

[0336] R2is selected from hydrogen and methyl, and is suitably hydrogen;

[0337] R3is hydrogen;

[0338] one of R4a, R4b, R4c, R4dand R4eis selected from hydrogen, methyl and CN, and the others are each hydrogen;

[0339] R5, R6and R7are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy;

[0340] with the proviso that one or two of the R5and R7substituents are each hydrogen.

[0341] In a yet more particularly preferred embodiment of each compound of formulae (I)(F), (I)(aF) and (I)(bF), and each of the substructures (i) to (vii) thereof:

[0342] R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl (suitably 1,2,3-triazolyl, more suitably 1H- 1,2, 3 -triazol- 1-yl);

[0343] when R1is hydrogen, R2is methyl;

[0344] when R1is other than hydrogen, R2is hydrogen;

[0345] R3, R4d, R4e, R5and R7are each hydrogen;

[0346] one of R4a, R4band R4cis selected from hydrogen, methyl and CN, and the others are each hydrogen; and

[0347] R6is selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3 and OCF3, and is suitably selected from hydrogen, CN, cyclopropyl and CF3.Preferred compounds of formula (I) are selected from:

[0348] l-(3-((37?,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)- 177-pyrazole-4-carbonitrile;

[0349] 1-(3-((3 / ?.5. S)- l-cyano-5-(mcthoxymcthyl)pyrrolidin-3-yl)-2-mcthyl-4-oxo-3.4-dihydropyrido|3.2 / |pyrimidin-6-yl)-l / 7-pyrazolc-4-carbonitrilc:

[0350] 2-(3-((3 / ?.5. S)- l-cyano-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2-d'|pyrimidin-6-yl)isonicotinonitrile;

[0351] (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifluoromcthyl)-l / 7-pyrazol-l-yl)pyrido|3.2 / |pyrimidin-3(4 / 7)-yl)pyrrolidine- 1 -carbonitrile;

[0352] 1 -(3-((2R,3R)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2-d] py rim idin-6-y 1 )- 1H-pyrazole -4-carbonitrile;

[0353] (2R,3R)-3 -(6-(3 -cyanophenyl)-4-oxopyrido [3.2 / | py rimidin-3 (4 / 7)-y I )-2-mcthy I py rrol idinc- 1 -carbonitrile;

[0354] (2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(4-(trifluoromcthyl)- l / 7-pyrazol-l-yl)pyrido|3.2-t / |pyrimidin-3 (4 / 7)- I (p rrol idinc- 1 -carbonitrile;

[0355] (2R.3 / ?)-2-mcthyl-3 -(4-oxo-6-(3 -(trifluoromethoxy )phenyl)pyrido [3.2 / |pyrimidin-3 (477)-yl)pyrrolidine- 1 -carbonitrile;

[0356] (2S,47?)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,2-<7]pyrimidin-3(477)-yl)-2-(methoxymethyl)pyrrolidine- 1 -carbonitrile;

[0357] (2S,47?)-4-(6-(5-cyano-2-cyclopropoxyphenyl)-4-oxopyrido[3,2-<7]pyrimidin-3(477)-yl)-2-(methoxymethyl)pyrrolidine - 1 -carbonitrile;

[0358] (2. S'.4 / ?)-2-(( l / 7-pyrazol-l-yl)mcthyl)-4-(6-(3-cyanophcnyl)-4-oxopyrido|3.2 / |pyrimidin-3(4 / 7)-yl)pyrrolidine- 1 -carbonitrile;

[0359] (2S,47?)-2-(( 177-pyrazol- 1 -yl)methyl)-4-(4-oxo-6-(4-(trifluoromethyl)- 177-pyrazol- 1 -yl)pyrido [3,2 / | py rimidin-3 (4 / )-y I (pyrrol idinc- 1 -carbonitrile;

[0360] 4-(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3, 2-d]pyrimidin-6-yl)picolinonitrile;

[0361] 2-(3-((37?,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)isonicotinonitrile;

[0362] 2-(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3.2 / | py rim idin-6-yl)isonicotinonitrile;

[0363] 4-(3 -((37?, 55)- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2-t / | py rimidin-6-yl)picolinonitrile;

[0364] (27?,37?)-2-methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-<7]pyrimidin-3(477)-yl)pyrrolidine- 1 -carbonitrile;

[0365] (7?)- 1 -(3 -( 1 -cyanopyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rim idin-6-y I )- 177-pyrazole-4-carbonitrile;5 -(3 -((3 R, 55)- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile;

[0366] 5 -(3 -((2R.3> R)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile;

[0367] 6-(3 -((2R.3 R)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile;

[0368] (27?,37?)-2-methyl-3-(4-oxo-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0369] (2S,4R)-4-(6-(4-cyclopropyl-1H-pyrazol-1-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carbonitrile;

[0370] (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0371] (2S,47?)-2-(methoxymethyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0372] (2R,3R)-3-(6-(3-cyanophenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carbonitrile;

[0373] (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0374] (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0375] (2R,3R)-3-(6-(3-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carbonitrile;

[0376] (2R,3R)-3-(6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carbonitrile;

[0377] (27?,37?)-2-methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0378] 3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;

[0379] (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0380] (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0381] 1-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile;

[0382] (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0383] 4-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinonitrile;4-(3-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinonitrile;

[0384] 2-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)isonicotinonitrile;

[0385] (2S,4R)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carbonitrile;

[0386] (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0387] (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0388] 1-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile;

[0389] (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0390] 4-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)picolinonitrile;

[0391] (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimido[5,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0392] (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimido[5,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0393] (2S,47?)-2-(methoxymethyl)-4-(l-oxo-7-(3-(trifluoromethoxy)phenyl)phthalazin-2(177)-yl)pyrrolidine-1 -carbonitrile;

[0394] 1-(3-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)-1H-pyrazole-4-carbonitrile;

[0395] (2S,47?)-2-(methoxymethyl)-4-(4-methyl-l-oxo-7-(3-(trifluoromethoxy)phenyl)phthalazin-2(177)-yl)pyrrolidine- 1 -carbonitrile;

[0396] (2R,3R)-3-(7-(3-cyanophenyl)-1-oxophthalazin-2(1H)-yl)-2-methylpyrrolidine-1-carbonitrile;

[0397] (2R,3R)-3-(7-(3-cyanophenyl)-4-methyl-1-oxophthalazin-2(1H)-yl)-2-methylpyrrolidine-1-carbonitrile;

[0398] 1-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)-1H-pyrazole-4-carbonitrile;

[0399] 4-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)picolinonitrile; 2-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)isonicotinonitrile; (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pteridin-3(4H)-yl)pyrrolidine-1-carbonitrile;

[0400] (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pteridin-3(4H)-yl)pyrrolidine-1-carbonitrile; and(2S,4R)-4-(6-(3-cyanophenyl)-4-oxopteridin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0401] Pharmaceutical acceptable salts of the compounds of formula (I) include the acid addition and base salts (including di-salts) thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, palmate, phosphate, saccharate, stearate, succinate sulfate, D-and L-tartrate, and tosylate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, ammonium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).

[0402] A pharmaceutical acceptable salt of a compound of formula (I) may be readily prepared by mixing solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

[0403] Pharmaceutical acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, acetone-d6, DMSO-6. Also, within the scope of the invention are clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in non-stoichiometric amounts. For a review of such complexes, see J. Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). Hereinafter all references to compounds of formula (I) include references to salts thereof and to solvates and clathrates of compounds of formula (I) and salts thereof.

[0404] The invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined. Also, within the scope of the invention are so-called "prodrugs" of the compounds of formula (I). Thus, certain derivatives of compounds of formula (I) which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to compounds of formula (I), having the desired activity. Such derivatives are referred to as "prodrugs".

[0405] Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in " Design of Prodrugs" by H Bundgaard (Elsevier,1985). Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

[0406] Also, within the scope of the invention are metabolites of the compounds of formula (I), that is, compounds formed in vivo upon administration of the compound of formula (I). Such metabolites may themselves be a compound of formula (I), which are particularly included with the scope of the present invention.

[0407] Included within the scope of the present invention are all tautomeric forms of the compounds of formula (I).

[0408] Certain derivatives of compounds of formula (I) which contain a nitrogen atom may also form the corresponding N-oxide, and such compounds are also within the scope of the present invention.

[0409] The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula (I). An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.

[0410] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as13C and14C, nitrogen, such as15N, oxygen, such as17O and18O, phosphorus, such as32P, sulfur, such as35S, fluorine, such as18F, and chlorine, such as36C1. Substitution of the compounds of the invention with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo halflife or reduced dosage requirements, and hence may be preferred in some circumstances.

[0411] Certain isotopic variations of the compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, and14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0412] Isotopic variations of the compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using appropriate isotopic variations of suitable reagents. The compounds of formula (I) are inhibitors of the deubiquitylating enzyme USP30.

[0413] According to a further aspect, the present invention provides a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer for use in inhibiting USP30, either in vitro or in vivo.According to a further aspect, the present invention provides a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer for use as a medicament.

[0414] According to a further aspect, the present invention provides a method of treatment or prevention of a disorder or condition where inhibition of USP30 is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. In one preferred embodiment of all aspects of the invention, the disorder or condition is a CNS indication. In a further preferred embodiment of all aspects of the invention, the disorder or condition is a peripheral indication.

[0415] According to a further aspect, the present invention provides the use of a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the treatment or prevention of a disorder or condition where inhibition of USP30 is known, or can be shown, to produce a beneficial effect. The manufacture of a medicament may include, inter alia, the chemical synthesis of the compound of formula (I) or a salt thereof, or the preparation of a composition or formulation comprising the compound or salt, or the packaging of any medicament comprising the compound. In one preferred embodiment of all aspects of the invention, the disorder or condition is a CNS indication. In a further preferred embodiment of all aspects of the invention, the disorder or condition is a peripheral indication.

[0416] According to a further aspect, the present invention provides a method of inhibition of USP30 in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

[0417] The disorder or condition benefiting from USP30 activity may be selected from a condition involving mitochondrial dysfunction, cancer and fibrosis.

[0418] In one preferred embodiment of all aspects of the invention, the disorder or condition benefiting from USP30 activity is a condition involving mitochondrial dysfunction. The condition involving mitochondrial dysfunction may be a CNS indication or a peripheral indication.

[0419] Mitochondrial dysfunctions result from defects of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When mitochondria fail, less and less energy is generated within the cell and cell injury or even cell death will follow. If this process is repeated throughout the body the life of the subject in whom this is happening is severely compromised. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.The condition involving mitochondrial dysfunction may be selected from a condition involving a mitophagy defect, a condition involving a mutation in mitochondrial DNA, a condition involving mitochondrial oxidative stress, a condition involving a defect in mitochondrial membrane potential, mitochondrial biogenesis, a condition involving a defect in mitochondrial shape or morphology, and a condition involving a lysosomal storage defect.

[0420] In particular, the condition involving mitochondrial dysfunction may be selected from: a neurodegenerative disease; multiple sclerosis (MS); mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome; maternally-inherited diabetes and deafness (MIDD); Leber's hereditary optic neuropathy (LHON); cancer (including, for example, breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone or other cancers of tissue organs and cancers of the blood cells, such as lymphoma and leukaemia, multiple myeloma, metastatic carcinoma, osteosarcoma, chondosarcoma, Ewing’s sarcoma, nasopharyngeal carcinoma, colorectal cancer, and non-small cell lung carcinoma); neuropathy, ataxia, retinitis pigmentosa, maternally inherited Leigh syndrome (NARP-MILS); Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric diseases, for example schizophrenia; multiple sulfatase deficiency (MSD); mucolipidosis II (ML II); mucolipidosis III (ML III); mucolipidosis IV (ML IV); GMl-gangliosidosis (GM1); neuronal ceroidlipofuscinoses (NCLl); Alpers disease; Barth syndrome; beta-oxidation defects; camitine-acyl-camitine deficiency; carnitine deficiency; creatine deficiency syndromes; co-enzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia syndrome (CPEO); CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCHAD); Leigh disease or syndrome; Leigh syndrome French-Canadian (LSFC) variant; lethal infantile cardiomyopathy (LIC); Luft disease; medium -chain acyl-CoA dehydrogenase deficiency (MCAD); myoclonic epilepsy and ragged-red fiber (MERRF) syndrome; mitochondrial cytopathy; mitochondrial recessive ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastrointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium / short-chain 3-hydroxyacyl-CoA dehydrogenase (M / SCHAD) deficiency; very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency; peroxisomal disorders; methylmalonic acidemia; mevalonate kinase deficiency; age-dependent decline in cognitive function and muscle strength; muscle structure disorders; and cognitive impairment associated with neurodegenerative and neuropsychiatric disorders.

[0421] The condition involving mitochondrial dysfunction may be a CNS disorder, for example a neurodegenerative disease.

[0422] Neurodegenerative diseases include, but are not limited to, Parkinson’s disease, Alzheimer’s disease,amyotrophic lateral sclerosis (ALS), Huntington’s disease, ischemia, stroke, dementia with Lewy bodies, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia.

[0423] In particular, the compounds of the invention may be useful in the treatment or prevention of Parkinson’s disease, including, but not limited to, PD related to mutations in a-synuclein, parkin, PINK1, GBA, and LRRK2, and autosomal recessive juvenile Parkinson’s disease (AR-JP), or early onset Parkinson’s disease (EOPD), where parkin or PINK1 is mutated, truncated, or deleted.

[0424] In particular, the compounds of the invention may be useful in treatment of cognitive impairment associated with neurodegenerative and neuropsychiatric disorders, including, for example, cognitive impairment associated with Alzheimer’s disease and Parkinson’s disease, preclinical or prodromal forms of AD and PD, Huntington’s disease, dementia with lewy body disease, cognitive impairment associated with schizophrenia, mood disorders, bipolar and major depressive disorders.

[0425] In a preferred embodiment, the present invention is directed to the treatment or prevention of Leigh syndrome or disease, including for example, X-linked Leigh's disease, Leigh syndrome French-Canadian variant, and / or the symptoms associated with Leigh’s disease. In particular, the compounds of the invention may be useful in the treatment of a muscle structure disorder selected from muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, Bethlem myopathy, central core disease, congenital fiber type disproportion, hyaline body myopathy, muscle sodium channel disorders, myotonic chondrodystrophy, myotubular myopathy, nemaline body disease, and stress urinary incontinence.

[0426] The compounds of the invention or pharmaceutical compositions thereof as described herein may be combined with one or more additional agents when used for the treatment or prevention of conditions involving mitochondrial dysfunction. The compounds may be combined with one or more additional agents selected from levodopa, a dopamine agonist, a monoamino oxygenase (MAO) B inhibitor, a catechol O-methyltransferase (COMT) inhibitor, an anticholinergic, riluzole, amantadine, a cholinesterase inhibitor, memantine, tetrabenazine, an antipsychotic, diazepam, clonazepam, an antidepressant, and an anti-convulsant. The compounds may be combined with agents which reduce / remove pathogenic protein aggregates in neurodegenerative diseases, such as agents which reduce / remove alpha-synuclein in Parkinson’s disease, multiple system atrophy or dementia with Lewy bodies; agents which reduce / remove Tau in Alzheimer’s disease or progressive supranuclear palsy; agents which reduce / remove TDP-43 in ALS or frontotemporal dementia.

[0427] The compounds may be combined with novel agents which may be used as treatments for mitochondrial disease, including, but not limited to, nicotinamide riboside.The compounds may be combined with agents which are used as treatments for muscular dystrophies such as DMD, including corticosteroids (e.g., prednisone and deflazacort), ataluren, eteplirsen, golodirsen, casimersen, viltepso, and other exon-skipping / nonsense readthrough / gene therapies, givinostat, pamrevlumab and vamorolone, and also heart medications, such as angiotensin-converting enzyme inhibitors and beta blockers.

[0428] In another preferred embodiment of all aspects of the invention, the disorder or condition benefiting from USP30 activity is cancer. The cancer may be linked to mitochondrial dysfunction. Preferred cancers include, for example, breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone or other cancers of tissue organs and cancers of the blood cells, such as lymphoma and leukaemia, multiple myeloma, metastatic carcinoma, osteosarcoma, chondosarcoma, Ewing’s sarcoma, nasopharyngeal carcinoma, colorectal cancer, and non-small cell lung carcinoma.

[0429] In particular, the compounds of the invention may be useful in the treatment or prevention of cancer where apoptotic pathways are dysregulated and more particularly where proteins of the BCL-2 family are mutated, or over or under expressed.

[0430] Fibrosis refers to the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. Fibrotic disorders that may be treated by the compounds and compositions of the present invention include, inter alia, fibrosis / fibrotic disorders associated with major organ diseases, for example, interstitial lung disease (ILD), liver cirrhosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) (hepatic fibrosis), kidney disease (renal fibrosis), acute kidney injury (AKI), acute kidney disease (AKD), chronic kidney disease (CKD), delayed kidney graft function, heart or vascular disease (cardiac fibrosis, hypertrophic cardiomyopathy (HCM)), and diseases of the eye; fibroproliferative disorders, for example, systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, restenosis, and Dupuytren’s contracture; scarring associated with trauma, for example, surgical complications, chemotherapeutics drug -induced fibrosis (e.g., bleomycin-induced fibrosis), radiation-induced fibrosis, accidental injury and bums); retroperitoneal fibrosis (Ormond's disease); and peritoneal fibrosis / peritoneal scarring in patients receiving peritoneal dialysis, usually following renal transplantation. See, for example, Wynn et al, 2004, Nat Rev Immunol. August; 4(8): 583-594. The present invention therefore relates to methods of treatment or prevention, and compounds and compositions used in said methods, of fibrosis / fibrotic disorders of and / or associated with the major organs, including for example, the lung, liver, kidney, heart, skin, eye, gastrointestinal tract, peritoneum and bone marrow, and other diseases / disorders herein described.

[0431] The compounds may be combined with agents which are used as treatments for kidney disease, including anti-diabetic agents, cardiovascular disease agents, and novel agents targeting diseaserelevant pathways such as oxidative stress (including, but not limited to, the nrf2 / keap-l pathway) and anti-apoptotic pathways (including, but not limited to, anti p53 agents).

[0432] Interstitial lung disease (ILD) includes disorders in which pulmonary inflammation and fibrosis are the final common pathways of pathology, for example, sarcoidosis, silicosis, drug reactions, infections, and collagen vascular diseases, such as rheumatoid arthritis and systemic sclerosis (scleroderma). The fibrotic disorder of the lung includes, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, and bronchiectasis.

[0433] Idiopathic pulmonary fibrosis (IPF) is the most common type of ILD and has no known cause.

[0434] The compounds may be combined with agents which are treatments for IPF and potentially for ILD, including nintedanib and pirfenidone.

[0435] Liver cirrhosis has similar causes to ILD and includes, for example, cirrhosis associated with viral hepatitis, schistosomiasis and chronic alcoholism.

[0436] Kidney disease may be associated with diabetes, which can damage and scar the kidneys leading to a progressive loss of function, and also hypertensive diseases. Kidney fibrosis may occur at any stage of kidney disease, from acute kidney disease (AKD) post injury and chronic kidney disease (CKD), such as incident CKD and progressive CKD, through to end-stage renal disease (ESRD). Kidney fibrosis can develop as a result of cardiovascular disease such as hypertension or diabetes, both of which place immense strain on kidney function which promotes a fibrotic response. However, kidney fibrosis can also be idiopathic (without a known cause), and certain genetic mitochondrial diseases also present kidney fibrosis manifestations and associated symptoms.

[0437] Heart disease may result in scar tissue that can impair the ability of the heart to pump.

[0438] Diseases of the eye include, for example, macular degeneration and retinal and vitreal retinopathy, which can impair vision.

[0439] In a preferred embodiment, the present invention is directed to the treatment or prevention of idiopathic pulmonary fibrosis (IPF).

[0440] In another preferred embodiment, the present invention is directed to the treatment or prevention of kidney fibrosis.

[0441] In another preferred embodiment, the present invention is directed to the treatment or prevention of acute kidney injury (AKI), especially in high-risk patients. Examples include post-surgical AKI, for example organ transplantation, such as due to ischemia reperfusion injury, delayed graft function; oncology, such as AKI due to chemotherapy; contrast medium-induced nephropathy, such as direct-tubular cytotoxicity, hemodynamic ischemia and osmotic effects; acute interstitial nephritis, such asdue to drugs or infection; AKI due to obstruction, such as kidney stones; and COVID-19-induced AKI. A particular high risk patient sub-group are those undergoing cardiac surgery, for example, coronary artery bypass graft and / or valve surgery. There are established static risk factors for AKI such as age 65 years or over, insulin dependent diabetes, CKD (adults with an estimated glomerular filtration rate [eGFR] less than 60 ml / min / 1.73 m2 are at particular risk), heart failure, liver disease, history of AKI. In another preferred embodiment, the present invention is directed to the treatment or prevention of acute kidney disease (AKD) or chronic kidney disease (CKD) stemming from such AKI, including for example, tubulointerstitial fibrosis and diabetic nephropathy.

[0442] In another preferred embodiment, the present invention is directed to the treatment or prevention of liver diseases, including, for example, NAFLD, NASH, liver cirrhosis, portal hypertension, acute liver failure, and hepatocellular carcinoma. Liver disease such as NAFLD and NASH may be associated with various metabolic conditions such as metabolic syndrome and Type II diabetes, which also would increase risk for various diabetes associated pathologies, including diabetic retinopathy and peripiheral neuropathies.

[0443] The compounds of the invention or pharmaceutical compositions thereof as described herein may be combined with one or more additional agents when used for the treatment or prevention of conditions involving liver disease and metabolic dysfunction, including metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, PP AR agonists, SGLT2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).

[0444] References to ‘treatment’ includes means to ameliorate, alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis. The compounds of the invention are useful in the treatment of the diseases disclosed herein in humans and other mammals.

[0445] In another embodiment, the invention encompasses prophylactic therapy of the diseases disclosed herein and includes means to prevent or slow the appearance of symptoms of the named disorder or condition. The compounds of the invention are useful in the prevention of the diseases disclosed herein in humans and other mammals.

[0446] A patient in need of treatment or prevention may, for example, be a human or other mammal suffering from the condition or at risk of suffering from the condition.

[0447] According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt of said compound or tautomer, together with a pharmaceutically acceptable diluent or carrier.

[0448] Pharmaceutical compositions of the invention comprise any of the compounds of the invention combined with any pharmaceutically acceptable carrier, adjuvant or vehicle. Examples of pharmaceutically acceptable carriers are known to those skilled in the art and include, but are not limitedto, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may be in the form of, for example, tablets, capsules, powders, granules, elixirs, lozenges, suppositories, syrups, and liquid preparations including suspensions and solutions. The term “pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms.

[0449] The compounds of the invention or pharmaceutical compositions thereof, as described herein, may be used alone or combined with one or more additional pharmaceutical agents. The compounds may be combined with an additional anti-tumour therapeutic agent, for example, chemotherapeutic drugs or inhibitors of other regulatory proteins. In one embodiment, the additional anti-tumour therapeutic agent is a BH-3 mimetic. In a further embodiment, BH-3 mimetics may be selected from but not limited to one or more of ABT-737, ABT-199, ABT-263, and Obatoclax. In a further embodiment, the additional anti-tumour agent is a chemotherapeutic agent. Chemotherapeutic agents may be selected from but not limited to, olaparib, mitomycin C, cisplatin, carboplatin, oxaliplatin, ionizing radiation (IR), camptothecin, irinotecan, topotecan, temozolomide, taxanes, 5-fluoropyrimidines, gemcitabine, and doxorubicin.

[0450] For the treatment or prevention of fibrotic disorders, for example, the compounds of the invention or pharmaceutical compositions thereof, as described herein, may be used alone or combined with one or more additional pharmaceutical agents selected from the group consisting of anticholinergic agents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK1 antagonists, LTD4 antagonists, EGFR inhibitors and endothelin antagonists.

[0451] In particular, the compounds of the invention or pharmaceutical compositions thereof, as described herein, may be used alone or combined with one or more additional pharmaceutical agents selected from the group consisting of general immunosuppressive drugs, such as a corticosteroid, immunosuppressive or cytotoxic agents, or antifibrotics, such as pirfenidone or a non-specific kinase inhibitor (e.g., nintedanib).

[0452] The pharmaceutical compositions of the invention may be administered in any suitably effective manner, such as oral, parenteral, topical, inhaled, intranasal, rectal, intravaginal, ocular and aural. Pharmaceutical compositions suitable for the delivery of compounds of the present invention andmethods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in " Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

[0453] Oral Administration

[0454] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

[0455] Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi-and nanoparticulates, gels, films (including muco- adhesive), ovules, sprays and liquid formulations.

[0456] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0457] The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

[0458] A typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion. The tablet formulation may comprise one or more layers and may be coated or uncoated.

[0459] Examples of excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulfate, preservatives, anti-oxidants, flavours and colourants.

[0460] Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other modified release formulations are described in US Patent No. 6,106,864.Parenteral Administration

[0461] The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0462] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffering agents (suitably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[0463] The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0464] The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray-dried dispersions and / or using appropriate formulation techniques, such as the use of solubility-enhancing agents.

[0465] Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted, and programmed release.

[0466] Pharmaceutical compositions of the present invention also include compositions and methods known in the art for bypassing the blood brain barrier or can be injected directly into the brain. Suitable areas for injection include the cerebral cortex, cerebellum, midbrain, brainstem, hypothalamus, spinal cord and ventricular tissue, and areas of the peripheral nervous system including the carotid body and the adrenal medulla.

[0467] The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and the route of administration. The selection of appropriate dosages is within the remit of the physician. The daily dose range is about 10 pg to about 100 mg per kg body weight of a human and non-human animal and in general may be around 10 pg to 30 mg per kg body weight per dose. The above dose may be given from one to three times per day.

[0468] For example, oral administration may require a total daily dose of from 5 mg to 1000 mg, such as from 5 to 500 mg, while an intravenous dose may only require from 0.01 to 30 mg / kg body weight, such as from 0.1 to 10 mg / kg, more suitably from 0.1 to 1 mg / kg body weight. The total daily dose may be administered in single or divided doses. The skilled person will also appreciate that, in the treatmentor prevention of certain conditions, compounds of the invention may be taken as a single dose on an "as required" basis (i.e. as needed or desired).

[0469] Synthetic methodologies

[0470] Compounds of formula (I) may be prepared using methods as described below in the general reaction schemes and the representative examples. Where appropriate, the individual transformations within a scheme may be completed in a different order. The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used. Compounds were characterised by liquid chromatography-mass spectrometry (LCMS) or

[0471]

[0472] NMR or both.

[0473] According to a further aspect, the present invention provides a process for the preparation of a compound of formula (I) comprising coupling an acid of formula (VI) (where Y is halo) with an amine of formula (V) (where PG is a protecting group, such as BOC or Cbz) in the presence of a coupling agent, such as HATU, and a base, such as DIPEA, to give the amide. A subsequent ring -forming reaction with an orthoformate, R4aC(OR)3, gives a compound of formula (IV) (Scheme 1). The compound of formula (IV) may be converted into the compound of formula (III) via a Suzuki coupling with an aryl or heteroaryl boronic acid or ester. Other coupling reagents may also be used, such as 2 -pyridylstannanes, together with a suitable Pd catalyst, such as XPhos Pd G3. The compound of formula (III) may be deprotected using standard methods to give amine (II) which may then be reacted with cyanogen bromide to give the corresponding compound of formula (I).

[0474]

[0475] (i) (ii)

[0476] Scheme 1 Alternatively, compounds of formula (IV) may be prepared according to the process of Scheme 2, which comprises reacting a compound of formula (VIII) with a compound of formula (IX) in the presence of a base, such as Cs2CO3.

[0477]

[0478] (VIII) Scheme 2 Alternatively, compounds of formula (III) may be prepared according to the process of Scheme 3, which comprises reacting a compound of formula (IV) with a pyrazole of formula (VII). Imidazolyl, triazolyl and tetrazolyl analogues may be prepared by an analogous process.

[0479]

[0480] In a further aspect, the present invention provides a compound selected from formulae (II) and (III):

[0481]

[0482] (Ill) wherein PG is a protecting group, and ring A, X1, X2, X3, X4, X5, R1, R2and R3are as defined herein for the compound of formula (I) and all embodiments thereof, a tautomer thereof, or a salt of said compound or tautomer.

[0483] For the intermediates of the synthesis of each of the compounds of formulae (I), (I)(A), (I)(B), (I)(C), (I)(D), (I)(E) and (I)(F) of the present invention, the corresponding compounds of formulae (II) and (III) [(II)(aA) to (II)(aF) and (III)(aA) to (III)(aF)], and each of the substructures (i) to (vii) thereof, suitably exist as single stereoisomers, in respect of the assigned stereocentres, having the absolute configuration of formulae (II)(a) and (III)(a), respectively:

[0484]

[0485] (III)(a). For the intermediates where R2is other than hydrogen, the corresponding compounds of formulae (II) and (III) [(II)(bA) to (II)(bF) and (III)(bA) to (III)(bF)] suitably exist as single stereoisomers, in respectof the assigned stereocentres, having the absolute configuration of formulae (II)(b) and (III)(b), respectively:

[0486]

[0487] (III)(b). Where the compounds of formulae (II) and (III) exist as single stereoisomers, they suitably exist with a stereoisomeric excess of at least 60%, more suitably at least 80%, yet more suitably at least 90%, and most suitably at least 95%, for example 96%, 97%, 98%, 99%, or 100%.

[0488] Protecting groups are suitably selected from tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (MeOZ), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), -methoxy phenyl (PMP), tosyl (Ts), trichloroethoxycarbonyl (Troc), 4-nitrobenzenesulfonyl (Nosyl) and 2-nitrophenylsulfenyl (Nps). Most preferred are BOC and Cbz.

[0489] Abbreviations

[0490] br s broad singlet (NMR signal) LCMS liquid chromatography - mass spectrometry

[0491] d doublet (NMR signal) m multiplet (NMR signal)

[0492] dd doublet of doublet (NMR signal) min minute(s)

[0493] DCM dichloromethane NMR nuclear magnetic resonance DEA diethylamine PDA photodiode-array

[0494] DIPEA N,N-diisopropylethylamine rt room temperature

[0495] DMAP 4-dimethylaminopyridine s singlet (NMR signal) DMF N,N-dimethylformamide SFC supercritical fluid chromatography DMSO dimethylsulfoxide t triplet (NMR signal)

[0496] ES electrospray TEA triethylamine

[0497] EtOAc ethyl acetate TFA trifluoroacetic acid

[0498] h hour(s) THF tetrahydrofuran

[0499] HPLC high performance liquid vol volumes

[0500] chromatography

[0501] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide

[0502] hexafluorophosphateLCMS Methods

[0503] Method A

[0504] Mobile (A) 2 mM Ammonium acetate & 0.1% formic acid in water phase (B) 0.1% Formic acid in acetonitrile

[0505] Instrument Shimadzu Nexera UFLC with 2020 single quadrupole mass detector Column Waters XBridge C18 (50 x 4.6 mm), 3.5 µm Column oven temperature Ambient

[0506] TIME Flow Rate

[0507] % A % B

[0508] (min) (mL / min)

[0509] 0.01 0.55 98 2

[0510] 0.30 0.55 98 2

[0511] 0.60 0.55 50 50

[0512] 1.10 0.55 25 75

[0513] 2.00 0.60 0 100

[0514] 2.70 0.60 0 100

[0515] 2.71 0.55 98 2

[0516]

[0517] 3.00 0.55 98 2

[0518] Method B

[0519] Mobile (A) 10 mM Ammonium acetate in water

[0520] phase (B) 100 % Acetonitrile

[0521] Agilent 1290 Infinity RRLC attached with Agilent 6120 Instrument

[0522] Mass detector and Diode array Detector Column Waters XSelect, Phenyl-Hexyl (250 mm x 4.6 mm) 5 pm Column oven temperature Ambient

[0523] TIME Flow Rate

[0524] %A %B

[0525] (min) (mL / min)

[0526] 0.00 1.0 90 10

[0527] 10.0 1.0 60 40

[0528] 20.0 1.0 30 70

[0529] 30.0 1.0 0 100

[0530] 33.0 1.0 0 100

[0531] 33.01 1.0 90 10

[0532]

[0533] 35.0 1.0 90 10Method C

[0534] Mobile (A) 5 mM Ammonium bicarbonate in water

[0535] phase (B) 100% Acetonitrile

[0536] Instrument Shimadzu Nexera UFLC with 2020 single quadrupole mass detector Column Waters XBridge C18 (50 x 4.6 mm), 3.5 pm Column oven temperature Ambient

[0537] TIME Flow Rate

[0538] %A % B

[0539] (min) (mL / min)

[0540] 0.01 1.0 95 5

[0541] 3.50 1.0 10 90

[0542] 4.50 1.0 5 95

[0543] 6.00 1.0 5 95

[0544] 6.01 1.0 95 5

[0545]

[0546] 8.00 1.0 95 5

[0547] Method D

[0548] Mobile (A) 2 mM Ammonium acetate & 0.1% formic acid in water phase (B) 0.1% Formic acid in acetonitrile

[0549] Instrument Waters ACQUITY UPLC H Class with PDA and SQ detector Column BEH C18 (50 x 2.1 mm), 1.7 μm

[0550] Column oven temperature Ambient

[0551] TIME Flow Rate

[0552] %A % B

[0553] (min) (mL / min)

[0554] 0.01 0.5 98 2

[0555] 0.40 0.5 98 2

[0556] 2.50 0.5 35 65

[0557] 3.50 0.5 5 95

[0558] 4.70 0.5 5 95

[0559] 4.71 0.5 98 2

[0560]

[0561] 5.00 0.5 98 2

[0562] Method L Method used for analytical chiral SFC

[0563] Mobile (A) Liquid carbon dioxide

[0564] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (50:50) Instrument Waters SFC Investigator with PDA Detector Column Chiralpak IB-N (250 x 4.6 mm), 5 pm

[0565] TIME Flow Rate

[0566] %B start %B end

[0567] (min) (mL / min)

[0568] 0 to 5 4.0 5 50

[0569] 5 to 10 4.0 50 50

[0570]

[0571] Method E

[0572] Mobile (A) 5 mM Ammonium bicarbonate in water

[0573] phase (B) 100% Acetonitrile

[0574] Instrument Shimadzu Nexera UFLC with 2020 single quadrupole mass detector Column Waters XBridge C18 (50 x 4.6 mm), 3.5 pm Column oven temperature Ambient

[0575] TIME Flow Rate

[0576] %A % B

[0577] (min) (mL / min)

[0578] 0.01 1.0 95 5

[0579] 2.80 1.0 15 85

[0580] 3.50 1.0 5 95

[0581] 5.00 1.0 5 95

[0582] 5.01 1.0 95 5

[0583] 6.00 1.0 95 5

[0584]

[0585] Method F Method used for analytical chiral HPLC

[0586] Mobile (A) 0.1% Diethylamine in w-hexane

[0587] Phase (B) 0.1% Diethylamine in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1260 Series HPLC and PDA detector Column Chiralpak IH (250 x 4.6 mm), 5 pm TIME Flow Rate

[0588] % A % B

[0589] (min) (mL / min)

[0590] 0.01 1.0 80 20

[0591] 5.00 1.0 50 50

[0592] 10.00 1.0 30 70

[0593] 20.00 1.0 30 70

[0594] 20.01 1.0 80 20

[0595]

[0596] 25.00 1.0 80 20

[0597] Method G Method used for analytical chiral HPLC

[0598] Mobile (A) 0.1% Diethylamine in w-hexane

[0599] Phase (B) 0.1% Diethylamine in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1260 series HPLC and PDA detector Column Chiralpak IC (250 x 4.6 mm), 5 pm TIME Flow Rate

[0600] %A start %B end

[0601] (min) (mL / min)

[0602] 0.01 1.0 80 20

[0603] 5.00 1.0 45 55

[0604] 10.00 1.0 30 70

[0605] 15.00 1.0 30 70

[0606] 20.00 1.0 80 20

[0607] 25.00 1.0 80 20

[0608]

[0609] Method H Method used for analytical chiral HPLC

[0610] Mobile (A) 0.1% Ammonia in n-hexane Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1100 series HPLC with PDA detector Column Chiralpak IH (250 x 4.6 mm), 5 pm TIME Flow Rate

[0611] %A %B (min) (mL / min)

[0612] 0.01 1.0 80 20 5.00 1.0 50 50 10.00 1.0 30 70 20.00 1.0 30 70 20.01 1.0 80 20 25.00 1.0 80 20

[0613]

[0614] Method I Method used for analytical chiral HPLC

[0615] Mobile (A) 0.1% Ammonia in w-hexane

[0616] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1260 infinity series HPLC with PDA detector Column Chiralpak IC (250 x 4.6 mm), 5 pm TIME Flow Rate

[0617] % A start % B end (min) (mL / min)

[0618] 0.01 1.0 80 20

[0619] 5.00 1.0 50 50

[0620] 10.00 1.0 30 70 20.00 1.0 30 70 20.01 1.0 80 20 25.00 1.0 80 20

[0621]

[0622] Method J Method used for analytical chiral HPLC

[0623] Mobile (A) 0.1% Ammonia in w-hexane

[0624] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1260 infinity series HPLC with PDA detector Column Chiralpak AD-H (250 x 4.6 mm), 5 pm TIME Flow Rate

[0625] %A %B (min) (mL / min)

[0626] 0.01 1.0 80 20

[0627] 5.00 1.0 50 50

[0628] 10.00 1.0 30 70 20.00 1.0 30 70 20.01 1.0 80 20 25.00 1.0 80 20

[0629]

[0630] Method J1

[0631] Mobile (A) 2 mM Ammonium acetate & 0.1% formic acid in water phase (B) 0.1% Formic acid in acetonitrile Agilent 1290 Infinity RRLC attached with Agilent 6120 Instrument

[0632] mass detector and diode array detector Column BEH C18 (50 x 2.1 mm), 1.7 μm Column oven temperature Ambient

[0633] TIME Flow Rate

[0634] % A % B

[0635] (min) (mL / min)

[0636] 0.01 0.450 98 2

[0637] 0.50 0.450 98 2

[0638] 3.00 0.450 30 70

[0639] 4.00 0.500 5 95

[0640] 5.50 0.500 5 95

[0641] 5.51 0.450 98 2

[0642]

[0643] 6.00 0.450 98 2 Method K Method used for analytical chiral SFC

[0644] Mobile (A) Liquid carbon dioxide

[0645] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (50:50) Instrument Waters SFC Investigator with PDA Detector Column Chiralpak IH (250 x 4.6 mm), 5 μmTIME Flow Rate %B start %B end (min) (mL / min) 0 to 5 4.0 5 50 5 to 12 4.0 50 50

[0646]

[0647] Method M Method used for reverse phase preparative HPLC

[0648] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0649] Instrument Shimadzu LC-20AP and UV detector Column Waters XBridge C18 (250 x 19 mm), 5 μm TIME Flow Rate

[0650] %A % B

[0651] (min) (mL / min)

[0652] 0.01 14.0 85 15 23.00 14.0 55 45

[0653] 23.01 14.0 0 100

[0654] 25.00 14.0 0 100

[0655] 25.01 14.0 85 15

[0656] 30.0 14.0 85

[0657]

[0658] 0 15Method N Method used for chiral preparative HPLC

[0659] Mobile (A) 0.1% Ammonia in n-hexane Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (70:30) Instrument Shimadzu LC-20AP with UV detector Column Chiralpak AD-H (250 x 30 mm), 5 μm TIME Flow Rate

[0660] % A % B (min) (mL / min)

[0661] 0 to 20 30.0 55 45

[0662]

[0663] Method O Method used for analytical chiral HPLC

[0664] Mobile (A) 0.1% Ammonia in n-hexane Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1260 infinity series HPLC with PDA detector Column Chiralpak IB-N (250 x 4.6 mm), 5 μm TIME Flow Rate

[0665] % A % B (min) (mL / min)

[0666] 0.01 1.0 80 20 5.00 1.0 50 50 10.00 1.0 30 70 20.00 1.0 30 70 20.01 1.0 80 20 25.00 1.0 80 20

[0667]

[0668] Method P Method used for analytical chiral SFC

[0669] Mobile (A) Liquid carbon dioxide

[0670] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (50:50) Instrument Waters SFC Investigator with PDA Detector Column Chiralpak IH (250 x 4.6 mm), 5 μm

[0671]

[0672] Method Q Method used for analytical chiral SFC

[0673] Mobile (A) Liquid carbon dioxide

[0674] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (50:50) Instrument Waters SFC Investigator with PDA Detector Column Chiralpak IB-N (250 x 4.6 mm), 5 μm

[0675]

[0676] Method R Method used for analytical chiral HPLC

[0677] Mobile (A) 0.1% Ammonia in n-hexane Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (70:30) Instrument Agilent 1260 infinity series HPLC with PDA detector Column Chiralpak IG (250 x 4.6 mm), 5 μm TIME Flow Rate

[0678] % A start % B end (min) (mL / min)

[0679] 0.01 1.0 80 20

[0680] 5.00 1.0 50 50

[0681] 10.00 1.0 30 70

[0682] 20.00 1.0 30 70

[0683] 20.01 1.0 80 20

[0684] 25.00 1.0 80 20

[0685]

[0686] Method S Method used for analytical chiral SFC

[0687] Mobile (A) Liquid carbon dioxide

[0688] Phase (B) 0.1% Ammonia in propan-2-ol: acetonitrile (50:50) Instrument Waters SFC Investigator with PDA Detector Column Chiralpak IH (250 x 4.6 mm), 5 μm

[0689]

[0690] Method T Method used for reverse phase preparative HPLC

[0691] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0692] Instrument Shimadzu LC-20AP and UV detector Column Waters XBridge C8 (250 x 19 mm), 5 μm TIME Flow Rate

[0693] %A % B

[0694] (min) (mL / min)

[0695] 0.01 12.0 90 10 23.00 12.0 55 45

[0696] 25.00 12.0 55 45

[0697] 25.01 12.0 0 100

[0698] 27.00 12.0 0 100

[0699] 27.01 12.0 90 10

[0700]

[0701] 33.00 12.0 90 10Method U Method used for reverse phase preparative HPLC

[0702] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0703] Instrument Shimadzu LC-20AP and UV detector Column Waters XBridge C8 (250 x 19 mm), 5 μm TIME Flow Rate

[0704] %A % B

[0705] (min) (mL / min)

[0706] 0.01 14.0 90 10 23.00 14.0 55 45

[0707] 23.01 14.0 55 45

[0708] 25.00 14.0 0 100

[0709] 25.01 14.0 0 100

[0710]

[0711] 30.00 14.0 90 10 Method V Method used for reverse phase preparative HPLC

[0712] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0713] Instrument Shimadzu LC-20AP and UV detector Column Waters XBridge C18 (250 x 19 mm), 5 μm TIME Flow Rate

[0714] %A % B

[0715] (min) (mL / min)

[0716] 0.01 12.0 95 5 23.00 12.0 35 65

[0717] 30.00 12.0 35 65

[0718] 30.01 12.0 0 100

[0719] 32.00 12.0 0 100

[0720] 32.01 12.0 95 5

[0721] 37.00 12.0

[0722]

[0723] 95 5 Method W Method used for reverse phase preparative HPLC

[0724] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0725] Instrument Shimadzu LC-20AP and UV detector Column Waters XBridge C18 (250 x 19 mm), 5 μm TIME Flow Rate

[0726] %A % B

[0727] (min) (mL / min)

[0728] 0.01 13.0 80 20 23.00 13.0 45 55

[0729] 23.01 13.0 0 100

[0730] 25.00 13.0 0 100

[0731] 25.01 13.0 80 20

[0732]

[0733] 30.00 13.0 80 20Method X Method used for reverse phase preparative HPLC

[0734] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0735] Instrument Shimadzu LC-20AP and UV detector Column Waters XBridge C18 (250 x 19 mm), 5 μm TIME Flow Rate

[0736] %A % B

[0737] (min) (mL / min)

[0738] 0.01 13.0 95 5 26.00 13.0 65 35

[0739] 28.00 13.0 65 35

[0740] 28.01 13.0 0 100

[0741] 30.00 13.0 0 100

[0742] 30.01 13.0 95 5

[0743] 35.00 13.0

[0744]

[0745] 95 5 Method Y Method used for reverse phase preparative HPLC

[0746] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0747] Instrument Shimadzu LC-20AP and UV detector Column Waters XSelect, Phenyl-Hexyl (250 x 19 mm), 5 μm TIME Flow Rate

[0748] %A % B

[0749] (min) (mL / min)

[0750] 0.01 11.0 75 25 25.00 11.0 30 70

[0751] 25.01 11.0 0 100

[0752] 27.00 11.0 0 100

[0753] 27.01 11.0 75 25

[0754] 35.00 11.0

[0755]

[0756] 75 25 Method Z Method used for reverse phase preparative HPLC

[0757] Mobile (A) 5mM Ammonium bicarbonate & 0.1% ammonia in water Phase (B) 100% Acetonitrile

[0758] Instrument Shimadzu LC-20AP and UV detector Column Welch Xtimate Polar (250 x 21.2 mm), 5 μm TIME Flow Rate

[0759] %A % B

[0760] (min) (mL / min)

[0761] 0.01 14.0 75 25 22.00 14.0 30 70

[0762] 25.00 14.0 30 70

[0763] 25.01 14.0 0 100

[0764] 27.00 14.0 0 100

[0765] 27.01 14.0 75 25

[0766] 34.00 14.0

[0767]

[0768] 75 25Synthesis of Intermediates

[0769] Intermediate 1

[0770] tert-Butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate

[0771] Step (i)

[0772]

[0773] 1-(tert-Butyl) 2-methyl (2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate

[0774] To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (CAS 102195-79-9, from Pharmablock, 500.0 g, 2038.3 mmol) in DCM (5000 mL) was added TEA (411.7 g, 4076.6 mmol) and methanesulfonyl chloride (302.1 g, 2649.8 mmol) dropwise at 0 °C, and the mixture was stirred for 2 h. The mixture was poured into water (2500 mL) and the organic phase was separated. The aqueous phase was further extracted with DCM (3000 mL). The combined organic phases were washed with dilute citric acid solution (800 mL), followed by brine (1500 mL), and dried over anhydrous Na2SO4and concentrated under reduced pressure to yield 1 -(tert-butyl) 2-methyl (2. S'.4. S)-4-((mcthylsulfonyl)-oxy)pyrrolidinc-l.2-dicarboxylatc as a brown semi-solid (610 g, 1887.96 mmol, 92% yield).

[0775] LCMS: Method A, 1.51 min, MS: ES+ 268.1 (M-56); ’H NMR (400 MHz, DMSO-6) 5 ppm: 5.26 -5.27 (m, 1H), 4.42 - 4.56 (m, 1H), 3.78 - 3.83 (m, 5H), 3.04 (s, 3H), 2.51 - 2.58 (m, 2H), 1.51 (s, 4.5H, BOC rotamer 1), 1.46 (s, 4.5H, BOC rotamer 2).

[0776] Step (ii)

[0777] l-(tert-Butyl) 2-methyl (2S, 4R)-4-azidopyrrolidine-l,2-dicarboxylate

[0778] To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (500.0 g, 1548.0 mmol) in DMF (5000 mL) was added sodium azide (139.3 g, 2322 mmol) in portions at 0 °C and then the mixture was gradually heated at 80 °C for 4 h. The mixture was cooled to rt, poured into ice-cold water (3500 mL) and extracted with EtOAc (3 x 3000 mL). The combined organic phases were washed with ice-cold water (4 x 1000 mL), brine (2 x 1000 mL), dried over Na2SO4and concentrated under reduced pressure to yield 1-(tert-butyl) 2-methyl (2S,4R)-4-azidopyrrolidine-1,2-dicarboxylate as a brown semi-solid (400.0 g, 1481.5 mmol, 95% yield).

[0779] LCMS: Method A, 1.65 min, MS: ES+ 271.2; *HNMR (400 MHz, DMSO-6) 5 ppm: 4.36 - 4.39 (m, 1H), 4.20 - 4.27 (m, 1H), 3.65 - 3.68 (m, 3H), 3.51 - 3.58 (m, 1H), 3.38 - 3.41 (d, 1H), 2.29 - 2.38 (m, 1H), 2.10 - 2.19 (m, 1H), 1.40 (s, 4.5H, BOC rotamer 1), 1.34 (s, 4.5H, BOC rotamer 2).Step (iii)

[0780] tert-Butyl (2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-l-carboxylate

[0781] To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-azidopyrrolidine-1,2-dicarboxylate (300 g, 1111.1 mmol) in THF (3000 mL) was added lithium borohydride solution (3 M in THF) (47.2 g, 2166.7 mmol) dropwise at -30 °C. The mixture was allowed to warm to rt and stirred for 3 h. The mixture was quenched by dropwise addition of a saturated solution of NaHCO3(4000 mL) at -78 °C and stirred at rt for 16 h. The mixture was extracted with EtOAc (3 x 3000 mL). The combined organic phases were washed with brine (1000 mL), dried over Na2SO4. and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 23% EtOAc in n-hexane) to yield tert-butyl (2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate as a pale-yellow liquid (202.5 g, 836.8 mmol, 75% yield).

[0782] LCMS: Method A, 1.51 min, MS: ES+ 243.2; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 4.77 (s, 1H), 4.24 (s, 1H), 3.77 (br s, 1H), 3.33 - 3.46 (m, 4H), 2.10 - 2.15 (m, 1H), 1.98 - 1.99 (m, 1H), 1.39 (s, 9H).

[0783] Step (iv)

[0784] (2S,4R)-4-Azido-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0785] To a stirred solution of tert-butyl (2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate (440.0 g, 1818.2 mmol) in DCM (4400 mL) was added TEA (552.0 g, 5454.5 mmol) at rt. After 10 min, methane sulfonyl chloride (312.4 g, 2727.3 mmol) was added dropwise at -10 °C. The mixture was allowed to warm to rt and stirred for 3 h, then poured into ice-cold water (4000 mL) and extracted with DCM (2 x 2000 mL). The combined organic phases were washed with dilute citric acid (2 x 1000 mL), dried over Na2SO4. fdtered and concentrated under reduced pressure to yield tert-butyl (2S,4R)-4-azido-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate as a brown liquid (550.0 g, quantitative yield).

[0786] LCMS: Method B, 17.67 min, MS: ES+ 265.0 (M-56).

[0787] Step (v)

[0788] tert-Butyl (2S,4R)-4-azido-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0789] To a stirred solution of tert-butyl (2S,4R)-4-azido-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (405.0 g, 1265.1 mmol) in toluene (4000 mL) was added 25% sodium methoxide solution (1093.4 mL, 5060.6 mmol) dropwise at 0 °C. The reaction mixture was gradually heated at 45 °C for 3 h. The mixture was then cooled to rt, poured into ice-cold water (8000 mL), and extracted with DCM (3 x 4000 mL). The combined organic phases were washed with brine (2 x 1000 mL), dried over Na2SO4and concentrated under reduced pressure to yield tert-butyl (2S,4R)-4-azido-2-(methoxymethyl)pyrrolidine-1-carboxylate (215.0 g, 839.3 mmol, 66% yield).

[0790] LCMS: Method A, 1.72 min, MS: ES+ 157.5 (M-100).

[0791] Step (vi)

[0792] tert-Butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-l-carboxylateTo a stirred solution of tert-butyl (2S,4R)-4-azido-2-(methoxymethyl)pyrrolidine-1-carboxylate (200 g, 780.79 mmol) in ethanol (2000 mL) was added ammonium chloride (146.2 g, 2732.77 mmol) and water (600 mL) at rt. The reaction mixture was cooled to 0 to 5 °C and zinc dust (357.33 g, 5465.54 mmol) was added in portions. A temperature rise to 20 to 30 °C was observed. The mixture was stirred at 20 to 30 °C for 2 h, the mixture was filtered through Celite® Hyflo and the filtrate was concentrated under reduced pressure. The residue was diluted with water (2000 mL), acidified up to pH 2 to 3 with IM citric acid solution (800 mL) and extracted with EtOAc (2 x 2000 mL). The aqueous phase was basified up to about pH 10 by 28% ammonia solution (600 mL) and extracted with EtOAc (2 x 2000 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure to yield tert-butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (150.0 g, 651.7 mmol, 83% yield). LCMS: Method A, 1.26 min, MS: ES+ 131.3 (M-100).

[0793] Intermediate 2

[0794] tert-Butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate

[0795] N3

[0796]

[0797] Step (i)

[0798] tert-Butyl (2S, 4R)-2-( (1H-1, 2, 3-triazol-l-yl)methyl)-4-azidopyrrolidine-l-carboxylate

[0799] To a stirred solution of 1H-1,2,3-triazole (0.76 g, 11.24 mmol) in DMF (30 mL) was added K2CO3 (3.88 g, 28.11 mmol) at 0°C. tert-Butyl (2S,4R)-4-azido-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (3.0 g, 9.37 mmol) was added at 0 °C. The mixture was allowed to warm to rt and stirred for 48 h, then poured into ice-cold water (700 mL) and extracted with EtOAc (5 x 100 mL). The combined organic phases were washed with ice-cold water (2 x 100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 15 to 20% EtOAc in n-hexane) to yield tert-butyl (2S,4R)-2-((2H-1,2,3-triazol-2-yl)methyl)-4-azidopyrrolidine-1-carboxylate (1.0 g, 3.41 mmol, 36% yield) and subsequently (40 to 50% EtOAc in n-hexane) tert-butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-azidopyrrolidine-1-carboxylate (1.0 g, 3.41 mmol, 36% yield).

[0800] For tert-butyl (2. S'.4 / ?)-2-((2H- 1.2.3-triazol-2-yl)mcthyl)-4-azidopyrrolidinc- 1 -carboxylate (less polar): LCMS: Method A, 1.67 min, MS: ES+ 294.0; ’H NMR (400 MHz, DMSO-6) 5 ppm: 7.83 (s, 2H), 4.63 - 4.65 (m, 2H), 4.02 - 4.19 (m, 2H), 3.41 - 3.44 (m, 1H), 3.04 - 3.14 (m, 1H), 2.00 - 2.17 (m, 2H), 1.43 (s, 9H).For tert-butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-azidopyrrolidine-1-carboxylate (more polar): LCMS: Method A, 1.52 min, MS: ES+ 294.2;1H NMR (400 MHz, DMSO-6) 5 ppm: 7.96 -8.02 (m, 1H), 7.77 (s, 1H), 4.56 - 4.63 (m, 2H), 4.01 - 4.21 (m, 2H), 3.41 - 3.49 (m, 1H), 3.07 - 3.15 (m, 1H), 1.95 - 2.08 (m, 2H), 1.39 (s, 9H).

[0801] tert-Butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate

[0802] To a stirred solution of tert-butyl (2. S'.4 / ?)-2-((l / / -l.2.3-triazol-l-yl)mcthyl)-4-azidopyrrolidinc-l-carboxylate (lower spot, 1.0 g, 3.41 mmol) in methanol (20 mL) was added 10% Pd / C (50% moisture) (0.50 g, 0.5% w / w). The mixture was purged with H2 gas for 1 h, then fdtered through Celite® Hyflo and the fdtrate was concentrated under reduced pressure to yield tert-butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate (0.85 g, 3.18 mmol, 93% yield).

[0803] LCMS: Method A, 1.26 min, MS: ES+ 268.5.

[0804] Intermediate 3

[0805] tert-Butyl (2S,4R)-2-((1H-pyrazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate

[0806] _Boc >

[0807]

[0808] tert-Butyl (2S,4R)-2-((1H-pyrazol-1-yl)methyl)-4-azidopyrrolidine-1-carboxylate

[0809] To a stirred solution of 1H-pyrazole (1.05 g, 15.46 mmol) in DMF (45 mL) was added K2CO3 (5.82 g, 42.18 mmol) at 0 °C. tert-Butyl (2S,4R)-4-azido-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (4.50 g, 14.06 mmol) was added at 0 °C. The mixture was allowed to warm to rt and stirred for 48 h, then poured into ice-cold water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phases were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 15% EtOAc in n-hexane) to yield tert-butyl (2S,4R)-2-((1H-pyrazol-1-yl)methyl)-4-azidopyrrolidine-1-carboxylate (2.42 g, 8.25 mmol, 58% yield). LCMS: Method J1, 3.92 min, MS: ES+ 293.0.

[0810] tert-Butyl (2S,4R)-2-((1H-pyrazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate To a stirred solution of tert-butyl (2S,4R)-2-((1H-pyrazol-1-yl)methyl)-4-azidopyrrolidine-1-carboxylate (0.42 g, 1.43 mmol) in methanol (4.5 mL) was added 10% Pd / C (50% moisture) (0.21 g, 0.5% w / w). The mixture was purged with H2 gas for 2 h, then filtered through Celite® Hyflo and the filtrate was concentrated under reduced pressure to yield tert-butyl (2S,4R)-2-((1H-pyrazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate (0.35 g, 1.31 mmol, 91% yield).

[0811] LCMS: Method J1, 2.64 min, MS: ES+ 267.0.Intermediate 4

[0812] tert-Butyl (2R, 3R)-3-amino-2-methylpyrrolidine-l-carboxylate

[0813] Step (i)

[0814]

[0815] tert-Butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1-hydroxy propan-2-yl) carbamate To a stirred solution of Boc-D-Alanine (125.0 g, 661.37 mmol) in DCM (6800 mL) was added DMAP (121.03 g, 992.06 mmol) and Meldrum’s acid (100 g, 694.44 mmol) in portions over a period of 30 min at 0 °C under N2atmosphere. Dicyclohexylcarbodiimide (156.67 g, 760.58 mmol) was added in portions at 0 °C over 30 min into the reaction mixture and allowed to warm to rt and stirred for 16 h. The reaction was repeated three more times (125 g scale) and the reaction mixtures were combined for work up. The combined reaction mixture was cooled to 0 °C, and the precipitated solid was fdtered through a Buchner funnel. The filtrate was washed with cold IM potassium bisulfate solution (3 x 6000 mL). The organic phase was dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure to give pale-yellow semi-solid product. The residue was suspended in cold acetone (750 mL) and solid was filtered off. The filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by trituration using n-hexane (2 x 3000 mL) and dried under reduced pressure to yield tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1-hydroxypropan-2-yl) carbamate (750.0 g, 2380.95 mmol, 90% yield).

[0816] LCMS: Method A, 1.46 min, MS: ES+ 316.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 12.28 (s, 1H), 7.31 (br s, 1H), 4.31 - 4.33 (m, 1H), 1.67 (s, 6H), 1.38 (s, 9H), 1.24 - 1.26 (m, 3H).

[0817] Step (ii)

[0818] tert-Butyl (R)-2-methyl-3, 5 -dioxopyrrolidine -1 -carboxylate

[0819] To a solution of tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1-hydroxypropan-2-yl) carbamate (750.0 g, 2380.9 mmol) in EtOAc (7500 mL) was added acetic acid (136.1 mL, 2.38 mmol) at rt and the mixture was heated at 90 °C for 45 min. The reaction mixture turned to a clear solution, then was cooled to 0 °C and extracted with saturated NaHCO3solution (3 x 2500 mL). The combined aqueous phases were acidified up to about pH 3 by adding solid citric acid (1000 g) in portions over a period of 30 min. The acidified aqueous layer was extracted with EtOAc (3 x 3000 mL). The combined organic phases were washed with brine (1500 mL), dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by trituration using n-hexane (4000 mL) and dried under reduced pressure to yield tert-butyl (R)-2-methyl-3,

[0820] 5 -dioxopyrrolidine- 1 -carboxylate (400.0 g, 1877.93 mmol, 79% yield).

[0821] LCMS: Method A, 1.42 min, MS: ES+ 214.1; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 4.82 (s, 1H), 4.31 (q, J = 6.6 Hz, 1H), 1.46 (d, J= 10.0 Hz, 1H), 1.46 (s, 9H), 1.38 (d, J= 6.6 Hz, 3H).Step (iii)

[0822] tert-Butyl (R)-3-amino-2-methyl-5-oxo-2, 5-dihydro-lH-pyrrole-l -carboxylate

[0823] To a stirred solution of tert-butyl (R)-2-methyl-3,5-dioxopyrrolidinc- 1 -carboxylate (400.0 g, 1877.93 mmol) in methanol (4000 mL) was added ammonium acetate (1013.2 g, 13145.53 mmol) at rt and the mixture was refluxed for 16 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with DCM (5000 mL) and washed with cold 2M sodium hydroxide solution (3 x 2000 mL) and saturated NaHCO, solution (2 x 2000 mL). The organic layer was washed with brine (2000 mL), dried over Na2SO4. fdtered, and concentrated under reduced pressure. The residue was purified by trituration using w-hexane (3000 mL) and dried under reduced pressure to yield tert-butyl ( / ?)-3-amino-2-mcthyl-5-oxo-2.5-dihydro- 1 H-pyrrolc- 1 -carboxylate (370.0 g,

[0824] 1745.28 mmol, 93% yield).

[0825] LCMS: Method A, 1.32 min, MS: ES+ 157.1 (M-56).

[0826] Step (iv)

[0827] tert-Butyl (2R,3R)-3-amino-2-methyl-5-oxopyrrolidine-l -carboxylate

[0828] A solution of tert-butyl ( / ?)-3-amino-2-mcthyl-5-oxo-2.5-dihydro- 1 H-pyrrolc- 1 -carboxylate (370 g, 1745.28 mmol) in EtOAc (1900 mL) and acetic acid (1900 mL) was stirred at rt for 1 h, followed by addition of sodium cyanoborohydride (658.04 g, 10471.69 mmol) in portions at 0 to 5 °C. The mixture was allowed to warm to rt and stirred for 2.5 h. The mixture was diluted with EtOAc (1000 mL) and IM hydrochloric acid (2000 mL) was added dropwise at 0 °C. The aqueous layer was separated, and the organic layer was again washed with IM hydrochloric acid (2 x 1500 mL). The combined aqueous phases were basified up to pH 8 to 9 with solid K2CO3 at 0 °C and extracted with DCM (3 x 2000 mL). The combined organic phases were washed with brine (1500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield tert-butyl (2 / ?.3 / ?)-3-amino-2-mcthyl-5-oxopyrrolidinc- 1 -carboxylate (166.0 g, 775.70 mmol, 44% yield).

[0829] LCMS: Method A, 1.23 min, MS: ES+ 159.0 (M-56).

[0830] Step (v)

[0831] tert-Butyl (2R, 3R)-3-amino-2-methylpyrrolidine-l-carboxylate

[0832] To a stirred suspension of sodium borohydride (42.4 g, 1121.49 mmol) in THF (3500 mL) was added a solution of iodine (213.48 g, 841.12 mmol) in THF (800 mL) dropwise at 0 °C, and stirred at 0 °C until the mixture decolourised. A solution of tert-butyl (2 / ?.3 / ?)-3-amino-2-mcthyl-5-oxopyrrolidinc-1-carboxylate (60.0 g, 280.37 mmol) in THF (800 mL) was added drop wise at 0 °C and the mixture was allowed to warm to rt and stirred for 2 h. The reaction was repeated (60 g scale) and the reaction mixtures combined for work up. The combined reaction mixture was cooled to 0 °C and IM hydrochloric acid (1000 mL) was added dropwise, then stirred for 1 h. The aqueous layer was washed with EtOAc (2 x 2000 mL), and then the aqueous layer was basified up to pH 8 to 9 by adding solid K2CO3 (about 2000 g), then extracted with DCM (4 x 2000 mL). The combined organic phases werewashed with brine (1500 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure to yield tert-butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (55.0 g, 275.0 mmol, 49% yield). LCMS: Method C, 2.68 min, MS: ES+ 144.9 (M-56).

[0833] Synthesis of Examples

[0834] Example 1

[0835] l-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[0836] CN

[0837]

[0838] tert-Butyl (2S,4R)-4-(3-amino-6-chloropicolinamido)-2-(methoxymethyl)pyrrolidine-l-carboxylate To a stirred solution of 3-amino-6-chloropicolinic acid (1.0 g, 5.79 mmol) in THF (10 mL) was added DIPEA (2.20 g, 17.38 mmol) and HATU (3.30 g, 8.60 mmol) in portions at 0 °C. After 30 min, a solution of tert-butyl (2. S'.4 / ?)-4-amino-2-(mcthoxymcthyl)pyrrolidinc-l -carboxylate (1.30 g, 5.79 mmol) in THF (2 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 16 h, then poured into saturated NaHCCf solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 23% EtOAc in M-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(3-amino-6-chloropicolinamido)-2-(methoxymethyl)pyrrolidine-l -carboxylate (1.80 g, 4.68 mmol, 81% yield).

[0839] LCMS: Method A, 1.71 min, MS: ES+ 285.2, 287.2 (M-100).

[0840] tert-Butyl (2S,4R)-4-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1 -carboxylate

[0841] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(3-amino-6-chloropicolinamido)-2-(mcthoxymcthyl)-pyrrolidine-1 -carboxylate (0.20 g, 0.52 mmol) in triethyl orthoformate (5.0 mL, 25 vol) was added concentrated hydrochloric acid (7 to 8 drops) dropwise at 0 °C. The mixture was heated at 100 °C for 16 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95% EtOAc in M-hexane) to yield tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.10 g, 0.25 mmol, 48% yield).

[0842] LCMS: Method D, 2.84 min, MS: ES+ 395.2, 397.2.Step (iii)

[0843] tert-Butyl (2S,4R)-4-(6-(4-cyano-lH-pyrazol-l-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate

[0844] To a stirred solution of tert-butyl (2S, 4R)-4-(6-chloro-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.10 g, 0.25 mmol) and lH-pyrazole-4-carbonitrile (0.02 g, 0.25 mmol) in DMF (3.0 mL) was added K2CO3 (0.10 g, 0.76 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of potassium iodide (0.06 g, 0.38 mmol). The mixture was heated at 100 °C for 6 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 56% EtOAc in n-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(6-(4-cyano-l / / -pyrazol-l-yl)-4-oxopyrido|3.2-t / |pyrimidin-3 (427)-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.04 g, 0.09 mmol, 39% yield).

[0845] LCMS: Method A, 1.62 min, MS: ES+ 452.2.

[0846] Step (iv)

[0847] l-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt

[0848] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-(4-cyano-l / / -pyrazol-l-yl)-4-oxopyrido|3.2 / |-pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.04 g, 0.09 mmol) in DCM (1.5 mL) was added TFA (0.2 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield l-(3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)- lH-pyrazole-4-carbonitrile TFA salt (0.06 g, quantitative yield).

[0849] LCMS: Method D, 2.00 min, MS: ES+ 352.4.

[0850] Step (v)

[0851] l-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin- 6-yl)-lH-pyrazole-4-carbonitrile

[0852] To a stirred solution of l-(3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt (0.06 g, 0.12 mmol) in THF (1.5 mL) was added K2CO3 (0.05 g, 0.38 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.02 g, 0.19 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 56% EtOAc in n-hexane) to yield l-(3-((3 / ?.5. S)- l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)- \H-pyrazole-4-carbonitrile (0.02 g, 0.04 mmol, 45% yield over 2 steps).

[0853] LCMS: Method E, 2.32 min, MS: ES+ 377.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.44 (s, 1H), 8.52(s, 1H), 8.47 (s, 1H), 8.40 - 8.42 (m, 2H), 5.26 - 5.29 (m, 1H), 4.23 - 4.24 (m, 1H), 3.87 - 3.92 (m, 1H), 3.78 - 3.80 (m, 1H), 3.47 - 3.56 (m, 2H), 3.37 (s, 3H), 2.51 - 2.56 (m, 1H), 2.24 - 2.28 (m, 1H); chiral HPLC: Method F, 10.22 min.

[0854] Example 2

[0855] l-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[0856] CN

[0857]

[0858] Step (i)

[0859] tert-Butyl (2S,4R)-4-(6-chloro-2-methyl-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0860] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(3-amino-6-chloropicolinamido)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (1.50g, 3.90 mmol) and 1,1,1 -triethoxy ethane (7.5 m, 5 vol) in ethanol (7.5 mL) was added iodine (0.09 g, 0.39 mmol) at rt and the mixture was heated at 90 °C for 16 h, then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100% EtOAc) to yield tert-butyl (2. S'.4 / ?)-4-(6-chloro-2-mcthyl-4-oxopyrido [3.2 / | py rim idin-3 (4H)-y I )-2-(mcthox mcthy I )py rrol idinc- 1 -carboxylate (0.35 g,

[0861] 0.85 mmol, 21% yield).

[0862] LCMS: Method A, 1.57 min, MS: ES+ 309.2, 311.2 (M-100).

[0863] Step (ii)

[0864] tert-Butyl (2S,4R)-4-(6-(4-cyano-lH-pyrazol-l-yl)-2-methyl-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0865] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-chloro-2-mcthyl-4-oxopyrido|3.2 / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.30 g, 0.73 mmol) and 1H-pyrazole-4-carbonitrile (0.08 g, 0.88 mmol) in DMF (3.0 mL) was added K2CO3 (0.30 g, 2.20 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of potassium iodide (0.18 g, 1.10 mmol). The mixture was heated at 100 °C for 16 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100% EtOAc) to yield tert-butyl (2. S'.4 / ?)-4-(6-(4-cyano-IH-pyrazol-l-yl)-2 -methyl -4-oxopyrido [3, 2 / |pyrimidin-3 (4H)-yl)-2-(mcthoxymcthyl)pyrrolidinc-l -carboxylate (0.19 g, 0.38 mmol, 55% yield).

[0866] LCMS: Method D, 3.06 min, MS: ES+ 466.5.Step (iii)

[0867] l-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt

[0868] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-(4-cyano-l / / -pyrazol-l-yl)-2 -methyl -4-oxopyrido| 3.2 / |pyrimidin-3(4 / / )-yl)-2-(mcthoxymcthyl)pyrrolidinc- 1 -carboxylate (0.17 g,

[0869] 0.36 mmol) in DCM (1.7 mL) was added TFA (0.35 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield l-(3-((37?,5S)-5 -(methoxymethyl)pyrrolidin-3 -yl)-2-methyl-4-oxo-3,4-dihydropyrido [3.2 / |pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt (0.17 g, quantitative yield).

[0870] LCMS: Method D, 2.06 min, MS: ES+ 366.2.

[0871] Step (iv)

[0872] 1-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[0873] To a stirred solution of l-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-2-mcthyl-4-oxo-3.4-dihydropyrido[3,2-<7]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt (0.17 g, 0.35 mmol) in THF (1.7 mL) was added K2CO3 (0.14 g, 1.06 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.05 g, 0.53 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (20 mL) and the precipitated solid was collected through a Buchner funnel, dried under reduced pressure to yield l-(3-((3 / ?.5. S)-l-cyano-5-(mcthoxymcthyl)pyrrolidin-3-yl)-2-mcthyl-4-oxo-3.4-dihydropyrido|3.2-t / |pyrimidin-6-yl)-l / / -pyrazolc-4-carbonitrilc (0.05 g,

[0874] 0.12 mmol, 35% yield over 2 steps).

[0875] LCMS: Method E, 2.39 min, MS: ES+ 391.2;1HNMR(400 MHz, DMSO-6) 5ppm: 9.43 (s, 1H), 8.50 (s, 1H), 8.36 (d, J= 8.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 5.14 - 5.18 (m, 1H), 4.26 - 4.29 (m, 1H), 3.82 - 3.92 (m, 2H), 3.46 - 3.54 (m, 2H), 3.34 (s, 3H), 2.70 (s, 3H), 2.51 - 2.56 (m, 1H), 2.18 - 2.23 (m, 1H); chiral HPLC: Method F, 9.40 min.

[0876] Example 3

[0877] 2-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile

[0878] CN

[0879]

[0880] 2-(T rimethylstannyl)isonicotinonitrile

[0881] To a stirred solution of 2-bromoisonicotinonitrile (0.50 g, 2.73 mmol) in toluene (5 mL) was added 1,1,1,2,2,2-hexamethyldistannane (1.78 g, 5.46 mmol). The mixture was purged with N2 gas for 15 min,followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.31 g, 0.27 mmol) and heated at 100 °C for 8 h. The mixture was poured into water (20 mL) and extracted with n-hexane (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure to yield 2-(trimethylstannyl) isonicotinonitrile (0.60 g, quantitative yield).

[0882] LCMS: Method E, 3.26 min, MS: ES+ 269.0.

[0883] Step (ii)

[0884] tert-Butyl (2S,4R)-4-(6-(4-cyanopyridin-2-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0885] A stirred solution of tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.25 g, 0.63 mmol) and

[0886] 2-(trimethylstannyl)isonicotinonitrile (1.27 g, 4.75 mmol) in THF (2.5 mL) was purged with N2gas for 10 min, followed by addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) (0.05 g, 0.06 mmol) and heated at 100 °C for 6 h. The mixture was then poured into water (25 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over anhydrous Na2SC>4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 83% EtOAc in n-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(6-(4-cyanopyridin-2-yl)-4-oxopyrido|3.2 / |-pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.04 g, 0.09 mmol, 13% yield). LCMS: Method E, 2.99 min, MS: ES+ 407.2 (M-56).

[0887] Step (iii)

[0888] 2-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile TFA salt

[0889] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-(4-cyanopyridin-2-yl)-4-oxopyrido|3.2-t / |pyrimidin-3 (4 / / )-yl)-2-(mcthoxymcthyl)pyrrolidinc- 1 -carboxylate (0.04 g, 0.09 mmol) in DCM (1 mL) was added TFA (0.2 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 2-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)isonicotinonitrile TFA salt (0.06 g, quantitative yield).

[0890] LCMS: Method A, 1.29 min, MS: ES+ 363.2.

[0891] Step (iv)

[0892] 2-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile

[0893] To a stirred solution of 2-(3-((3J?,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido|3.2 / |pyrimidin-6-yl)isonicotinonitrilc TFA salt (0.06 g, 0.12 mmol) in THF (1 mL) was added K2CO3 (0.05 g, 0.37 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.02 g, 0.18 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried overanhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 85% EtOAc in n-hexane) to yield 2-(3-((3 / ?.5. S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)isonicotinonitrile (0.02 g, 0.05 mmol, 59% yield over 2 steps).

[0894] LCMS: Method E, 2.35 min, MS: ES+ 388.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.01 (dd, J= 0.8, 5.2 Hz, 1H), 8.78 (d, J= 8.8 Hz, 1H), 8.72 (s, 1H), 8.47 (s, 1H), 8.30 (d, J= 8.8 Hz, 1H), 8.02 (dd, J= 1.6, 4.8 Hz, 1H), 5.26 - 5.30 (m, 1H), 4.21 - 4.24 (m, 1H), 3.88 - 3.93 (m, 1H), 3.79 - 3.83 (m, 1H), 3.49 - 3.61 (m, 2H), 3.35 (s, 3H), 2.51 - 2.56 (m, 1H), 2.22 - 2.28 (m, 1H); chiral HPLC: Method F, 9.63 min.

[0895] Example 4

[0896] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[0897] CN

[0898]

[0899] Step (i)

[0900] tert-Butyl (2R,3R)-3-(3-amino-6-chloropicolinamido)-2-methylpyrrolidine-l-carboxylate

[0901] To a stirred solution of 3-amino-6-chloropicolinic acid (0.70 g, 4.07 mmol) in THF (5 mL) was added DIPEA (1.57 g, 12.20 mmol) and HATU (1.86 g, 6.10 mmol) in portions at 0 °C. After 30 min, a solution of tert-butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (0.81 g, 4.07 mmol) in THF (2 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 5 h, then poured into saturated NaHCCF solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 26% EtOAc in w-hexane) to yield tert-butyl (2R,3R)-3-(3-amino-6-chloropicolinamido)-2-methylpyrrolidine-l-carboxylate (0.60 g, 1.69 mmol, 42% yield).

[0902] LCMS: Method A, 1.81 min, MS: ES+ 255.2, 257.2 (M-100).

[0903] Step (ii)

[0904] tert-Butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[0905] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(3-amino-6-chloropicolinamido)-2-mcthylpyrrolidinc-l-carboxylate (0.60 g, 1.69 mmol) in triethyl orthoformate (6.0 mL, 10 vol) was added concentrated hydrochloric acid (7 to 8 drops) dropwise at 0 °C. The mixture was heated at 100 °C for 16 h, then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography (silica gel, 83% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4H)-yl)-2-mcthylpyrrolidinc-l-carboxylate (0.31 g, 0.85 mmol, 50% yield).

[0906] LCMS: Method A, 1.57 min, MS: ES+ 309.2, 311.2 (M-56).

[0907] Step (iii)

[0908] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,2-d]pyrimidin-3 ( 4H)-yl) pyrrolidine- 1 -carboxylate

[0909] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1 -carboxylate (0.12 g, 0.34 mmol) and 4-(trifluoromcthyl)-IH-pyrazolc (0.05 g, 0.39 mmol) in DMF (3 mL) was added K2CO3 (0.14 g, 0.99 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of potassium iodide (0.08 g, 0.49 mmol) and heated at 100 °C for 1.5 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with ice-cold water (3 x 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc in n-hexane) to yield to yield tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifluoromcthyl)-IH-pyrazol-l-yl)pyrido [3, 2 / |pyrimidin-3(4H)-yl)pyrrolidinc-l -carboxylate (0.09 g, 0.19 mmol, 59% yield).

[0910] LCMS: Method A, 1.79 min, MS: ES+ 465.3.

[0911] Step (iv)

[0912] 3-(( 2R 3R)-2-Methylpyrrolidin-3-yl)-6-(4-(trifluoromethyl)-lH-pyrazol-l -yl)pyrido[3, 2-d]pyrimidin-4(3H)-one TFA salt

[0913] To a stirred solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifluoromcthyl)-IH-pyrazol-l-yl)pyrido [3, 2 / |pyrimidin-3(4H)-yl)pyrrolidinc- 1 -carboxylate (0.09 g, 0.19 mmol) in DCM (2 mL) was added TFA (0.9 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(4-(trifliioromcthyl)-IH-pyrazol-l-yl)pyrido|3.2 / |pyrimidin-4(jrtJ-onc TFA salt (0.12 g, quantitative yield).

[0914] LCMS: Method C, 1.34 min, MS: ES+ 365.2.

[0915] Step (v)

[0916] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[0917] To a stirred solution of 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(4-(trifluoromcthyl)-IH-pyrazol-l-yl)pyrido[3,2-<7]pyrimidin-4(3F()-one TFA salt (0.12 g, 0.25 mmol) in THF (1 mL) was added K2CO3 (0.10 g, 0.75 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.03 g, 0.28 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into ice-cold water (10 mL) and the precipitated solid was collected through a Buchner funnel. The residue waspurified by trituration with n-pentane (2 x 5 mL) and dried under reduced pressure to yield (2R.3R)-2-mcthyl-3-(4-oxo-6-(4-(trifliioromcthyl)-l / / -pyrazol-l-yl)pyrido|3.2-t / |pyrimidin-3(4 / / )-yl)pyrrolidine-l -carbonitrile (0.04 g, 0.11 mmol, 59% yield over two steps).

[0918] LCMS: Method E, 2.82 min, MS: ES+ 390.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.19 (s, 1H), 8.40 - 8.42 (m, 3H), 8.33 (s, 1H), 5.31 - 5.38 (m, 1H), 4.06 - 4.09 (m, 1H), 3.87 - 3.92 (m, 1H), 3.50 - 3.59 (m, 1H), 2.46 - 2.50 (m, 2H), 0.96 (d, J= 6.8 Hz, 3H); chiral HPLC: Method F, 6.91 min.

[0919] Example 5

[0920] l-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[0921] CN

[0922]

[0923] Step (i)

[0924] tert-Butyl (2R, 3R)-3-( 6-( 4-cyano-lH-pyrcizol-l -yl)-4-oxopyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)-2-methylpyrrolidine-1 -carboxylate

[0925] To a stirred solution of tert-butyl (2 / .3 / )-3-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.10 g, 0.27 mmol) and lH-pyrazole-4-carbonitrile (0.03 g, 0.33 mmol) in DMF (1.0 mL) was added K2CO3 (0.11 g, 0.82 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of potassium iodide (0.07 g, 0.41 mmol). The mixture was heated at 100 °C for 3 h, then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 59% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(4-cyano-l / / -pyrazol- l-yl)-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.05 g, 0.12 mmol, 43% yield).

[0926] LCMS: Method A, 1.63 min, MS: ES+ 422.3.

[0927] Step (ii)

[0928] l-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt

[0929] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-(4-cyano-l / / -pyrazol-l-yl)-4-oxopyrido|3.2 / |-pyrimidin-3(427)-yl)-2 -methylpyrrolidine-1 -carboxylate (0.05 g, 0.12 mmol) in DCM (0.5 mL) was added TFA (0.25 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield l-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2-d'|pyrimidin-6-yl)- lH-pyrazole-4-carbonitrile TFA salt (0.06 g, quantitative yield).

[0930] LCMS: Method A, 1.27 min, MS: ES+ 322.2.Step (iii)

[0931] l-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[0932] To a stirred solution of l-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2 / |-pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt (0.06 g, 0.13 mmol) in THF (0.6 mL) was added K2CO3 (0.06 g, 0.41 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.01 g, 0.13 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (30 mL). The precipitated solid was collected through a Buchner funnel, washed with n-hexane (20 mL), and dried under reduced pressure to yield l-(3-((2R,3R)-l-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 2 / |pyrimidin-6-yl)- lH-pyrazole-4-carbonitrile (0.02 g, 0.06 mmol, 49% yield over two steps).

[0933] LCMS: Method E, 2.35 min, MS: ES+ 347.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.45 (s, 1H), 8.54 (s, 1H), 8.41 (br s, 2H), 8.33 (s, 1H), 5.32 - 5.35 (m, 1H), 4.06 - 4.09 (m, 1H), 3.88 - 3.93 (m, 1H), 3.50 - 3.56 (m, 1H), 2.52 - 2.56 (m, 2H), 0.95 (d, J= 6.4 Hz, 3H); chiral HPLC: Method G, 10.89 min. Example 6

[0934] (2R, 3R)-3-( 6-( 3-Cyanophenyl)-4-oxopyrido[3, 2-d]pyrimidin-3( 4H)-yl)-2-methylpyrrolidine-l -carbonitrile

[0935] CN

[0936]

[0937] Step (i)

[0938] tert-Butyl (2R,3R)-3-(6-(3-cyanophenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1 -carboxylate

[0939] To a stirred solution of tert-butyl (2 / .3 / )-3-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.16 g, 0.43 mmol) and (3-cyanophenyl)boronic acid (0.08 g, 0.52 mmol) in 1,4-dioxane: water (1.6 mL, 4:1) was added K2CO3 (0.18 g, 1.31 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3) (0.04 g, 0.04 mmol) and heated at 80 °C for 20 min. The mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 63% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(3-cyanophcnyl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-methylpyrrolidine-l-carboxylate (0.10 g, 0.23 mmol, 53% yield).

[0940] LCMS: Method A, 1.69 min, MS: ES+ 432.3.Step (ii)

[0941] 3-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzonitrile TFA salt

[0942] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-(3-cyanophcnyl)-4-oxopyrido|3.2 / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-l -carboxylate (0.10 g, 0.23 mmol) in DCM (1.0 mL) was added TFA (0.5 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido- 13.2-t / |pyri idin-6-y I (benzonitrile TFA salt (0.12 g, quantitative yield).

[0943] LCMS: Method A, 1.30 min, MS: ES+ 332.1.

[0944] Step (iii)

[0945] (2R, 3R)-3-( 6-( 3-Cyanophenyl)-4-oxopyrido[3, 2-d]pyrimidin-3( 4H)-yl)-2-methylpyrrolidine-l -carbonitrile

[0946] To a stirred solution of 3-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2 / |-pyrimidin-6-yl)benzonitrile TFA salt (0.12 g, 0.27 mmol) in THF (1.2 mL) was added K2CO3 (0.11 g, 0.80 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.03 g, 0.27 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (30 mL). The precipitated solid was collected through a Buchner funnel, washed with n-hexane (20 mL), and dried under reduced pressure to yield f2 / ?.3 / ?)-3-(6-(3-cyanophcnyl)-4-oxopyrido|3.2-d'|pyrimidin-3 (4 / / )-yl)-2-mcthylpyrrolidinc- 1 -carbonitrile (0.05 g, 0.13 mmol, 56% yield over two steps).

[0947] LCMS: Method E, 2.31 min, MS: ES+ 357.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 8.65 (s, 1H), 8.56 - 8.57 (m, 2H), 8.26 - 8.30 (m, 2H), 7.98 (d, J= 7.6 Hz, 1H), 7.78 (t, J= 8.0 Hz, 1H), 5.32 - 5.38 (m, 1H), 4.05 - 4.09 (m, 1H), 3.88 - 3.90 (m, 1H), 3.51 - 3.58 (m, 1H), 2.51 - 2.56 (m, 2H), 0.95 (t, J= 6.4 Hz, 3H); chiral HPLC: Method F, 9.95 min.

[0948] Example 7

[0949] (2S,4R)-2-(Methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,2-d]pyrimidin- 3 ( 4H)-yl) pyrrolidine- 1 -carbonitrile

[0950] CN

[0951]

[0952] Step (i)

[0953] tert-Butyl (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l -carboxylate

[0954] To a stirred solution of tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.12 g, 0.30 mmol) in DMF (3 mL) was added K2CO3 (0.13 g, 0.91 mmol). The mixture was purged with N2 gas for 20 min, followed by addition of potassiumiodide (0.07 g, 0.46 mmol) and heated at 100 °C for 2 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with ice-cold water (3 x 30 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 68% EtOAc in n-hexane) to yield tert-butyl (2SAR)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)- IH-pyrazol- 1 -yl)pyrido [3.2-t / |pyrimidin-3 (427)-yl)pyrrolidine-l -carboxylate (0.05 g, 0.10 mmol, 33% yield).

[0955] LCMS: Method A, 1.81 min, MS: ES+ 495.3.

[0956] Step (ii)

[0957] 3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,2-d]pyrimidin-4(3H)-one TFA salt

[0958] To a stirred solution of tert-butyl (2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(4-(trifluoromcthyl )-! / / -pyrazol-l-yl)pyrido [3, 2 / |pyrimidin-3(4 / / )-yl)pyrrolidinc-l -carboxylate (0.05 g, 0.10 mmol) in DCM (1 mL) was added TEA (0.5 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(4-(trifliioromcthyl)-l / / -pyrazol-l-yl)pyrido|3.2 / |pyrimidin-4(j / / t-onc TFA salt (0.07 g, quantitative yield).

[0959] LCMS: Method A, 1.37 min, MS: ES+ 395.2.

[0960] Step (iii)

[0961] (2S, 4R)-2-(Methoxymethyl)-4-( 4-oxo-6-( 4-(trifluoromethyl)-lH-pyrazol-l -yl)pyrido[3, 2-d]pyrimidin-3 ( 4H)-yl) pyrrolidine- 1 -carbonitrile

[0962] To a stirred solution of 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(4-(trifluoromcthyl)-l / / -pyrazol-l-yl)pyrido[3,2-<7]pyrimidin-4(327)-one TFA salt (0.07 g, 0.15 mmol) in THF (1 mL) was added K2CO3 (0.06 g, 0.45 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.02 g, 0.16 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous NazSO-i, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc in n-hexane) to yield (2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(4-(trifluoromcthyl)-l / / -pyrazol- I -yl )pyrido| 3.2-<s / | pyrimidin-3(4 / / )-yl (pyrrolidine- 1 -carbonitrile (0.02 g, 0.06 mmol, 61% yield over two steps).

[0963] LCMS: Method E, 2.59 min, MS: ES+ 437.3 (M+18); ’H NMR (400 MHz, DMSO-6) 5 ppm: 9.17 (s, 1H), 8.45 (s, 1H), 8.39 - 8.41 (m, 3H), 5.22 - 5.30 (m, 1H), 4.17 - 4.24 (m, 1H), 3.86 - 3.90 (m, 1H), 3.76 - 3.80 (m, 1H), 3.46 - 3.55 (m, 2H), 3.35 (s, 3H), 2.43 - 2.47 (m, 1H), 2.20 - 2.27 (m, 1H); chiral HPLC: Method G, 9.57 min.

[0964] Example 8

[0965] (2R,3R)-2-Methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[0966]

[0967] Step (i)

[0968] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l -carboxylate

[0969] To a stirred solution of tert-butyl (2 / .3 / )-3-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.15 g, 0.41 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (0.13 g, 0.62 mmol) in 1,4-dioxane: water (2 mL, 4:1) was added K2CO3 (0.17 g, 1.23 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1, 1 '-biphenyl) [2-(2'-amino- 1, 1 '-biphenyl)] -palladium(II) methanesulfonate (Ruphos PD G3) (0.02 g, 0.02 mmol) and heated at 80 °C for 15 min. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 84% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(3 -(trifluoromethoxy )phenyl)pyrido [3.2 / | py rim idin-3 (4 / / )-y I (pyrrol idinc- 1 -carboxylate (0.12 g, 0.24 mmol, 58% yield). LCMS: Method A, 1.93 min, MS: ES+ 491.1.

[0970] Step (ii)

[0971] 3-((2R3R)-2-Methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)pyrido[3, 2-d]pyrimidin-4(3H)-one TFA salt

[0972] To a stirred solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(3-(trifluoromcthoxy)phcnyl)-pyrido[3,2-<7]pyrimidin-3(427)-yl)pyrrolidine-l-carboxylate (0.12 g, 0.24 mmol) in DCM (4 mL) was added TFA (1.2 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(3-(trifluoromcthoxy)phcnyl)pyrido|3.2-d'|pyrimidin-4(3 / / )-onc TFA salt (0.16 g, quantitative yield). LCMS: Method A, 1.39 min, MS: ES+ 391.1.

[0973] Step (iii)

[0974] (2R,3R)-2-Methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[0975] To a stirred solution of 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(3-(trifluoromcthoxy)phcnyl)-pyrido[3,2-aQpyrimidin-4(327)-one TFA salt (0.16 g, 0.32 mmol) in THF (2 mL) was added K2CO3 (0.13 g, 0.95 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.04 g, 0.35 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 3.4% methanol in DCM) to yield (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy )phenyl)pyrido [3.2 / | py rimidin-3 (4 / / )- I (p rrolidine- 1 -carbonitrile (0.03 g, 0.08 mmol, 35% yield over two steps).

[0976] LCMS: Method E, 3.04 min, MS: ES+ 416.4; ’H NMR (400 MHz, DMSO-6) 5 ppm: 8.55 (d, J = 8.4 Hz, 1H), 8.22 - 8.31 (m, 4H), 7.72 (t, J= 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 5.33 - 5.38 (m, 1H), 4.05 - 4.12 (m, 1H), 3.87 - 3.93 (m, 1H), 3.50 - 3.56 (m, 1H), 2.51 - 2.56 (m, 2H), 0.97 (d, J= 6.4 Hz, 3H); chiral HPLC: Method H, 7.28 min.

[0977] Example 9

[0978] (2S, 4R)-4-( 6-(3-Cyanophenyl)-4-oxopyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)-2-(methoxymethyl)pyrrolidine-1 -carbonitrile

[0979]

[0980] Step (i)

[0981] tert-Butyl (2S,4R)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0982] To a stirred solution of tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.20 g, 0.51 mmol) and (3-cyanophenyl)boronic acid (0.08 g, 0.55 mmol) in 1,4-dioxane: water (4 mL, 4:1) was added K2CO3 (0.21 g, 1.52 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of 11.1 '- / v.s(diphcnylphosphino)fcrroccnc| dichloropalladium (II) (0.04 g, 0.05 mmol) and heated at 100 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 26% EtOAc in n-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(6-(3-cyanophcnyl)-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.20 g, 0.43 mmol, 85% yield).

[0983] LCMS: Method A, 1.73 min, MS: ES+ 406.2 (M-56).

[0984] Step (ii)

[0985] 3-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzonitrile TFA salt

[0986] To a stirred solution of tert-butyl (2. S'.4 / )-4-(6-(3-cyanophcnyl)-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.20 g, 0.43 mmol) in DCM (3.0 mL) was added TFA (1.0 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to 3-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2-d'|pyri idin-6-y I (benzonitrile TFA salt (0.25 g, quantitative yield).

[0987] LCMS: Method A, 1.32 min, MS: ES+ 362.2.Step (iii)

[0988] (2S, 4R)-4-( 6-(3-cyanophenyl)-4-oxopyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)-2-(methoxymethyl)pyrrolidine-1 -carbonitrile

[0989] To a stirred solution of 3-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido-[3,2-<7]pyrimidin-6-yl)benzonitrile TFA salt (0.25 g, 0.52 mmol) in THF (2.5 mL) was added K2CO3 (0.21 g, 1.57 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.08 g, 0.78 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (50 mL) and the precipitated solid was collected through a Buchner funnel, dried under reduced pressure to yield (2S,4R)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)-pyrrolidine-1 -carbonitrile (0.14 g, 0.04 mmol, 84% yield over two steps).

[0990] LCMS: Method E, 2.48 min, MS: ES+ 387.2; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.65 (s, 1H), 8.56 (t, J= 8.0 Hz, 2H), 8.43 (s, 1H), 8.25 (d, J= 8.4 Hz, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 5.24 - 5.31 (m, 1H), 4.17 - 4.22 (m, 1H), 3.86 - 3.90 (m, 1H), 3.77 - 3.81 (m, 1H), 3.45 -3.55 (m, 2H), 3.35 (s, 3H), 2.47 - 2.50 (m, 1H), 2.22 - 2.27 (m, 1H); chiral HPLC: Method I, 15.73 min.

[0991] Example 10

[0992] (2S,4R)-4-(6-(5-Cyano-2-cyclopropoxyphenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l -carbonitrile

[0993]

[0994] Step (i)

[0995] 3-Bromo-4-cyclopropoxybenzonitrile

[0996] To a stirred solution of cyclopropanol (0.29 g, 5.00 mmol) and 3-bromo-4-fluorobenzonitrile (1.0 g, 5.00 mmol) in DMF (10.8 mL) was added Cs2CO3(3.25 g, 10.00 mmol) in portions at 0 °C. The mixture was stirred at rt for 8 h, then poured into ice-cold water (100 mL) and the precipitated solid was collected through a Buchner funnel, dried under reduced pressure to yield 3-bromo-4-cyclopropoxybenzonitrile (0.30 g, 1.26 mmol, 25% yield).

[0997] ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.13 (d, J= 1.6 Hz, 1H), 7.89 (dd, J= 1.6, 8.4 Hz, 1H), 7.53 (d, J= 8.8 Hz, 1H), 4.06 - 4.09 (m, 1H), 0.85 - 0.90 (m, 2H), 0.71 - 0.79 (m, 2H).

[0998] Step (ii)

[0999] 4-Cyclopropoxy-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)benzonitrile

[1000] To a stirred solution of 3-bromo-4-cyclopropoxybenzonitrile (0.20 g, 0.84 mmol) and / v.s(pinacolato)diboron (0.42 g, 1.68 mmol) in 1,4-dioxane (2 mL) was added potassium acetate (0.25 g,2.53 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.06 g, 0.08 mmol) and heated at 100 °C for 3 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure to yield 4-cyclopropoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (0.25 g, quantitative yield).

[1001] LCMS: Method E, 2.51 min, MS: ES- 202.2 (m / z support for (5-cyano-2-cyclopropoxyphenyl)boronic acid).

[1002] Step (iii)

[1003] tert-Butyl (2S,4R)-4-(6-(5-cyano-2-cyclopropoxyphenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[1004] To a stirred solution of tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.23 g, 0.58 mmol) and 4-cyclopropoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (0.25 g, 0.87 mmol) in 1,4-dioxane: water (2.3 mL, 4: 1) was added K2CO3 (0.24 g, 1.75 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of | l. l'- / v.s(diphcnylphosphmo)fcrroccnc|dichloropalladiiim(II) (0.04 g, 0.05 mmol) and heated at 100 °C for 3 h. The mixture was poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 2.6% methanol in DCM) to yield tert-butyl (2. S'.4 / ?)-4-(6-(5-cyano-2-cyclopropoxyphcnyl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate (0.18 g,

[1005] 0.34 mmol, 59% yield).

[1006] LCMS: Method E, 3.26 min, MS: ES+ 462.2 (M-56).

[1007] Step (iv)

[1008] 4-Cyclopropoxy-3-(3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzonitrile TFA salt

[1009] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-(5-cyano-2-cyclopropoxyphcnyl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate (0.18 g,

[1010] 0.34 mmol) in DCM (1.8 mL) was added TFA (0.9 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 4-cyclopropoxy-3-(3-((3 / .5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2-d'|-pyrimidin-6-yl)benzonitrile TFA salt (0.20 g, quantitative yield).

[1011] LCMS: Method E, 2.44 min, MS: ES+ 418.2.Step (v)

[1012] (2S,4R)-4-(6-(5-Cyano-2-cyclopropoxyphenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l -carbonitrile

[1013] To a stirred solution of 4-cyclopropoxy-3-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido[3,2-aQpyrimidin-6-yl)benzonitrile TFA salt (0.20 g, 0.37 mmol) in THF (2 mL) was added K2CO3 (0.15 g, 1.12 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.06 g, 0.56 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 5.3% methanol in DCM). T he residue was further purified by chiral preperative HPLC using Method N to yield (2. S'.4 / ?)-4-(6-(5-cy ano-2-cyclopropoxyphcnyl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l-carbonitrile (0.05 g,

[1014] 0.06 mmol, 32% yield over two steps).

[1015] LCMS: Method E, 2.74 min, MS: ES+ 443.2;1HNMR(400 MHz, DMSO-6) 5ppm: 8.43 (s, 1H), 8.15 - 8.20 (m, 3H), 8.00 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 5.23 - 5.31 (m, 1H), 4.14 - 4.22 (m, 1H), 4.09 - 4.13 (m, 1H), 3.85 - 3.87 (m, 1H), 3.78 - 3.79 (m, 1H), 3.48 - 3.53 (m, 2H), 3.34 (s, 3H), 2.45 - 2.50 (m, 1H), 2.23 - 2.25 (m, 1H), 0.83 - 0.88 (m, 2H), 0.72 - 0.79 (m, 2H), chiral HPLC: Method J, 8.67 min.

[1016] Example 11

[1017] (2S, 4R)-2-( 1 H-Pyrazol-1 -yl)methyl)-4-( 6-(3-cyanophenyl)-4-oxopyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l-carbonitrile

[1018] N'

[1019]

[1020] Step (i)

[1021] tert-Butyl (2S,4R)-2-((lH-pyrazol-l-yl)methyl)-4-(3-amino-6-chloropicolinamido)pyrrolidine-l-carboxylate

[1022] To a stirred solution of 3-amino-6-chloropicolinic acid (0.36 g, 2.10 mmol) in THF (3.0 mL) was added DIPEA (0.81, 6.31 mmol) and HATU (1.19 g, 3.15 mmol) in portions at 0 °C. After 1 h, a solution of tert-butyl (2. S'.4 / ?)-2-((IH-pyrazol- 1 -yl)mcthyl)-4-aminopyrrolidinc- 1 -carboxylate (0.56 g, 2.10 mmol) in THF (1 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 10 h, then poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc in n-hexane) to yield tert-butyl (2. S'.4 / ?)-2-(( IH-pyrazol-l-yl)methyl)-4-(3-amino-6-chloropicolinamido)pyrrolidine-l -carboxylate (0.80 g, 1.90 mmol, 90% yield).

[1023] LCMS: Method A, 1.71 min, MS: ES+ 321.2, 323.2 (M-100).

[1024] Step (ii)

[1025] tert-Butyl (2S,4R)-2-((lH-pyrazol-l-yl)methyl)-4-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l -carboxylate

[1026] To a stirred solution of tert-butyl (2. S'.4 / ?)-2-((IH-pyrazol-l-yl)mcthyl)-4-(3-amino-6-chloropicolinamido)pyrrolidine-l -carboxylate (0.50 g, 1.18 mmol) in triethyl orthoformate (10 mb, 20 vol) was added concentrated hydrochloric acid (4 drops) dropwise at 0 °C. The mixture was heated at 100 °C for 3 h, then poured into water (50 mb) and extracted with EtOAc (3 x 70 mL). The combined organic phases were dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100% EtOAc) to yield tert-butyl (2. S'.4 / ?)-2-(( IH-pyrazol-l-yl)mcthyl)-4-(6-chloro-4-oxopyrido|3.2 / |pyrimidin-3(4H)-yl)pyrrolidinc- 1-carboxylate (0.18 g, 0.41 mmol, 35% yield).

[1027] LCMS: Method A, 1.56 min, MS: ES+ 431.2, 433.2.

[1028] Step (iii)

[1029] tert-Butyl (2S,4R)-2-((lH-pyrazol-l-yl)methyl)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,2-d]pyrimidin- 3 ( 4H)-yl) pyrrolidine- 1 -carboxylate

[1030] To a stirred solution of / ert-biityl (2. S'.4 / ?)-2-(( IH-pyrazol-l-yl)mcthyl)-4-(6-chloro-4-oxopyrido [3, 2-<7]pyrimidin-3(427)-yl)pyrrohdine- 1-carboxylate (0.15 g, 0.34 mmol) and (3-cyanophenyl)boronic acid (0.07 g, 0.52 mmol) in 1,4-dioxane: water (2 mL, 3:1) was added K2CO3 (0.14 g, 1.04 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1, 1 '-biphenyl) [2-(2'-amino- 1, 1 '-biphenyl)]-palladium(II) methane sulfonate (RuPhos Pd G3) (0.01 g, 0.01 mmol). The mixture was heated at 80 °C for 1 h, then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100% EtOAc) to yield tert-butyl (2. S'.4 / ?)-2-(( IH-pyrazol- l-yl)mcthyl)-4-(6-(3-cyanophcnyl)-4-oxopyrido|3.2-t / |pyrimidin-3 (4H)-y I (pyrrolidine- 1-carboxylate (0.08 g, 0.16 mmol, 46% yield).

[1031] LCMS: Method A, 1.65 min, MS: ES+ 498.2.

[1032] Step (iv)

[1033] 3-(3-((3R,5S)-5-((lH-Pyrazol-l-yl)methyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzonitrile TFA salt

[1034] To a stirred solution of tert-butyl (2. S'.4 / ?)-2-((IH-pyrazol-l-yl)mcthyl)-4-(6-(3-cyanophcnyl)-4-oxopyrido [3, 2 / |pyrimidin-3(4H)-yl)pyrrolidinc- 1-carboxylate (0.08 g, 0.16 mmol) in DCM (0.8 mL) was added TFA (0.5 mL, 6.5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirredfor 1.5 h, then concentrated under reduced pressure to yield 3-(3-((3 / ?.5. S)-5-((l / / -pyrazol-l-yl)methyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rimidin-6-y I (bcnzonitri Ic TFA salt (0.15 g, quantitative yield).

[1035] LCMS: Method A, 1.34 min, MS: ES+ 398.2.

[1036] Step (v)

[1037] (2S, 4R)-2-( 1 H-Pyrazol-1 -yl)methyl)-4-( 6-(3-cyanophenyl)-4-oxopyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l-carbonitrile

[1038] To a stirred solution of 3-(3-((3 / ?.5. S)-5-((l / / -pyrazol-l-yl)mcthyl)pyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2-d'|pyrimidin-6-yl)bcnzonitrilc TFA salt (0.15 g, 0.29 mmol) in THF (3 mL) was added K2CO3 (0.12 g, 0.88 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.29 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (70 mL) and extracted with with 10% methanol in DCM (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC using Method M to yield (2. S'.4 / ?)-2-(( 17 / -pyrazol- 1 -yl)methyl)-4-(6-(3 -cyanophcny I )-4-oxopy rido 13,2 / | py rim idin-3 (4 / / )- I (p rrol idinc- 1 -carbonitrile (0.02 g, 0.04 mmol, 31% yield over two steps).

[1039] LCMS: Method E, 2.45 min, MS: ES+ 423.2;1HNMR(400 MHz, DMSO-6) 5ppm: 8.65 (s, 1H), 8.56 (t, J= 9.6 Hz, 2H), 8.41 (s, 1H), 8.23 (d, J= 8.8 Hz, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.76 - 7.81 (m, 2H), 7.52 (s, 1H), 6.31 (s, 1H), 5.04 - 5.07 (m, 1H), 4.45 - 4.47 (m, 1H), 4.36 - 4.38 (m, 2H), 3.73 - 3.81 (m, 2H), 2.53 - 2.55 (m, 1H), 2.27 - 2.32 (m, 1H); chiral HPLC: Method K, 5.14 min.

[1040] Example 12

[1041] (2S, 4R)-2-( ( I H-Pyrazol-1 -yl)methyl)-4-( 4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l -yl)pyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l -carbonitrile

[1042] N

[1043] N

[1044]

[1045] Step (i)

[1046] tert-Butyl (2S,4R)-2-((lH-pyrazol-l-yl)methyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l -carboxylate

[1047] To a stirred solution of tert-butyl (2S,47?)-2-((lH-pyrazol-l-yl)methyl)-4-(6-chloro-4-oxopyrido [3, 2-<7]pyrimidin-3(427)-yl)pyrrohdine-l -carboxylate (0.08 g, 0.18 mmol) and 4-(trifluoromcthyl)-l / / -pyrazolc (0.03 g, 0.22 mmol) in DMF (1.0 mb) was added K2CO3 (0.07 g, 0.55 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of potassium iodide (0.05 g, 0.27 mmol). The mixture was heated at 100 °C for 12 h, then poured into water (25 mL) and extracted with EtOAc (4 x 25 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80% EtOAc in w-hexane) to yield tert-butyl (2. S'.4 / ?)-2-((l / / -pyrazol-l-yl)mcthyl)-4-(4-oxo-6-(4-(trifliioromcthyl)-l / / -pyrazol-l-yl)pyrido|3.2 / |pyrimidin-3(4 / / )-yl)pyrrolidine-l -carboxylate (0.04 g, 0.07 mmol, 41% yield).

[1048] LCMS: Method A, 1.78 min, MS: ES+ 531.2.

[1049] Step (ii)

[1050] 3-(( 3R, 5S)-5-( ( 1 H-Pyrcizol-1 -yl)methyl)pyrrolidin-3-yl)-6-(4-(trifluoromethyl)-lH-pyrazol-l -yl)pyrido[3,2-d]pyrimidin-4(3H)-one TFA salt

[1051] To a stirred solution of tert-butyl (2. S'.4 / ?)-2-((l / / -pyrazol-l-yl)mcthyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido [3, 2 / |pyrmiidm-3(4 / / )-yl)pyrrolidinc-l -carboxylate (0.04 g, 0.07 mmol) in DCM (1.0 mL) was added TFA (0.2 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((37?,5S)-5 -(( IH-pyrazol- 1 -yl)methyl)pyrrolidin-3 -y I )-6-(4-(trifl uoromcthy I )- 17 / -py razol- 1 -yl)pyrido|3.2 / |pyrimidin-4(3 / / )-onc TFA salt (0.07 g, quantitative yield).

[1052] LCMS: Method A, 1.43 min, MS: ES+ 431.2.

[1053] Step (iii)

[1054] (2S, 4R)-2-( ( I H-Pyrazol-1 -yl)methyl)-4-( 4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l -yl)pyrido[3, 2-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l -carbonitrile

[1055] To a stirred solution of 3-((3 / ?.5. S)-5-(( l / / -pyrazol-l-yl)mcthyl)pyrrolidin-3-yl)-6-(4-(trifluoromcthyl)- IH-pyrazol- l-yl)pyrido|3.2-t / |pyrimidin-4(3 / / )-onc TFA salt (0.07 g, 0.13 mmol) in THF (1.0 mL) was added K2CO3 (0.03 g, 0.27 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.02 g, 0.20 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 2 h, then poured into water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 2% methanol in DCM) to yield (2. S'.4 / ?)-2-((l / / -pyrazol-l-yl)mcthyl)-4-(4-oxo-6-(4-(trifliioromcthyl)-l / / -pyrazol-l-yl)pyrido|3.2 / |pyrimidin-3(4 / / )-yl)pyrrolidine-l -carbonitrile (0.01 g, 0.03 mmol, 41% yield over two steps).

[1056] LCMS: Method E, 2.69 min, MS: ES+ 456.2;1HNMR(400 MHz, DMSO-6) 5ppm: 9.18 (s, 1H), 8.36 - 8.44 (m, 4H), 7.82 (s, 1H), 7.53 (s, 1H), 6.31 (s, 1H), 5.03 - 5.07 (m, 1H), 4.44 - 4.49 (m, 1H), 4.37 -4.41 (m, 2H), 3.73 - 3.82 (m, 2H), 2.50 - 2.55 (m, 1H), 2.28 - 2.34 (m, 1H); chiral HPLC: Method H, 7.34 min.

[1057] Example 13

[1058] 4-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile

[1059]

[1060] Step (i)

[1061] tert-Butyl (2R,3R)-3-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1062] To a stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.20 g, 0.54 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinonitrile (0.15 g, 0.65 mmol) in 1,4-dioxane: water (2 mL, 4:1) was added K2CO3 (0.18 g, 1.37 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 g, 0.03 mmol) and heated at 80 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-3-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.09 g, 0.20 mmol, 38% yield).

[1063] LCMS: Method A, 1.56 min, MS: ES+ 377.2 (M-56).

[1064] Step (ii)

[1065] 4-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile TFA salt

[1066] To a stirred solution of tert-butyl (2R,3R)-3-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.09 g, 0.20 mmol) in DCM (0.9 mL) was added TFA (0.45 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 4-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido[3,2-<7]pyrimidin-6-yl)picolinonitrile TFA salt (0.09 g, quantitative yield).

[1067] LCMS: Method A, 1.26 min, MS: ES+ 333.2.

[1068] Step (iii)

[1069] 4-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile

[1070] To a stirred solution of 4-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile TFA salt (0.09 g, 0.20 mmol) in THF (0.9 mL) was added K2CO3 (0.08 g, 0.60 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.30 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (10 mL). The precipitated solid was collected through a Buchner funnel, washed with n-hexane (20 mL), and dried under reduced pressure. The residue was purified by flash column chromatography (silica gel,2.4% methanol in DCM) to yield 4-(3-((27?,37?)-l-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido|3.2 / |pyrimidin-6-yl)picolinonitrile (0.02 g, 0.05 mmol, 25% yield over two steps). LCMS: Method E, 2.27 min, MS: ES+ 358.2; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.95 (d, J = 4.8 Hz, 1H), 8.80 (s, 1H), 8.68 (d, J= 9.2 Hz, 1H), 8.54 (d, J= 4.0 Hz, 1H), 8.34 - 8.37 (m, 2H), 5.35 -5.36 (m, 1H), 4.05 - 4.09 (m, 1H), 3.89 - 3.91 (m, 1H), 3.51 - 3.53 (m, 1H), 2.39 - 2.50 (m, 2H), 0.95 (d, J= 6.8 Hz, 3H); chiral SFC: Method L, 5.63 min.

[1071] Example 14

[1072] 2-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile

[1073]

[1074] Step (i)

[1075] tert-Butyl (2S,4R)-4-(6-(4-cyanopyridin-2-yl)-2-methyl-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate

[1076] The solution of tert-butyl (2S,4R)-4-(6-chloro-2-methyl-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.30 g, 0.73 mmol) and 2-(trimethylstannyl)-isonicotinonitrile (0.19 g, 0.73 mmol) in THF (3 mL) was purged with N2 gas for 10 min, followed by addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1, l'-biphenyl) [2-(2'-amino- 1, 1 '-biphenyl)] -palladium(II) methanesulfonate (XPhos Pd G3) (0.06 g, 0.07 mmol) and heated at 100 °C for 16 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100% EtOAc) to yield tert-butyl (2. S'.4 / ?)-4-(6-(4-cyanopyridin-2-yl)-2-methyl-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine- 1-carboxylate (0.12 g, 0.25 mmol, 34% yield).

[1077] LCMS: Method D, 3.44 min, MS: ES+ 421.3 (M-56).

[1078] Step (ii)

[1079] 2-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile TFA salt

[1080] To a stirred solution of tert-butyl (2S,4R)-4-(6-(4-cyanopyridin-2-yl)-2-methyl-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.12 g, 0.25 mmol) in DCM (1.2 mL) was added TFA (0.6 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 2-(3-((3 / ?.5. S)-5-(methoxymethyl)pyrrolidin-3 -yl)-2-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile TFA salt (0.12 g, quantitative yield). LCMS: Method D, 2.09 min, MS: ES+ 377.2.Step (iii)

[1081] 2-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile

[1082] To a stirred solution of 2-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-2-mcthyl-4-oxo-3.4-dihydropyrido[3,2-<7]pyrimidin-6-yl)isonicotinonitrile TFA salt (0.12 g, 0.24 mmol) in THF (1.2 mL) was added K2CO3 (0.10 g, 0.37 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.04 g, 0.04 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by reverse phase prep HPLC purification using Method T to yield 2-(3-((3 / ?.5. S)-l-cyano-5-(methoxymethyl)pyrrolidin-3 -yl)-2-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile (0.02 g, 0.06 mmol, 25% yield over two steps).

[1083] LCMS: Method E, 2.41 min, MS: ES+ 402.2;1H NMR (400 MHz, DMSO-6) 5 ppm: 9.00 (dd, J= 0.8, 5.2 Hz, 1H), 8.73 - 8.75 (m, 2H), 8.19 (d, J = 8.8 Hz 1H), 8.00 (dd, J = 1.6, 5.2 Hz, 1H), 5.13 - 5.21 (m, 1H), 4.26 - 4.32 (m, 1H), 3.87 - 3.90 (m, 2H), 3.47 - 3.54 (m, 2H), 3.36 (s, 3H), 2.71 (s, 3H), 2.54 - 2.59 (m, 1H), 2.18 - 2.24 (m, 1H); chiral HPLC: Method G, 15.67 min.

[1084] Example 15

[1085] 2-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile

[1086] N

[1087] N 'N

[1088]

[1089] Step (i)

[1090] tert-Butyl (2R,3R)-3-(6-(4-cyanopyridin-2-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1091] A stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.30 g, 0.82 mmol) and 2-(trimethylstannyl)isonicotinonitrile(0.24 g, 0.90 mmol) in THF (3.0 mL) was purged with N2 gas for 10 min, followed by addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1, 1 '-biphenyl) [2-(2'-amino- 1, 1 '-biphenyl)]palladium(II) methane sulfonate (XPhos Pd G3) (0.08 g, 0.08 mmol) and heated at 90 °C for 1 h. The mixture was then poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SOi, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 89.5% EtOAc in n-hexane) to yield tert-butyl (27?,37?)-3-(6-(4-cyanopyridin-2-yl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-methylpyrrolidine-l-carboxylate (0.10 g, 0.23 mmol, 28% yield).

[1092] LCMS: Method A, 1.66 min, MS: ES+ 377.2 (M-56).Step (ii)

[1093] 2-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile TFA salt

[1094] To a stirred solution of tert-butyl (2R,3R)-3-(6-(4-cyanopyridin-2-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.10 g, 0.23 mmol) in DCM (1 mL) was added TFA (0.5 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 2-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile TFA salt (0.10 g, quantitative yield).

[1095] LCMS: Method A, 1.25 min, MS: ES+ 333.2.

[1096] Step (iii)

[1097] 2-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile

[1098] To a stirred solution of 2-(3-((37?,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido|3.2-d'|pyrimidin-6-yl)isonicotinonitrilc TFA salt (0.10 g, 0.22 mmol) in THF (1 mL) was added K2CO3 (0.09 g, 0.67 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.33 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 67% EtOAc in w-hexane) to yield 2-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)isonicotinonitrile (0.01 g, 0.03 mmol, 15% yield over two steps).

[1099] LCMS: Method E, 2.40 min, MS: ES+ 358.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 9.00 (d, J = 4.4 Hz, 1H), 8.79 (d, J= 8.8 Hz, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 8.32 (d, J= 8.4 Hz, 1H), 8.01 (dd, J= 1.6, 5.2 Hz, 1H), 5.34 - 5.39 (m, 1H), 4.05 - 4.11 (m, 1H), 3.87 - 3.93 (m, 1H), 3.50 - 3.56 (m, 1H), 2.50 - 2.51 (m, 2H), 0.96 (d, J= 6.4 Hz, 3H); chiral SFC: Method L, 5.13 min.

[1100] Example 16

[1101] 4-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile

[1102]

[1103] Step (i)

[1104] tert-Butyl (2S,4R)-4-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylateTo a stirred solution of tert-butyl (2S,4R)-4-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.20 g, 0.50 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinonitrile (0.11 g, 0.50 mmol) in 1,4-dioxane: water (2.0 mL, 4:1) was added K2CO3 (0.21 g, 1.52 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.04 g, 0.05 mmol) and heated at 100 °C for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90% EtOAc in n-hexane) to yield tert-butyl (2S,4R)-4-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.20 g, 0.43 mmol, 85% yield).

[1105] LCMS: Method D, 2.92 min, MS: ES+ 363.3 (M-100).

[1106] Step (ii)

[1107] 4-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile TFA salt

[1108] To a stirred solution of tert-butyl (2S,4R)-4-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.20 g, 0.43 mmol) in DCM (2.0 mL) was added TFA (1.0 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 4-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)picolinonitrile TFA salt (0.32 g, quantitative yield). LCMS: Method D, 1.94 min, MS: ES+ 363.3.

[1109] Step (iii)

[1110] 4-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile

[1111] To a stirred solution of 4-(3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile TFA salt (0.32 g, 0.67 mmol) in THF (3.2 mL) was added K2CO3 (0.27 g, 2.01 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.08 g, 0.80 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (20 mL). The precipitated solid was collected through a Buchner funnel, washed with n-hexane (20 mL), and dried under reduced pressure to yield 4-(3-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)picolinonitrile (0.10 g, 0.25 mmol, 60% yield over two steps).

[1112] LCMS: Method E, 2.28 min, MS: ES+ 388.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 8.95 (d, J = 5.6 Hz, 1H), 8.78 (s, 1H), 8.66 (d, J= 8.4Hz, 1H), 8.52 (dd, J= 1.2, 4.8 Hz, 1H), 8.47 (s, 1H), 8.33 (d, J= 8.4 Hz, 1H), 5.24 - 5.27 (m, 1H), 4.19 - 4.25 (m, 1H), 3.86 - 3.90 (m, 1H), 3.77 - 3.83 (m, 1H), 3.45 - 3.56 (m, 2H), 3.35 (s, 3H), 2.43 - 2.50 (m, 1H), 2.20 - 2.27 (m, 1H); chiral SFC: Method L, 5.75 min.Example 17

[1113] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3, 2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1114]

[1115] Step (i)

[1116] (E)-2-Bromo-4-(hydrazineylidenemethyl)pyridine

[1117] To a stirred solution of 2-bromoisonicotinaldehyde (1.0 g, 5.37 mmol) in methanol (10 mL) was added hydrazine hydrate (0.27 g, 5.37 mmol) at rt and stirred for 2 h. The mixture was concentrated under reduced pressure to yield (£)-2-bromo-4-(hydrazineylidenemethyl)pyridine (1.0 g, 5.00 mmol, 93% yield).

[1118] LCMS: Method A, 1.36 min, MS: ES+ 200.0, 202.0.

[1119] Step (ii)

[1120] 2-Bromo-4-(2, 2, 2-trifluoroethyl)pyridine

[1121] To a stirred solution of (£)-2-bromo-4-(hydrazineylidenemethy 1 )pyridine (1.0 g, 5.00 mmol) in DMSO (10 mL) was added Togni reagent II (1.73 g, 5.49 mmol) and TFA (0.57 g, 4.99 mmol) at rt and the mixture was heated at 100 °C for 12 h. The mixture was then poured into water (50 mL) and extracted with EtOAc (4 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 34% EtOAc in w-hexane) to yield 2-bromo-4-(2,2,2-trifluoroethyl)pyridine (0.50 g, 2.08 mmol, 47% yield).

[1122] LCMS: Method A, 1.66 min, MS: ES+ 239.9, 242.0.

[1123] Step (iii)

[1124] 4-(2,2,2-Trifluoroethyl)-2-(trimethylstannyl)pyridine

[1125] To a stirred solution of 2-bromo-4-(2,2,2-trifluoroethyl)pyridine (0.30 g, 1.26 mmol) in toluene (6 mL) was added 1,1,1,2,2,2-hexamethyldistannane (0.74 g, 2.26 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) and heated at 100 °C for 2 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 4-(2,2,2-trifluoroethyl)-2-(trimethylstannyl)pyridine (0.25 g, quantitative yield).

[1126] Step (iv)

[1127] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-3 ( 4H)-yl) pyrrolidine- 1 -carboxylateA stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.14 g, 0.38 mmol) and 4-(2,2,2-trifluoroethyl)-2-(trimethylstannyl)-pyridine (0.22 g, 0.69 mmol) in toluene (7.0 mL) was purged with N2 gas for 30 min, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol) and heated at 130 °C in microwave for 2 h. The mixture was then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.09 g, 0.18 mmol, 47% yield).

[1128] LCMS: Method E, 3.24 min, MS: ES+ 490.2.

[1129] Step (v)

[1130] 3-((2R3R)-2-Methylpyrrolidin-3-yl)-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-4(3H)-one TFA salt

[1131] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.09 g, 0.18 mmol) in DCM (1.8 mL) was added TFA (0.9 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-4(3H)-one TFA salt (0.12 g, quantitative yield).

[1132] LCMS: Method A, 1.35 min, MS: ES+ 390.3.

[1133] Step (vi)

[1134] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3, 2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1135] To a stirred solution of 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(4-(2.2.2-trifluorocthyl)pyridin-2-yl)pyrido[3,2-<7]pyrimidin-4(327)-one TFA salt (0.12 g, 0.23 mmol) in THF (2.4 mL) was added K2CO3 (0.06 g, 0.47 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.28 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC using Method U to yield (2R,3R)-2-methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.01 g, 0.03 mmol, 20% yield over two steps).

[1136] LCMS: Method E, 2.72 min, MS: ES+ 415.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 8.81 - 8.84 (m, 1H), 8.76 (d, J= 5.2 Hz, 1H), 8.53 (s, 1H), 8.27 - 8.32 (m, 2H), 7.54 (d, J= 4.4 Hz, 1H), 5.31 - 5.36 (m, 1H), 4.02 - 4.10 (m, 1H), 3.87 - 3.99 (m, 3H), 3.49 - 3.56 (m, 1H), 2.49 - 2.50 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H); chiral HPLC: Method F, 8.03 min.Example 18

[1137] (R)-l-(3-(l -Cyanopyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[1138] CN

[1139]

[1140] Step (i)

[1141] tert-Butyl (R)-3-(3-amino-6-chloropicolinamido)pyrrolidine-l-carboxylate

[1142] To a stirred solution of 3-amino-6-chloropicolinic acid (0.50 g, 2.90 mmol) in THF (4.0 mL) was added DIPEA (1.12 g, 8.72 mmol) and HATU (1.65 g, 4.36 mmol) in portions at 0 °C. After 1 h, a solution of tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (0.54 g, 2.90 mmol) in THF (1 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 4 h, then poured into water (80 mL) and extracted with EtOAc (3 x 40 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30% EtOAc in n-hexane) to yield tert-butyl ( / ?)-3-(3-amino-6-chloropicolinamido)-pyrrolidine- 1 -carboxylate (0.70 g, 2.05 mmol, 71% yield).

[1143] LCMS: Method A, 1.69 min, MS: ES+ 285.1, 287.1 (M-56).

[1144] Step (ii)

[1145] tert-Butyl (R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carboxylcite

[1146] To a stirred solution of tert-butyl (R)-3-(3-amino-6-chloropicolinamido)pyrrolidine-1-carboxylate (0.50 g, 1.47 mmol) in ethanol (5 mL) was added triethyl orthoformate (5 mL, 10 vol) and concentrated hydrochloric acid (5 to 6 drops). The mixture was heated at 130 °C for 16 h, then poured into water (80 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 75% EtOAc in n-hexane) to yield tert-butyl (t?)-3-(6-chloro-4-oxopyrido [3, 2-<7]pyrimidin-3(427)-yl)pyrrolidine-l -carboxylate (0.23 g, 0.65 mmol, 45% yield).

[1147] LCMS: Method A, 1.52 min, MS: ES+ 295.1, 297.0 (M-56).

[1148] Step (iii)

[1149] tert-Butyl (R)-3-(6-(4-cyano-lH-pyrazol-l -yl)-4-oxopyrido[3, 2-d]pyrimidin-3 ( 4H)-yl) pyrrolidine- 1 -carboxylate

[1150] To a stirred solution of tert-butyl (R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.20 g, 0.57 mmol) and 1H-pyrazole-4-carbonitrile (0.08 g, 0.85 mmol) in 1,4-dioxane (2.0 mL) was added Cs2CO3(0.55 g, 1.71 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (0.03 g, 0.06 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.05 g, 0.06 mmol). The mixture washeated at 100 °C for 5 h, then poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 75% EtOAc in n-hexane) to yield tert-butyl (R)-3-(6-(4-cyano-1H-pyrazol-1-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.17 g, 0.41 mmol, 73% yield).

[1151] LCMS: Method A, 1.57 min, MS: ES+ 352.2 (M-56).

[1152] Step (iv)

[1153] (R)-l-(4-Oxo-3-(pyrrolidin-3-yl)-3, 4-dihydropyrido[3, 2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt

[1154] To a stirred solution of tert-butyl (R)-3-(6-(4-cyano-1H-pyrazol-1-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.17 g, 0.41 mmol) in DCM (1.7 mL) was added TFA (0.85 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield (7?)-l-(4-oxo-3-(pyrrolidin-3-yl)-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile TFA salt (0.22 g, quantitative yield).

[1155] LCMS: Method A, 1.26 min, MS: ES+ 308.1.

[1156] Step (v)

[1157] (R)-l-(3-(l -Cyanopyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 2-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[1158] To a stirred solution of <7?)-l-(4-oxo-3-(pyrrolidin-3-yl)-3.4-dihydropyrido|3.2 / |pyrimidin-6-yl)-IH-pyrazole-4-carbonitrile TFA salt (0.22 g, 0.52 mmol) in THF (2.2 mL) was added K2CO3 (0.21 g, 1.56 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.05 g, 0.52 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice cold water (50 mL). The precipitated solid was collected through a Buchner funnel, washed with diethyl ether: w-pcntanc (15 mL, 1:4), and dried under reduced pressure to yield (R)-l-(3-(l-cyanopyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido|3.2-t / |pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile (0.02 g, 0.07 mmol, 17% yield over two steps).

[1159] LCMS: Method E, 2.23 min, MS: ES+ 333.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 9.43 (s, 1H), 8.49 (s, 1H), 8.43 - 8.44 (m, 1H), 8.38 - 8.39 (m, 2H), 5.25 - 5.28 (m, 1H), 3.78 - 3.84 (m, 1H), 3.71 -3.75 (m, 2H), 3.53 - 3.59 (m, 1H), 2.35 - 2.44 (m, 2H); chiral HPLC: Method R, 11.71 min.

[1160] Example 19

[1161] 5-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin- 6-yl)nicotinonitrile

[1162] CN

[1163] ^"il0

[1164]

[1165] Step (i)

[1166] 5-(4, 4,5, 5-Tetramethyl-l, 3, 2-dioxaborolan-2-yl)nicotinonitrile

[1167] To a stirred solution of 5-bromonicotinonitrile (1.0 g, 5.49 mmol) and / ? / .s(pinacolato)diboron (2.0 g, 8.24 mmol) in 1,4-dioxane (10 mL) was added potassium acetate (1.6 g, 16.48 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.28 g, 0.38 mmol) and heated at 100 °C for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure to yield 5 -(4, 4, 5, 5 -tetramethyl - I,3,2-dioxaborolan-2-yl)nicotinonitrile (2.0 g, quantitative yield).

[1168] LCMS: Method A, 1.58 min, MS: ES+ 149.1 (m / z support for ((5-cyanopyridin-3-yl)boronic acid). Step (ii)

[1169] tert-Butyl (2S,4R)-4-(6-(5-cyanopyridin-3-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[1170] To a stirred solution of tert-butyl (2S,4R)-4-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.14 g, 0.35 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinonitrile (0.05 g, 0.35 mmol) in 1,4-dioxane: water (1.4 mL, 4:1) was added K2CO3 (0.14 g, 1.06 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.02 g, 0.02 mmol) and heated at 100 °C for 1 h. The mixture was poured into water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 3% methanol in DCM) to yield tert-butyl (2. S'.4 / ?)-4-(6-(5-cyanopyridin-3-yl)-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.13 g, 0.28 mmol, 79% yield).

[1171] LCMS: Method A, 1.57 min, MS: ES+ 407.2 (M-56).

[1172] Step (iii)

[1173] 5-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile TFA salt

[1174] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-(5-cyanopyridin-3-yl)-4-oxopyrido|3.2-t / |pyrimidin-3 (427)-yl)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.13 g, 0.28 mmol) in DCM (1.3 mL) was added TFA (0.65 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 5-(3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)nicotinonitrile TFA salt (0.15 g, quantitative yield). LCMS: Method A, 1.26 min, MS: ES+ 363.2.

[1175] Step (iv)

[1176] 5-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin- 6-yl)nicotinonitrileTo a stirred solution of 5-(3-((37?,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido|3.2-d'|pyrimidin-6-yl)nicotinonitrilc TFA salt (0.15 g, 0.31 mmol) in THF (1.5 mL) was added K2CO3 (0.13 g, 0.94 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.31 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 3% methanol in DCM) to yield 5-(3-((37?,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)nicotinonitrile (0.03 g, 0.09 mmol, 32% yield over two steps).

[1177] LCMS: Method E, 2.12 min, MS: ES+ 388.2; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 9.64 (d, J = 2.0 Hz, 1H), 9.15 (d, J= 2.0 Hz, 1H), 9.03 (t, J= 2.4 Hz, 1H), 8.60 (d, J= 8.8 Hz, 1H), 8.45 (s, 1H), 8.30 (d, J= 8.8 Hz, 1H), 5.26 - 5.29 (m, 1H), 4.20 - 4.21 (m, 1H), 3.86 - 3.90 (m, 1H), 3.77 - 3.81 (m, 1H), 3.47 - 3.55 (m, 2H), 3.36 (s, 3H), 2.50 - 2.55 (m, 1H), 2.20 - 2.26 (m, 1H); chiral HPLC: Method O, 13.02 min.

[1178] Example 20

[1179] 5-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile

[1180]

[1181] Step (i)

[1182] tert-Butyl (2R,3R)-3-(6-(5-cyanopyridin-3-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1183] To a stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.20 g, 0.54 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinonitrile (0.12 g, 0.54 mmol) in 1,4-dioxane: water (2.2 mL, 10:1) was added K3PO4 (0.35 g, 1.64 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of LI '-A.s(diphcnylphosphmo)fcrroccnc|dichloropalladiiim(II) (0.04 g, 0.05 mmol) and heated at 100 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 4% methanol in DCM) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(5-cyanopyridin-3-yl)-4-oxopyrido|3.2 / |pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1 -carboxylate (0.13 g, 0.31 mmol, 56% yield).

[1184] LCMS: Method A, 1.58 min, MS: ES+ 433.2.Step (ii)

[1185] 5-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile TFA salt

[1186] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-(5-cyanopyridin-3-yl)-4-oxopyrido|3.2-t / |pyrimidin-3 (4H)-yl)-2-mcthylpyrrolidinc- 1 -carboxylate (0.13 g, 0.30 mmol) in DCM (3.0 mL) was added TFA (1.3 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 5-(3-((27?,37?)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido|3.2 / |pyri idin-6-yl)nicotinonitrilc TFA salt (0.21 g, quantitative yield).

[1187] LCMS: Method A, 1.25 min, MS: ES+ 333.2.

[1188] Step (iii)

[1189] 5-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile

[1190] To a stirred solution of 5-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2 / |-pyrimidin-6-yl)nicotinonitrile TFA salt (0.21 g, 0.47 mmol) in THF (2 mL) was added K2CO3 (0.19 g, 1.41 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.04 g, 0.47 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4and concentrated under reduced pressure to yield 5-(3-((2 / ?.3 / ?)-l-cyano-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2-d'|pyrimidin-6-yl)nicotinonitrilc (0.07 g, 0.21 mmol, 70% yield over two steps).

[1191] LCMS: Method E, 2.14 min, MS: ES+ 358.2;1H NMR (400 MHz, DMSO-6) 5 ppm: 9.64 (d, J = 2.4 Hz, 1H), 9.15 (d, J = 2.0Hz, 1H), 9.03 (t, J=2.0Hz, 1H), 8.60 - 8.62 (m, 1H), 8.31 - 8.34 (m, 2H), 5.32 - 5.38 (m, 1H), 4.05 - 4.09 (m, 1H), 3.89 - 3.91 (m, 1H), 3.51 - 3.53 (m, 1H), 2.49 - 2.50 (m, 2H), 0.95 (d, J= 6.4 Hz, 3H); chiral SFC: Method P, 5.31 min.

[1192] Example 21

[1193] 6-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile

[1194] CN

[1195]

[1196] Step (i)

[1197] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(trimethylstannyl)pyrido[3,2-d]pyrimidin-3(4H)-yl)pyrrolidine-l -carboxylate

[1198] To a stirred solution of tert-butyl (2 / .3 / )-3-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.15 g, 0.41 mmol) in 1,4-dioxane (4 mL) was added 1, 1,1, 2,2,2-hexamethyldistannane (0.27 g, 0.82 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of dichlorobis(triphenylphosphine)palladium(II) (0.02 g, 0.04 mmol) and heated at 100 °C for 1 h. The reaction mixture was used for next step directly, without isolating product.

[1199] LCMS: Method A, 1.78 min, MS: ES+ 495.4.

[1200] Step (ii)

[1201] tert-Butyl (2R,3R)-3-(6-(6-cyanopyrimidin-4-yl)-4-oxopyrido[ 3,2-d ]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1202] To a stirred solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(trimcthylstannyl)pyrido|3.2 / |-pyrimidin-3(427)-yl)pyrrolidine-l -carboxylate (0.20 g, 0.41 mmol) in 1,4-dioxane (4.0 mL) was added 6-chloropyrimidine-4-carbonitrile (0.08 g, 0.61 mmol) and purged with N2gas for 10 min, followed by addition of dichlorobis(triphenylphosphine)palladium(II) (0.03 g, 0.04 mmol). The mixture was heated at 100 °C for 3 h, then poured into water (50 mL) and extracted with EtOAc (2x 50 mL). The combined organic phases were dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(6-cyanopyrimidin-4-yl)-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.13 g, 0.30 mmol, 73% yield over two steps).

[1203] LCMS: Method A, 1.67 min, MS: ES+ 378.2 (M-56).

[1204] Step (iii)

[1205] 6-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile TFA salt

[1206] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-(6-cyanopyrimidin-4-yl)-4-oxopyrido|3.2-t / |pyrimidin-3 (4H)-yl)-2-mcthylpyrrolidinc- 1 -carboxylate (0.13 g, 0.30 mmol) in DCM (3 mL) was added TEA (1.3 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 6-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2 / |pyri idin-6-yl)pyri idinc-4-carbonitrilc TFA salt (0.16 g, quantitative yield). LCMS: Method A, 1.27 min, MS: ES+ 334.4.

[1207] Step (iv)

[1208] 6-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3,2-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile

[1209] To a stirred solution of 6-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.2 / |-pyrimidin-6-yl)pyrimidine-4-carbonitrile TFA salt (0.16 g, 0.35 mmol) in THF (4 mL) was added K2CO3 (0.15 g, 1.07 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.04 g, 0.35 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 3% methanol in DCM) to yield 6-(3-((27?,37?)-l-cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rim idin-6-y I )py rim idinc-4-carboni tri Ic (0.04 g, 0.12 mmol, 42% yield over two steps).

[1210] LCMS: Method E, 2.40 min, MS: ES+ 359.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 9.57 (d, J = 1.6 Hz, 1H), 8.83 - 8.85 (m, 2H), 8.37 - 8.41 (m, 2H), 5.34 - 5.38 (m, 1H), 4.06 - 4.09 (m, 1H), 3.88 -3.94 (m, 1H), 3.49 - 3.56 (m, 1H), 2.50 - 2.55 (m, 2H), 0.96 (d, J= 6.4 Hz, 3H); chiral HPLC: Method R, 16.36 min.

[1211] Example 22

[1212] (2R,3R)-2-Methyl-3-(4-oxo-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido[3, 2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1213] CN

[1214] N^N O \"IX

[1215] Xx, Ji. N J. )

[1216] F3c^^y 'll

[1217]

[1218] Step (i)

[1219] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido[3,2-d]pyrimidin- 3 ( 4H)-yl) pyrrolidine- 1 -carboxylate

[1220] To a stirred solution of 4-bromo-6-(trifluoromethyl)pyrimidine (0.25 g, 1.11 mmol) and tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(trimethylstannyl)pyrido[3,2-<7]pyrimidin-3(427)-yl)pyrrolidine-l-carboxylate (1.09 g, 2.21 mmol) in THF (5 mL) was purged with N2 gas for 15 min, followed by addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, l'-biphenyl)[2-(2'-amino-l, l'-biphenyl)]-palladium(II) methanesulfonate (XPhos Pd G3) (0.09 g, 0.11 mmol) and heated at 100 °C for 2 h. The mixture was then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 60 to 70% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(6-(trifliioromcthyl)pyrimidin-4-yl)pyrido|3.2 / |-pyrimidin-3(427)-yl)pyrrolidine-l -carboxylate (0.09 g, 0.18 mmol, 16% yield).

[1221] LCMS: Method A, 1.81 min, MS: ES+ 421.2 (M-56).

[1222] Step (ii)

[1223] 3-((2R,3R)-2-Methylpyrrolidin-3-yl)-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido[3, 2-d]pyrimidin-4(3H)-one TFA salt

[1224] To a stirred solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(6-(trifluoromcthyl)pyrimidin-4-yl)pyrido[3,2-<7]pyrimidin-3(427)-yl)pyrrolidine-l-carboxylate (0.09 g, 0.19 mmol) in DCM (2 mL) was added TFA (0.9 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(6-(trifhioromcthyl)pyrimidin-4-yl)pyrido|3.2-d'|pyrimidin-4(3H)-onc TFA salt (0.13 g, quantitative yield). LCMS: Method A, 1.35 min, MS: ES+ 377.2.Step (iii)

[1225] (2R,3R)-2-Methyl-3-(4-oxo-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido[3, 2-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1226] To a stirred solution of 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(6-(trifluoromcthyl)pyrimidin-4-yl)pyrido[3,2-< ]pyrimidin-4(327)-one TFA salt (0.13 g, 0.27 mmol) in THF (2 mL) was added K2CO3 (0.11 g, 0.79 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.29 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into ice-cold water (30 mL) and the precipitated solid was collected through a Buchner funnel. The residue was purified by trituration with w-hexane (2x 5 mL) and dried under reduced pressure to yield (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido [3.2 / | py rimidin-3 (4 / / )-y I (pyrrolidine- 1 -carbonitrile (0.05 g, 0.11 mmol, 59% yield over two steps).

[1227] LCMS: Method E, 2.69 min, MS: ES+ 402.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.65 (s, 1H), 8.89 (d, J = 8.4Hz, 1H), 8.75 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H), 5.33 - 5.38 (m, 1H), 4.08 - 4.11 (m, 1H), 3.89 - 3.94 (m, 1H), 3.51 - 3.57 (m, 1H), 2.55 - 2.57 (m, 2H), 0.98 (d, J= 6.8 Hz, 3H); chiral SFC: Method S, 4.08 min.

[1228] Example 23

[1229] (2S, 4R)-4-( 6-(4-Cyclopropyl-lH-pyrazol-l -yl)-4-oxopyrido[3, 2-d ]pyrimidin-3 ( 4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carbonitrile

[1230]

[1231] Step (i)

[1232] tert-Butyl (2S,4R)-4-(6-(4-cyclopropyl-lH-pyrazol-l-yl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[1233] To a stirred solution of tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.20 g, 0.50 mmol) and 4-cyclopropyl-lH-pyrazole (0.08 g, 0.76 mmol) in DMF (2.0 mL) was added K2CO3 (0.21 g, 1.52 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of ( I / .2R)-N. N' -dimethyl- 1,2-cyclohexanediamine (0.06 g, 0.40 mmol) and copper(I) iodide (0.02 g, 0.10 mmol). The mixture was heated at 100 °C for 16 h, then poured into water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc in w-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(6-(4-cyclopropyl-l / / -pyrazol-l-yl)-4-oxopyrido|3.2-t / |pyrimidin-3(4 / / )-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (0.13 g, 0.28 mmol, 55% yield).

[1234] LCMS: Method A, 1.77 min, MS: ES+ 467.3.Step (ii)

[1235] 6-(4-Cyclopropyl-lH-pyrazol-l-yl)-3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)pyrido[3,2-d]pyrimidin-4(3H)-one TFA salt

[1236] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-(4-cyclopropyl-IH-pyrazol-l-yl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate (0.13 g, 0.28 mmol) in DCM (1.3 mL) was added TFA (0.65 mb, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 6-(4-cyclopropyl-IH-pyrazol- l-yl)-3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)pyrido|3.2-t / |pyrimidin-4(3H)-onc TFA salt (0.15 g, quantitative yield).

[1237] LCMS: Method A, 1.36 min, MS: ES+ 367.4.

[1238] Step (iii)

[1239] (2S, 4R)-4-( 6-(4-Cyclopropyl-lH-pyrazol-l -yl)-4-oxopyrido[3, 2-d ]pyrimidin-3 ( 4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carbonitrile

[1240] To a stirred solution of 6-(4-cyclopropyl- IH-pyrazol- 1 -yl)-3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)pyrido[3,2-<7]pyrimidin-4(327)-one TFA salt (0.15 g, 0.31 mmol) in THF (1.5 mL) was added K2CO3 (0.13 g, 0.93 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.03 g, 0.31 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 2% methanol in DCM) to yield (2. S'.4 / ?)-4-(6-(4-cyclopropyl-IH-pyrazol-l-yl)-4-oxopyrido[3,2-<7]pyrimidin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l-carbonitrile (0.03 g, 0.09 mmol, 32% yield over two steps).

[1241] LCMS: Method E, 2.68 min, MS: ES+ 392.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 8.39 (d, J = 4.4 Hz, 2H), 8.24 - 8.32 (m, 2H), 7.74 (s, 1H), 5.24 - 5.27 (m, 1H), 4.19 - 4.22 (m, 1H), 3.86 - 3.90 (m, 1H), 3.76 - 3.80 (m, 1H), 3.46 - 3.55 (m, 2H), 3.36 (s, 3H), 2.46 - 2.47 (m, 1H), 2.20 - 2.23 (m, 1H), 1.85 - 1.89 (m, 1H), 0.90 - 0.94 (m, 2H), 0.66 - 0.68 (m, 2H); chiral HPLC: Method O, 10.21 min. Example 24

[1242] (2R,3R)-2-Methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1243] 'N

[1244]

[1245] Step (i)

[1246] tert-Butyl (2R,3R)-3-(2-amino-5-bromobenzamido)-2-methylpyrrolidine-l-carboxylate

[1247] To a stirred solution of 2-amino-5 -bromobenzoic acid (0.40 g, 1.86 mmol) in THF (3 mL) was addedDIPEA (0.72 g, 5.88 mmol) and HATU (0.70 g, 1.86 mmol) in portions at 0 °C. After 30 min, a solution of tert-butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (0.40 g, 2.04 mmol) in THF (1 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 2 h, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure to yield tert-butyl (2 / ?.3 / ?)-3-(2-amino-5-bromobenzamido)-2-methylpyrrolidine-l -carboxylate (0.60 g, 1.51 mmol, 81% yield).

[1248] LCMS: Method A, 1.81 min, MS: ES+ 298.1, 300.1 (M-100).

[1249] tert-Butyl (2R,3R)-3-(6-bromo-4-oxoqumazolm-3(4H)-yl)-2-methylpyrrol dme-l-carboxylate To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(2-amino-5-bromobcnzamido)-2-mcth lpyrrolidinc-l-carboxylate (0.50 g, 1.26 mmol) in ethanol (2.5 mL) was added iodine (0.03 g, 0.12 mmol) and triethyl orthoformate (2.5 mL, 5 vol) at rt. The mixture heated at 90 °C for 4 h, then mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 45% EtOAc in n-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1 -carboxylate (0.15 g, 0.37 mmol, 29% yield).

[1250] LCMS: Method A, 1.89 min, MS: ES+ 408.2, 410.2.

[1251] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1 -carboxylate

[1252] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-mcthylpyrrolidinc-1-carboxylate (0.15 g, 0.37 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (0.08 g, 0.40 mmol) in 1,4-dioxane: water (1.5 mL, 4:1) was added K2CO3 (0.15 g, 1.10 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of [ l.l'- / v.s(diphcnylphosphino)fcrroccnc|-dichloropalladium(II) (0.03 g, 0.04 mmol) and heated at 100 °C for 3 h. The mixture was poured into water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 78% EtOAc in n-hexane) to yield tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(3-(trifliioromcthoxy)phcnyl)quinazolin-3(4H)-y I (pyrrolidine- 1 -carboxylate (0.15 g, 0.30 mmol, 83% yield).

[1253] LCMS: Method A, 2.16 min, MS: ES+ 490.3.

[1254] 3-((2R,3R)-2-Methylpyrrol dm-3-yl)-6-(3-(trfluoromethoxy)phenyl)qumazolm-4(3H)-one TFA salt To a stirred solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(3-(trifluoromcthoxy)phcnyl)-quinazolin-3(4H)-yl)pyrrolidinc-l -carboxylate (0.15 g, 0.30 mmol) in DCM (1.5 mL) was added TFA (0.45 mL, 3 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, thenconcentrated under reduced pressure to yield 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(327)-one TFA salt (0.15 g, quantitative yield).

[1255] LCMS: Method E, 2.95 min, MS: ES+ 390.2.

[1256] Step (v)

[1257] (2R,3R)-2-Methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1258] To a stirred solution of 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(3-(trifluoromcthoxy)phcnyl)-quinazolin-4(327)-one TFA salt (0.15 g, 0.29 mmol) in THF (1.5 mL) was added K2CO3 (0.12 g, 1.15 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.03 g, 0.29 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (50 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC using Method V to yield (27?,37?)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3 (4H)- I (pyrrolidine- 1 -carbonitrile (0.03 g, 0.08 mmol, 27% yield over two steps).

[1259] LCMS: Method E, 3.39 min, MS: ES+ 415.2;1H NMR (400 MHz, DMSO- g) 5 ppm: 8.44 (d, J = 2.4 Hz, 1H), 8.23 - 8.26 (m, 2H), 7.80 - 7.87 (m, 3H), 7.67 (t, J= 8.0 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 5.34 - 5.38 (m, 1H), 4.04 - 4.10 (m, 1H), 3.88 - 3.93 (m, 1H), 3.50 - 3.56 (m, 1H), 2.51 - 2.52 (m, 2H), 0.94 (d, J= 6.4 Hz, 3H); chiral HPLC: Method G, 6.52 min.

[1260] Example 25

[1261] (2S,4R)-2-(Methoxymethyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1 -carbonitrile

[1262] o

[1263]

[1264] \

[1265] Step (i)

[1266] tert-Butyl (2S,4R)-4-(2-amino-5-bromobenzamido)-2-(methoxymethyl)pyrrolidine-l-carboxylate To a stirred solution of 2-amino-5 -bromobenzoic acid (0.50 g, 2.32 mmol) in THF (4.0 mL) was added DIPEA (0.90 g, 6.98 mmol) and HATU (1.32 g, 3.49 mmol) in portions at 0 °C. After 1 h, a solution of tert-butyl (2. S'.4 / ?)-4-amino-2-(mcthoxymcthyl)pyrrolidinc-l -carboxylate (0.53 g, 2.32 mmol) in THF (1 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1.5 h, then poured into water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25% EtOAc in n-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(2-amino-5-bromobenzamido)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.77 g, 1.80 mmol, 77% yield). LCMS: Method A, 1.75 min, MS: ES+ 328.1, 330.0 (M-100).Step (ii)

[1267] tert-Butyl (2S,4R)-4-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-(rnethoxymethyl)pyrrolidine-l-carboxylate

[1268] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(2-amino-5-bromobcnzamido)-2-(mcthoxymcthyl)-pyrrolidine- 1 -carboxylate (0.77 g, 1.80 mmol) in ethanol (3.85 mL) was added triethyl orthoformate (3.85 mL, 5 vol) and iodine (0.04 g, 0.18 mmol). The mixture was heated at 90 °C for 4 h, then poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25% EtOAc in w-hexane) to yield tert-butyl (2. S'.4 / ?)-4-(6-bromo-4-oxoquinazolin-3(427)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate (0.50 g, 1.14 mmol, 63% yield).

[1269] LCMS: Method A, 1.79 min, MS: ES+ 438.2, 440.2.

[1270] Step (iii)

[1271] tert-Butyl (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l -carboxylate

[1272] To a stirred solution of tert-butyl (2. S'.4 / ?)-4-(6-bromo-4-oxoquinazolin-3(4 / / )-yl)-2-(mcthoxymcthyl)-pyrrolidine- 1 -carboxylate (0.25 g, 0.57 mmol) and (3-(trifhioromethoxy)phenyl)boronic acid (0.12 g, 0.57 mmol) in 1,4-dioxane: water (2.5 mL, 4:1) was added K2CO3 (0.23 g, 1.71 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of [ L I '-A.s(di phenyl phosphino)fc rroccnc|-dichloropalladium(II) (0.03 g, 0.04 mmol). The mixture was heated at 100 °C for 3 h, then poured into water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40% EtOAc in n-hexane) to yield tert-butyl (2. S'.4 / ?)-2-(methoxymethyl)-4-(4-oxo-6-(3 -(trifluoromethoxy )phenyl)-quinazolin-3 (4 / / )-y I (pyrrolidine- 1 -carboxylate (0.20 g, 0.38 mmol, 67% yield).

[1273] LCMS: Method A, 2.08 min, MS: ES+ 520.3.

[1274] Step (iv)

[1275] 3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt

[1276] To a stirred solution of tert-butyl (2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(3-(trifluoromcthoxy)-phenyl)quinazolin-3(427)-yl)pyrrolidine-l -carboxylate (0.20 g, 0.38 mmol) in DCM (2.0 mL) was added TFA (1.0 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-6-(3 -(trifluoromethoxy )phcnyl)quinazolin-4(3 / / )-onc TFA salt (0.20 g, quantitative yield).

[1277] LCMS: Method A, 1.49 min, MS: ES+ 420.0.Step (v)

[1278] (2S,4R)-2-(Methoxymethyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1 -carbonitrile

[1279] To a stirred solution of 3-((3 / ?.5. S)-5-(mcthoxymcthyl)pyrrolidin-3-yl)-6-(3-(trifluoromcthoxy)phcnyl)-quinazolin-4(327)-one TFA salt (0.20 g, 0.37 mmol) in THF (2 mL) was added K2CO3 (0.15 g, 1.12 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.04 g, 0.37 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1.5 h, then poured into water (10 mL) and extracted with with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% EtOAc in n-hexane) to yield (2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(427)-yl)pyrrolidine-l-carbonitrile (0.04 g, 0.09 mmol, 23% yield over two steps).

[1280] LCMS: Method E, 3.34 min, MS: ES+ 445.2; ’H NMR (400 MHz, DMSO-6) 5 ppm: 8.41 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.21 (dd, J= 2.4, 8.4 Hz, 1H), 7.77 - 7.85 (m, 3H), 8.65 (t, J= 8.0 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 5.25 - 5.28 (m, 1H), 4.17 - 4.20 (m, 1H), 3.85 - 3.89 (m, 1H), 3.74 - 3.78 (m, 1H), 3.45 - 3.54 (m, 2H), 3.35 (s, 3H), 2.49 - 2.50 (m, 1H), 2.19- 2.23 (m, 1H); chiral HPLC: Method G, 9.05 min.

[1281] Example 26

[1282] (2R,3R)-3-(6-(3-Cyanophenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carbonitrile

[1283] || \ N-CN

[1284]

[1285] Step (i)

[1286] tert-Butyl (2R,3R)-3-(6-(3-cyanophenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1287] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-bromo-4-oxoquinazolin-3(4 / / )-yl)-2-mcthylpyrrolidinc-1-carboxylate (0.26 g, 0.63 mmol) and (3-cyanophenyl)boronic acid (0.09 g, 0.63 mmol) in 1,4-dioxane: water (6.5 mL, 9: 1) was added K2CO3 (0.26 g, 1.91 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of L I '-A.s(diphcnylphosphmo)fcrroccnc|dichloropalladiiim(II) (0.05 g, 0.06 mmol) and heated at 100 °C for 4 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 82% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(3-cyanophcnyl)-4-oxoquinazolin-3 (4H)-yl)-2-mcthylpyrrolidinc- 1 -carboxylate (0.18 g, 0.41 mmol, 65% yield).

[1288] LCMS: Method A, 1.82 min, MS: ES+ 431.2.Step (ii)

[1289] 3-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzonitrile TFA salt To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-(3-cyanophcnyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1 -carboxylate (0.18 g, 0.41 mmol) in DCM (4.0 m ) was added TFA (1.8 m, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3.4-dihydroquinazolin-6-yl)benzonitrile TFA salt (0.19 g, quantitative yield).

[1290] LCMS: Method A, 1.35 min, MS: ES+ 331.2.

[1291] Step (iii)

[1292] (2R,3R)-3-(6-(3-Cyanophenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carbonitrile To a stirred solution of 3-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3.4-dihydroquinazolin-6-yl)benzonitrile TFA salt (0.19 g, 0.43 mmol) in THF (3.0 mb) was added K2CO3 (0.18 g, 1.31 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.05 g, 0.44 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h. The mixture was poured into water (50 mb) and extracted with EtOAc (2 x 50 mb). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80% EtOAc in w-hexane) to yield (2 / ?.3 / ?)-3-(6-(3-cyanophcnyl)-4-oxoquinazolin-3(4 / / )-yl)-2-methylpyrrolidine-l -carbonitrile (0.08 g, 0.23 mmol, 56% yield over two steps).

[1293] ECMS: Method E, 2.80 min, MS: ES+ 356.2; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.47 (d, J= 2.0 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J= 2.0 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J= 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.83 (d, J= 8.8 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 5.33 - 5.37 (m, 1H), 4.04 - 4.07 (m, 1H), 3.86 - 3.92 (m, 1H), 3.48 - 3.55 (m, 1H), 2.49 - 2.50 (m, 2H), 0.92 (d, J= 6.4 Hz, 3H); chiral HPLC: Method G, 10.21 min.

[1294] Example 27

[1295] (2S,4R)-2-((lH-l,2,3-Triazol-l-yl)methyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1296] N-CN

[1297] N'

[1298]

[1299] Step (i)

[1300] tert-Butyl (2S,4R)-2-((lH-l,2,3-triazol-l-yl)methyl)-4-(2-amino-5-bromobenzamido)pyrrolidine-l-carboxylate

[1301] To a stirred solution of 2-amino-5 -bromobenzoic acid (0.40 g, 1.87 mmol) in THF (1.5 mb) was added DIPEA (0.72 g, 5.61 mmol) andHATU (0.71 g, 1.87 mmol) in portions at 0 °C. After 10 min, a solutionof tert-butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-aminopyrrolidine-1-carboxylate (0.50 g, 1.87 mmol) in THF (1 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 2 h, then poured into ice cold water (50 mL) and extracted with 5% methanol in DCM (3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70-80% EtOAc in M-hexane) to yield tert-butyl (2S,47?)-2-(( \H- 1,2, 3 -triazol- l-yl)methyl)-4-(2-amino-5-bromobenzamido)pyrrolidine-l -carboxylate (1.0 g, quantitative yield).

[1302] LCMS: Method A, 1.61 min, MS: ES+ 365.1, 367.1 (M-100).

[1303] Step (ii)

[1304] tert-Butyl (2S,4R)-2-((lH-l,2,3-triazol-l-yl)methyl)-4-(6-bromo-4-oxoquinazolin-3(4H)-yl)pyrrolidine-l -carboxylate

[1305] To a stirred solution of tert-butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-(2-amino-5-bromobenzamido)pyrrolidine-1-carboxylate (1.0 g, 2.15 mmol) in ethanol (5 mL) was added triethyl orthoformate (5 mL, 5 vol) and iodine (0.05 g, 0.21 mmol) at rt. The mixture was heated at 90 °C for 2 h, then concentrated under reduced pressure. The residue was poured into 5% sodium thaiosulphate solution (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure to yield tert-butyl (2. S'.4 / ?)-2-(( 1H- 1,2,3 -triazol- 1 -yl)methyl)-4-(6-bromo-4-oxoquinazolin-3 (4H)- yl)pyrrolidine-1-carboxylate (0.45 g, 0.94 mmol, 51% yield over two steps).

[1306] LCMS: Method A, 1.64 min, MS: ES+ 475.2, 477.1.

[1307] Step (iii)

[1308] tert-Butyl (2S,4R)-2-((lH-l,2,3-triazol-l-yl)methyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l-carboxylate

[1309] To a stirred solution of tert-butyl (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-(6-bromo-4-oxoquinazolin-3(4H)-yl)pyrrolidine-1-carboxylate (0.20 g, 0.42 mmol) and (3-(trifluoromethoxy)-phenyl)boronic acid (0.10 g, 0.50 mmol) in 1,4-dioxane: water (4 mL, 4: 1) was added K2CO3 (0.17 g, 1.26 mmol). The mixture was purged with N2 gas for 30 min, followed by addition of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.03 g, 0.04 mmol). The mixture was heated at 100 °C for 4 h, then poured into water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% EtOAc in M-hexane) to yield tert-butyl (2S,47?)-2-(( IH-l.2.3-triazol-l-yl)mcthyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(427)-yl)pyrrolidine-l -carboxylate (0.08 g, 0.14 mmol, 29% yield).

[1310] LCMS: Method A, 1.86 min, MS: ES+ 557.3.Step (iv)

[1311] 3-(( 3R, 5S)-5-( ( 1 H-1,2, 3-Triazol-l -yl) methyl) pyrrolid in-3-yl)-6-( 3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt

[1312] To a stirred solution of tert-butyl (2S,47?)-2-((lH- 1,2, 3 -triazol- 1 -yl)methyl)-4-(4-oxo-6-(3 -(trifluoromcthoxy)phcnyl)quinazolin-3(4H)-yl)pyrrolidinc- 1 -carboxylate (0.07 g, 0.12 mmol) in DCM (2.0 mb) was added TFA (0.4 mb, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to 0 °C and stirred for 1 h, then concentrated under reduced pressure to yield 3-((3R,5S)-5-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt (0.07 g, quantitative yield).

[1313] LCMS: Method A, 1.46 min, MS: ES+ 457.3.

[1314] Step (v)

[1315] (2S,4R)-2-((lH-l,2,3-Triazol-l-yl)methyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1316] To a stirred solution of 3-((3R,5S)-5-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt (0.07 g, 0.12 mmol) in THF (0.7 mL) was added K2CO3 (0.05 g, 0.36 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.01 g, 0.12 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into water (30 mL) and extracted with with DCM (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 3% methanol in DCM) to yield (2S,4R)-2-((1H-1,2,3-triazol-1-yl)methyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.01 g, 0.02 mmol, 16% yield over two steps).

[1317] LCMS: Method E, 2.99 min, MS: ES+ 482.0; ’H NMR (400 MHz, DMSO-6) 5 ppm: 8.40 (d, J = 16 Hz, 2H), 8.21 - 8.23 (m, 2H), 7.85 (d, J= 6.8 Hz, 2H), 7.79 (d, J= 5.2 Hz, 2H), 7.64 - 7.68 (m, 1H), 7.43 - 7.48 (m, 1H), 5.08 - 5.17 (m, 1H), 4.68 - 4.72 (m, 2H), 4.53 - 4.58 (m, 1H), 3.82 - 3.91 (m, 1H), 3.77 - 3.82 (m, 1H), 3.58 - 3.62 (m, 1H), 2.23 - 2.31 (m, 1H); chiral HPLC: Method G, 10.51 min. Example 28

[1318] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1319]

[1320] Step (i)

[1321] 4-(T rifluoromethoxy)-2-(trimethylstannyl)pyridine

[1322] To a stirred solution of 2-chloro-4-(trifluoromethoxy)pyridine (0.30 g, 1.52 mmol) in 1,4-dioxane (3.0 mL) was added 1,1,1,2,2,2-hexamethyldistannane (0.99 g, 3.04 mmol). The mixture was purgedwith N2 gas for 30 min, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30 mmol). The mixture was again purged with N2 gas for 15 min, and heated at 100 °C for 2 h, then poured into water (20 mL) and extracted with n-hexane (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure to yield 4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine (0.55 g, quantitative yield).

[1323] LCMS: Method E, 3.82 min, MS: ES+ 328.0.

[1324] Step (ii)

[1325] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(4H)-yl)pyrrolidine-l -carboxylate

[1326] To a stirred solution of tert-butyl (2R,3R)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.20 g, 0.41 mmol) and 4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine (0.17 g, 0.54 mmol) in THF (2.0 mL) was added (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, T-biphenyl)[2-(2'-amino-l, T-biphenyl)]palladium(II) methanesulfonate (Xphos Pd G3) (0.03 g, 0.04 mmol). The mixture was heated at 100 °C for 16 h, then poured into water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% EtOAc in n-hexane) to yield tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(427)-yl)pyrrolidine-l -carboxylate (0.10 g, 0.20 mmol, 41% yield).

[1327] LCMS: Method A, 1.95 min, MS: ES+ 491.3.

[1328] Step (iii)

[1329] 3-((2R3R)-2-Methylpyrrolidin-3-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-4(3H)-one TFA salt

[1330] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(4H)-yl)pyrrolidine-1-carboxylate (0.10 g, 0.20 mmol) in DCM (1.0 mL) was added TFA (0.30 mL, 3 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-4(3H)-one TFA salt (0.10 g, quantitative yield).

[1331] LCMS: Method E, 2.72 min, MS: ES+ 391.2.

[1332] Step (iv)

[1333] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1334] To a stirred solution of 3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-4(3H)-one TFA salt (0.10 g, 0.25 mmol) in THF (1 mL) was added K2CO3 (0.10 g, 0.76 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.25 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (20 mL).The precipitated solid was collected through a Buchner funnel, washed with n-hexane (20 mL), and dried under reduced pressure to yield (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethoxy)pyridin-2-yl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.02 g, 0.05 mmol, 27% yield over two steps). LCMS: Method E, 3.07 min, MS: ES+ 416.2; ‘H NMR (400 MHz, CDC13) 5 ppm: 8.86 (d, J= 2.0 Hz, 1H), 8.76 (d, J= 5.6 Hz, 1H), 8.54 (dd, J= 2.0, 8.4 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.69 (s, 1H), 7.16 - 7.18 (m, 1H), 5.58 - 5.63 (m, 1H), 4.04 - 4.07 (m, 1H), 3.84 - 3.90 (m, 1H), 3.62 - 3.68 (m, 1H), 2.66 - 2.68 (m, 1H), 2.34 - 2.38 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H); chiral HPLC: Method F, 7.05 min.

[1335] Example 29

[1336] (2R,3R)-3-(6-(3-Cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1 -carbonitrile

[1337]

[1338] Step (i)

[1339] tert-Butyl (2R,3R)-3-(6-(3-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1340] To a stirred solution of tert-butyl (2R,3R)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.20 g, 0.49 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)benzonitrile (0.17 g, 0.54 mmol) in 1,4-dioxane: water (2.0 mL, 4:1) was added K2CO3 (0.20 g, 1.47 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.03 g, 0.05 mmol) and heated at 100 °C for 4 h. The mixture was poured into water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (53% EtOAc in w-hexane) to yield tert-butyl (2R,3R)-3-(6-(3-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.13 g, 0.31 mmol, 51% yield).

[1341] LCMS: Method E, 3.73 min, MS: ES+ 515.4.

[1342] Step (ii)

[1343] 3-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydroquinazolin-6-yl)-5-(trifluoromethoxy)benzonitrile TFA salt

[1344] To a stirred solution of tert-butyl (2R,3R)-3-(6-(3-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.13 g, 0.31 mmol) in DCM (1 mL) was added TFA (0.65 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-5-(trifluoromethoxy)benzonitrile TFA salt (0.11 g, 0.21 mmol, 84% yield).

[1345] LCMS: Method E, 3.02 min, MS: ES+ 415.4.

[1346] Step (iii)

[1347] (2R,3R)-3-(6-(3-Cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1 -carbonitrile

[1348] To a stirred solution of 3-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3.4-dihydroquinazolin-6-yl)-5-(trifluoromethoxy)benzonitrile TFA salt (0.11 g, 0.21 mmol) in THF (1.1 mL) was added K2CO3 (0.09 g, 0.63 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.32 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (54% EtOAc in w-hexane) to yield (2R,3R)-3-(6-(3-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carbonitrile (0.03 g, 0.06 mmol, 33% yield).

[1349] LCMS: Method E, 3.22 min, MS: ES+ 440.4; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.53 (d, J = 1.6 Hz, 1H), 8.43 (s, 1H), 8.30 (dd, J= 2.0, 8.8 Hz, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.83 (d, J= 8.4 Hz, 1H), 5.32 - 5.37 (m, 1H), 4.04 - 4.07 (m, 1H), 3.86 - 3.92 (m, 1H), 3.48 - 3.55 (m, 1H), 2.48 - 2.52 (m, 2H), 0.92 (d, J= 6.8 Hz, 3H); chiral HPLC: Method F, 10.50 min.

[1350] Example 30

[1351] (2R,3R)-3-(6-(2-Cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine- 1 -carbonitrile

[1352] N-

[1353]

[1354] Step (i)

[1355] 2-(4,4,5,5-Tetramethyl-l,3, 2-dioxaborolan-2-yl)-4-(trifluoromethoxy)benzonitrile

[1356] To a stirred solution of 2-bromo-4-(trifhioromethoxy)benzonitrile (1.0 g, 3.77 mmol) and / v.s(pinacolato)diboron (1.14 g, 4.92 mmol) in 1,4-dioxane (40 mL) was added potassium acetate (1.11 g, 11.32 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.27 g, 0.37 mmol) and heated at 80 °C for 3 h. The mixture was poured into water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure to yield 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)benzonitrile (2.0 g, quantitative yield).LCMS: Method A, 1.85 min, MS: ES- 230.2 (m / z support for ((2-cyano-5-(trifluoromethoxy)-phenyl)boronic acid).

[1357] Step (ii)

[1358] tert-Butyl(2R,3R)-3-(6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1359] To a stirred solution of tert-butyl (2R,3R)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.20 g, 0.49 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)benzonitrile (0.23 g, 0.73 mmol) in 1,4-dioxane : water (2.0 mL, 4:1) was added K2CO3 (0.20 g, 1.47 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 g, 0.05 mmol) and heated at 100 °C for 4 h. The mixture was poured into water (10 mL) and extracted with EtOAc (3 x 20 mb). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (46% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(2-cyano-5-(trifluoromcthoxy)phcnyl)-4-oxoqiiinazolin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.05 g, 0.10 mmol, 21% yield).

[1360] LCMS: Method E, 3.65 min, MS: ES+ 515.2.

[1361] Step (iii)

[1362] 2-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydroquinazolin-6-yl)-4-(trifluoromethoxy)benzonitrile TFA salt

[1363] To a stirred solution of tert-Butyl (2R,3R)-3-(6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.05 g, 0.10 mmol) in DCM (0.5 mL) was added TFA (0.25 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 2-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-4-(trifluoromethoxy)benzonitrile TFA salt (0.06 g, quantitative yield). LCMS: Method E, 2.95 min, MS: ES+ 415.4.

[1364] Step (iv)

[1365] (2R,3R)-3-(6-(2-Cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1 -carbonitrile

[1366] To a stirred solution of 2-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-4-(trifluoromethoxy)benzonitrile TFA salt (0.06 g, 0.12 mmol) in THF (0.6 mL) was added K2CO3 (0.05 g, 0.36 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.02 g, 0.18 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (53% EtOAc in n-hexane) to yield (2 / ?.3 / ?)-3-(6-(2-cyano-5-(trifluoromcthoxy)-phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carbonitrile (0.02 g, 0.04 mmol, 40% yield over two steps).

[1367] LCMS: Method E, 3.17 min, MS: ES+ 440.4; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.40 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 8.19 (d, J= 8.8 Hz, 1H), 8.12 (dd, J= 2.0, 8.4 Hz, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J= 8.4 Hz, 1H), 5.33 - 5.38 (m, 1H), 4.05 - 4.08 (m, 1H), 3.87 - 3.93 (m, 1H), 3.49 - 3.55 (m, 1H), 2.47 -2.55 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H); chiral HPLC: Method F, 10.75 min.

[1368] Example 31

[1369] (2R,3R)-2-Methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1 -carbonitrile

[1370]

[1371] Step (i)

[1372] tert-Butyl (2R,3R)-3-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1373] To a stirred solution of tert-butyl (2R,3R)-3-(2-amino-5-bromobenzamido)-2-methylpyrrolidine-1-carboxylate (0.25 g, 0.63 mmol) and 1,1,1 -triethoxyethane (1.25 mb, 5 vol) in ethanol (1.25 mb) was added iodine (0.02 g, 0.06 mmol) at rt and the mixture was heated at 100 °C for 48 h, then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 49% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-3-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.13 g, 0.30 mmol, 49% yield).

[1374] LCMS: Method D, 3.58 min, MS: ES+ 422.2, 424.2.

[1375] Step (ii)

[1376] tert-Butyl (2R,3R)-2-methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-l -carboxylate

[1377] To a stirred solution of tert-butyl (2R,3R)-3-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.13 g, 0.31 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (0.06 g, 0.30 mmol) in 1,4-dioxane: water (1.3 mL, 4:1) was added K2CO3 (0.13 g, 0.92 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.02 g, 0.03 mmol) and heated at 100 °C for 45 min. The mixture was poured into water (20 mb) and extracted with EtOAc (2 x 15 mb). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-2-methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carboxylate (0.14 g, 0.28 mmol). LCMS: Method D, 3.98 min, MS: ES+ 504.4.Step (iii)

[1378] 2-Methyl-3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt

[1379] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carboxylate (0.14 g, 0.28 mmol) in DCM (1.7 mL) was added TFA (0.7 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 2-methyl-3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt (0.19 g, quantitative yield).

[1380] LCMS: Method D, 3.15 min, MS: ES+ 404.3.

[1381] Step (iv)

[1382] (2R,3R)-2-Methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1 -carbonitrile

[1383] To a stirred solution of 2-methyl-3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one TFA salt (0.19 g, 0.36 mmol) in THF (1.9 mL) was added K2CO3 (0.15 g, 1.10 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.05 g, 0.44 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (20 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80% EtOAc in w-hexane) to yield (2R,3R)-2-methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.07 g, 0.16 mmol, 57% yield over two steps).

[1384] LCMS: Method E, 3.19 min, MS: ES+ 429.2;1HNMR(400 MHz, DMSO-6) 5ppm: 8.38 (s, 1H), 8.18 (d, J= 8.8 Hz, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.42 (d, J = 7.6Hz, 1H), 5.11 - 5.17 (m, 1H), 4.10 - 4.13 (m, 1H), 3.89 - 3.93 (m, 1H), 3.42 - 3.45 (m, 1H), 2.67 (s, 3H), 2.42 - 2.49 (m, 2H), 1.06 (d, J= 6.4 Hz, 3H); chiral HPLC: Method G, 6.83 min.

[1385] Example 32

[1386] 3-(( 2R 3R)-1 -Cyano-2-methylpyrrolidin-3-yl)-6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxo-3, 4-dihydroquinazoline-8-carbonitrile

[1387] CN

[1388]

[1389] Step (i)

[1390] 2-Amino-5-bromo-3-iodobenzoic acid

[1391] To a stirred solution of 2-amino-5 -bromobenzoic acid (2.0 g, 9.03 mmol) in DMF (20 mL) was added N-iodosuccinimide (4.2 g, 18.60 mmol) in portions at rt and stirred for 16 h, then poured into ice coldwater (100 mL) and the precipitated solid was collected through a Buchner funnel. The residue was washed with w-hexane (2 x 10 mL) and dried under reduced pressure to yield 2-amino-5-bromo-3 -iodobenzoic acid (2.50 g, 7.33 mmol, 79% yield).

[1392] LCMS: Method A, 1.74 min, MS: ES+ 341.9, 344.0.

[1393] tert-Butyl (2R,3R)-3-(2-ammo-5-bromo-3- odobenzam do)-2-methylpyrrol dme- 1 -carboxylate To a stirred solution of 2-amino-5-bromo-3 -iodobenzoic acid (1.50 g, 4.40 mmol) in THF (13 mL) was added DIPEA (1.70 g, 13.20 mmol) and HATU (2.50 g, 6.60 mmol) in portions at 0 °C. After 1 h, a solution of tert-butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (0.70 g, 3.52 mmol) in THF (2 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 16 h, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 2.7% methanol in DCM) to yield tert-butyl (2 / ?.3 / ?)-3-(2-amino-5-bromo-3-iodobenzamido)-2-methylpyrrolidine-l-carboxylate (1.0 g, 1.91 mmol, 44% yield).

[1394] LCMS: Method D, 3.80 min, MS: ES+ 524.3, 526.2.

[1395] tert-Butyl (2R,3R)-3-(6-bromo-8-iodo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate To a stirred solution of tert-butyl (2R,3R)-3-(2-amino-5-bromo-3-iodobenzamido)-2-methylpyrrolidine-1-carboxylate (1.0 g, 1.91 mmol) in ethanol (5 mL) was added triethyl orthoformate (5.0 mL, 5 vol) and iodine (0.10 g, 0.38 mmol) at rt. The mixture was heated at 130 °C for 6 h, then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 22% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-3-(6-bromo-8-iodo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.55 g, 1.03 mmol, 54% yield).

[1396] LCMS: Method D, 3.88 min, MS: ES+ 534.3, 536.2.

[1397] Step (iv)

[1398] tert-Butyl (2R,3R)-3-(6-bromo-8-cyano-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate To a stirred solution of tert-butyl (2R,3R)-3-(6-bromo-8-iodo-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.55 g, 1.03 mmol) in DMF (5.5 mL) was added Zn(CN)₂ (0.06 g, 0.51 mmol) and Zn dust (0.01 g, 0.20 mmol) at rt. The mixture was purged with N2 gas for 15 min, followed by addition of 1,1'-bis(diphenylphosphino)ferrocene (0.04 g, 0.07 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.05 g, 0.05 mmol). The mixture was heated at 80 °C for 6 h, then poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 23% EtOAc in w-hexane) to yieldtert-butyl (2 / ?.3 / ?)-3-(6-bromo-8-cyano-4-oxoquinazolin-3(4 / / )-yl)-2-mcthylpyrrolidinc- 1 -carboxylate (0.25 g, 0.58 mmol, 56% yield).

[1399] LCMS: Method D, 3.46 min, MS: ES+ 433.3, 435.3.

[1400] tert-Butyl (2R,3R)-3-(8-cyano-6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate

[1401] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-bromo-8-cyano-4-oxoquinazolin-3(4 / / )-yl)-2-methylpyrrolidine- 1 -carboxylate (0.23 g, 0.53 mmol) and 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)benzonitrile (0.16 g, 0.53 mmol) in 1,4-dioxane: water (2.3 mL, 4:1) was added K2CO3 (0.15 g, 1.06 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 g, 0.04 mmol) and heated at 80 °C for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 27% EtOAc in n-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(8-cyano-6-(2-cyano-5-(trifluoromcthoxy)phcnyl)-4-oxoquinazolin-3(427)-yl)-2-methylpyrrolidine-l-carboxylate (0.12 g, 0.22 mmol, 42% yield).

[1402] LCMS: Method D, 3.66 min, MS: ES+ 540.5.

[1403] 6-(2-Cyano-5-( trifluoromethoxy)phenyl)-3-((2R, 3R)-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydroquinazoline-8-carbonitrile TFA salt

[1404] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(8-cyano-6-(2-cyano-5-(trifluoromcthoxy)phcnyl)-4-oxoquinazolin-3(427)-yl)-2-methylpyrrolidine-l-carboxylate (0.12 g, 0.22 mmol) in DCM (1.2 mL) was added TFA (0.6 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 6-(2-cyano-5 -(trifluoromethoxy )phenyl)-3-((27?,37?)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile TFA salt (0.12 g, quantitative yield).

[1405] LCMS: Method D, 2.67 min, MS: ES+ 440.4.

[1406] 3-(( 2R 3R)-1 -Cyano-2-methylpyrrolidin-3-yl)-6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxo-3, 4-dihydroquinazoline-8-carbonitrile

[1407] To a stirred solution of 6-(2-cyano-5-(trifluoromcthoxy)phcnyl)-3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)- 4-oxo-3,4-dihydroquinazoline-8-carbonitrile TFA salt (0.12 g, 0.21 mmol) in THF (1.2 mL) was added K2CO3 (0.09 g, 0.65 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.03 g, 0.32 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (20 mL) and the precipitated solid was collected through a Buchner funnel. The residue was purified by flash column chromatography (silica gel, 30% EtOAc in w-hexane) to yield 3-((2 / .3 / )- 1 -cyano-2-methylpyrrolidin-3-yl)-6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile (0.04 g, 0.09 mmol, 39% yield over two steps).

[1408] LCMS: Method E, 3.27 min, MS: ES+ 465.0; ‘H NMR (400 MHz, DMSO-6) 5 ppm: 8.73 (d, J = 2.0 Hz, 1H), 8.68 (d, J= 2.0 Hz, 1H), 8.50 (s, 1H), 8.22 (d, J= 8.8 Hz, 1H), 7.90 (d, J= 1.6 Hz, 1H), 7.71 (dd, J= 1.2, 8.4 Hz, 1H), 5.32 - 5.36 (m, 1H), 4.04 - 4.07 (m, 1H), 3.90 - 3.95 (m, 1H), 3.52 - 3.56 (m, 1H), 2.53 - 2.56 (m, 1H), 2.46 - 2.48 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H); chiral HPLC: Method O, 9.30 min.

[1409] Example 33

[1410] (2S,4R)-2-(Methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 4-d]pyrimidin- 3 ( 4H)-yl) pyrrolidine- 1 -carbonitrile

[1411]

[1412] tert-Butyl (2S,4R)-4-(5-amino-2-chloroisonicotinamido)-2-(methoxymethyl)pyrrolidine-l-carboxylate To a stirred solution of 5 -amino-2 -chloroisonicotinic acid (0.50 g, 2.89 mmol) in THF (3 mL) was added DIPEA (1.12 g, 8.69 mmol) and HATU (1.65 g, 4.35 mmol) in portions at 0 °C. After 30 min, a solution of tert-butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.67 g, 2.89 mmol) in THF (2 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 3 h, then poured into saturated NaHCCF solution (120 mL) and extracted with EtOAc (3 x 120 mL). The combined organic phases were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30% EtOAc in n-hexane) to yield tert-butyl (2S,4R)-4-(5-amino-2-chloroisonicotinamido)-2-(methoxymethyl)-pyrrolidine-1-carboxylate (1.0 g, 2.60 mmol, 89% yield).

[1413] LCMS: Method A, 1.63 min, MS: ES+ 385.19, 387.2.

[1414] tert-Butyl (2S,4R)-4-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1 -carboxylate

[1415] To a stirred solution of tert-butyl (2S,4R)-4-(5-amino-2-chloroisonicotinamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.50 g, 1.30 mmol) in triethyl orthoformate (5.0 mL, 10 vol) was added concentrated hydrochloric acid (3 drops) dropwise at 0 °C. The mixture was heated at 120 °C for 16 h, then poured into water (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40% EtOAc inn-hexane) to yield tert-butyl (2. S'.4 / )-4-(6-chloro-4-oxop rido|3.4-t / |p rimidin-3(4 / / )- l)-2-(methoxymethyl)pyrrolidine-l -carboxylate (0.23 g, 0.58 mmol, 45% yield).

[1416] LCMS: Method A, 1.70 min, MS: ES+ 395.2, 397.2.

[1417] Step (iii)

[1418] tert-Butyl (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 4-d]pyrimidin-3 ( 4H)-yl)pyrrolidine-l -carboxylate

[1419] To a stirred solution of tert-butyl (2S,4R)-4-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.20 g, 0.51 mmol) and 4-(trifluoromethyl)-1H-pyrazole (0.10 g, 0.76 mmol) in 1,4-dioxane (2.0 mb) was added K2CO3 (0.21 g, 1.52 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of copper(I) iodide (0.02 g, 0.10 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.06 g, 0.41 mmol). The mixture was heated at 110 °C for 48 h, then poured into water (50 mb) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 4.6% methanol in DCM) to yield tert-butyl (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]-pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.06 g, 0.13 mmol, 25% yield).

[1420] LCMS: Method A, 1.96 min, MS: ES+ 439.2 (M-56).

[1421] Step (iv)

[1422] 3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt

[1423] To a stirred solution of tert-butyl (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.06 g, 0.13 mmol) in DCM (3 mL) was added TFA (0.5 mL, 8 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt (0.08 g, quantitative yield).

[1424] LCMS: Method A, 1.45 min, MS: ES+ 395.2.

[1425] Step (v)

[1426] (2S,4R)-2-(Methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 4-d]pyrimidin-3 ( 4H)-yl) pyrrolidine- 1 -carbonitrile

[1427] To a stirred solution of 3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt (0.08 g, 0.16 mmol) in THF (0.8 mL) was added K2CO3 (0.07 g, 0.47 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.02 g, 0.17 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (10 mL). The precipitated solid was collected through a Buchner funnel, washed withn-hexane (20 mL), and dried under reduced pressure. The residue was purified by trituration with diethyl ether (2 x 3 mL) and w-pcntanc (2 x 3 mL) to yield (2S,4R)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.02 g, 0.04 mmol, 34% yield over two steps).

[1428] LCMS: Method E, 3.08 min, MS: ES+ 420.2; 1H NMR (400 MHz, DMSO-d6) 5 ppm: 9.29 (s, 1H), 9.08 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 5.26 - 5.29 (m, 1H), 4.19 - 4.22 (m, 1H), 3.84 -3.89 (m, 1H), 3.77 - 3.81 (m, 1H), 3.47 - 3.55 (m, 2H), 3.36 (s, 3H), 2.52 - 2.58 (m, 1H), 2.20 - 2.27 (m, 1H); chiral HPLC: Method O, 10.35 min.

[1429] Example 34

[1430] (2R,3R)-2-Methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3, 4-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1431]

[1432] Step (i)

[1433] tert-Butyl (2R,3R)-3-(5-amino-2-chloroisonicotinamido)-2-methylpyrrolidine-l-carboxylate

[1434] To a stirred solution of 5-amino-2-chloroisonicotinic acid (0.50 g, 2.90 mmol) in THF (4 mL) was added DIPEA (1.12 g, 8.72 mmol) and HATU (1.10 g, 2.90 mmol) in portions at 0 °C. After 30 min, a solution of tert-butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (0.64 g, 3.19 mmol) in THF (1 mL) was added dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 16 h, then poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 38% EtOAc in n-hexane) to yield tert-butyl (27?, 3 / ?)-3-(5-amino-2-chloroisonicotinamido)-2-methylpyrrolidine-l -carboxylate (0.50 g, 1.41 mmol, 48% yield).

[1435] LCMS: Method A, 1.66 min, MS: ES+ 299.1, 301.1 (M-56).

[1436] Step (ii)

[1437] tert-Butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1438] To a stirred solution of tert-butyl (27?,37?)-3-(5-amino-2-chloroisonicotinamido)-2-methylpyrrolidine- 1-carboxylate (0.40 g, 1.12 mmol) in triethyl orthoformate (8.0 mL, 20 vol) was added concentrated hydrochloric acid (20 drops) dropwise at 0 °C. The mixture heated at 130 °C for 16 h, then mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 46% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-chloro-4-oxopyrido|3.4 / |-pyrimidin-3(477)-yl)-2-methylpyrrolidine-l -carboxylate (0.12 g, 0.33 mmol, 29% yield).

[1439] LCMS: Method A, 1.72 min, MS: ES+ 365.2, 367.2.Step (iii)

[1440] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-l -carboxylate

[1441] To a stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.11 g, 0.30 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (0.07 g, 0.33 mmol) in 1,4-dioxane: water (1.1 mb, 9:1) was added K2CO3 (0.12 g, 0.90 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, T-biphenyl)[2-(2'-amino-l, T-biphenyl)]-palladium(II) methanesulfonate (Xphos Pd G3) (0.03 g, 0.03 mmol) and heated at 100 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 52% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.08 g, 0.16 mmol, 54% yield).

[1442] LCMS: Method A, 1.93 min, MS: ES+ 491.3.

[1443] Step (iv)

[1444] 3-((2R3R)-2-Methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)pyrido[3, 4-d]pyrimidin-4(3H)-one TFA salt

[1445] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)-pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.08 g, 0.16 mmol) in DCM (0.8 mL) was added TFA (0.24 mL, 3 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt (0.08 g, quantitative yield). LCMS: Method E, 3.01 min, MS: ES+ 391.2.

[1446] Step (v)

[1447] (2R,3R)-2-Methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3, 4-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1448] To a stirred solution of 3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(3-(trifluoromethoxy)phenyl)-pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt (0.08 g, 0.16 mmol) in THF (0.8 mL) was added K2CO3 (0.06 g, 0.47 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.02 g, 0.16 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 1 h, then poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 62% EtOAc in n-hexane) to yield (2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.02 g, 0.06 mmol, 29% yield over two steps).

[1449] LCMS: Method E, 3.37 min, MS: ES+ 416.2;1HNMR(400 MHz, DMSO-6) 5ppm: 9.23 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.27 (d, J= 8.0 Hz, 1H), 8.20 (s, 1H), 7.68 (t, J= 8.0 Hz, 1H), 7.49 (d, J = 7.2 Hz,1H), 5.32 - 5.37 (m, 1H), 4.05 - 4.08 (m, 1H), 3.88 - 3.94 (m, 1H), 3.49 - 3.56 (m, 1H), 2.46 - 2.51 (m, 2H), 0.95 (d, J= 6.4 Hz, 3H); chiral HPLC: Method H, 6.89 min.

[1450] Example 35

[1451] l-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[1452]

[1453] Step (i)

[1454] tert-Butyl (2R,3R)-3-(6-(4-cyano-lH-pyrazol-l-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1 -carboxylate

[1455] To a stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.15 g, 0.41 mmol) and 1H-pyrazole-4-carbonitrile (0.07 g, 0.74 mmol) in DMF (1.5 mL) was added K2CO3 (0.17 g, 1.24 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of potassium iodide (0.07 g, 0.41 mmol). The mixture was heated at 130 °C for 3 h, then poured into ice-cold water (10 mL) and the precipitated solid was collected through a Buchner funnel, dried under reduced pressure to yield tert-butyl (2R,3R)-3-(6-(4-cyano-1H-pyrazol-1-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.10 g, 0.24 mmol, 58% yield).

[1456] LCMS: Method D, 3.63 min, MS: ES+ 366.3 (M-56).

[1457] Step (ii)

[1458] l-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile TFA salt

[1459] To a stirred solution of tert-butyl (2R,3R)-3-(6-(4-cyano-1H-pyrazol-1-yl)-4-oxopyrido[3,4-d]-pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.10 g, 0.24 mmol) in DCM (1 mL) was added TFA (0.5 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 1-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile TFA salt (0.10 g, quantitative yield). LCMS: Method D, 2.41 min, MS: ES+ 322.3.

[1460] Step (iii)

[1461] l-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)-lH-pyrazole-4-carbonitrile

[1462] To a stirred solution of 1-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]-pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile TFA salt (0.10 g, 0.23 mmol) in THF (1 mL) was added K2CO3 (0.09 g, 0.69 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.04 g, 0.34 mmol) wasadded into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (10 mL) and the precipitated solid was collected through a Buchner funnel. The residue was purified by flash column chromatography (silica gel, 51% EtOAc in n-hexane) to yield 1-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-1H-pyrazole-4-carbonitrile (0.02 g, 0.06 mmol, 24% yield over two steps).

[1463] LCMS: Method E, 2.57 min, MS: ES+ 347.2;1H NMR (400 MHz, DMSO-6) 5 ppm: 9.51 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 5.33 - 5.34 (m, 1H), 4.04 - 4.07 (m, 1H), 3.89 - 3.91 (m, 1H), 3.51 - 3.53 (m, 1H), 2.48 - 2.52 (s, 2H), 0.94 (d, J= 6.4 Hz, 3H); chiral SFC: Method L, 5.40 min.

[1464] Example 36

[1465] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 4-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1466]

[1467] Step (i)

[1468] tert-Butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3,4-d]pyrimidin-3 ( 4H)-yl) pyrrolidine- 1 -carboxylate

[1469] To a stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.20 g, 0.54 mmol) and 4-(trifluoromethyl)-1H-pyrazole (0.11 g, 0.82 mmol) in 1,4-dioxane (2.0 mL) was added K2CO3 (0.22 g, 1.64 mmol). The mixture was purged with N2 gas for 15 min, followed by addition of (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.06 g, 0.43 mmol). The mixture was again purged with N2 gas for 30 min, followed by addition of copper(I) iodide (0.02 g, 0.10 mmol). The mixture was heated at 140 °C for 18 h, then poured into water (20 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40% EtOAc in n-hexane) to yield tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.09 g, 0.19 mmol, 36% yield).

[1470] LCMS: Method E, 3.69 min, MS: ES+ 409.2 (M-56).

[1471] Step (ii)

[1472] 3-((2R3R)-2-Methylpyrrolidin-3-yl)-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 4-d]pyrimidin-4(3H)-one TFA salt

[1473] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carboxylate (0.09 g, 0.19 mmol) in DCM (0.9 mL) was added TFA (0.45 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt (0.11 g, quantitative yield).

[1474] LCMS: Method D, 2.96 min, MS: ES+ 365.2.

[1475] Step (iii)

[1476] (2R,3R)-2-Methyl-3-(4-oxo-6-(4-(trifluoromethyl)-lH-pyrazol-l-yl)pyrido[3, 4-d]pyrimidin-3(4H)-yl)pyrrolidine-l-carbonitrile

[1477] To a stirred solution of 3-((2R,3R)-2-methylpyrrolidin-3-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt (0.11 g, 0.23 mmol) in THF (1.5 mL) was added K2CO3 (0.09 g, 0.69 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.27 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice cold water (10 mL) and the precipitated solid was collected through a Buchner funnel, washed with n-hexane (10 mL), dried under reduced pressure to yield (2R,3R)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)pyrrolidine-1-carbonitrile (0.03 g, 0.08 mmol, 46% yield over two steps).

[1478] LCMS: Method E, 3.11 min, MS: ES+ 390.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.28 (s, 1H), 9.09 (s, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H) 5.30 - 5.35 (m, 1H), 4.03 - 4.08 (m, 1H), 3.87 - 3.92 (m, 1H), 3.48 - 3.54 (m, 1H), 2.43 - 2.47 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H); chiral HPLC: Method O, 8.92 min.

[1479] Example 37

[1480] 4-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)picolinonitrile

[1481]

[1482] Step (i)

[1483] tert-Butyl (2R,3R)-3-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1484] To a stirred solution of tert-butyl (2R,3R)-3-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.35 g, 0.96 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.22 g, 0.96 mmol) in 1,4-dioxane: water (3.5 mL, 4:1) was added K2CO3 (0.39 g, 2.88 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 g, 0.07 mmol) and heated at 100 °C for 1 h. The mixture was poured into water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc inn-hexane) to yield tert-butyl (2R,3R)-3-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.10 g, 0.23 mmol, 24% yield).

[1485] LCMS: Method A, 1.71 min, MS: ES+ 433.2.

[1486] Step (ii)

[1487] 4-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)picolinonitrile TFA salt

[1488] To a stirred solution of tert-butyl (2R,3R)-3-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-1-carboxylate (0.10 g, 0.23 mmol) in DCM (1.0 mL) was added TFA (0.5 mL, 5 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 4-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinonitrile TFA salt (0.13 g, quantitative yield).

[1489] LCMS: Method A, 1.34 min, MS: ES+ 333.2.

[1490] Step (iii)

[1491] 4-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)picolinonitrile

[1492] To a stirred solution of 4-(3-((2R,3R)-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]-pyrimidin-6-yl)picolinonitrile TFA salt (0.13 g, 0.29 mmol) in THF (1.3 mL) was added K2CO3 (0.12 g, 0.87 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.03 g, 0.29 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (10 mL) and extracted with with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95% EtOAc in n-hexane). The residue was further purified by reverse phase preparative HPLC using Method W to yield 4-(3-((2 / ?.3 / ?)-l-cyano-2-mcthylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-<7]pyrimidin-6-yl)picolinonitrile (0.01 g, 0.03 mmol, 12% yield over two steps). LCMS: Method E, 2.61 min, MS: ES+ 358.4;1HNMR(400 MHz, DMSO-6) 5ppm: 9.27 (s, 1H), 8.87 - 8.89 (m, 2H), 8.50 (s, 1H), 8.54 (dd, J= 2.0, 5.2 Hz, 1H), 8.41 (s, 1H), 5.33 - 5.35 (m, 1H), 4.04 - 4.07 (m, 1H), 3.89 - 3.91 (m, 1H), 3.51 - 3.53 (m, 1H), 2.45 - 2.50 (m, 2H), 0.94 (d, J= 6.8 Hz, 3H); chiral HPLC: Method H, 10.19 min.

[1493] Example 38

[1494] 4-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido [3, 4-d]pyrimidin-6-yl)picolinonitrile

[1495] o

[1496]

[1497] \Step (i)

[1498] tert-Butyl (2S,4R)-4-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[1499] To a stirred solution of tert-butyl (2S,4R)-4-(6-chloro-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.40 g, 1.01 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinonitrile (0.35 g, 1.52 mmol) in 1,4-dioxane: water (4.0 mb, 9:1) was added K2CO3 (0.42 g, 3.04 mmol). The mixture was purged with N2 gas for 10 min, followed by addition of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.07 g, 0.10 mmol) and heated at 100 °C for 3 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40% EtOAc in n-hexane) to yield tert-butyl (2S,4R)-4-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.15 g, 0.32 mmol, 31% yield).

[1500] LCMS: Method A, 1.67 min, MS: ES+ 463.4.

[1501] Step (ii)

[1502] 4-(3-((3R,5S)-5-(Methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)picolinonitrile TFA salt

[1503] To a stirred solution of tert-butyl (2S,4R)-4-(6-(2-cyanopyridin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.15 g, 0.32 mmol) in DCM (2.0 mL) was added TFA (1.5 mL, 10 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 4-(3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinonitrile TFA salt (0.20 g, quantitative yield). LCMS: Method A, 1.26 min, MS: ES+ 363.3.

[1504] Step (iii)

[1505] 4-(3-((3R,5S)-l-Cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)picolinonitrile

[1506] To a stirred solution of 4-(3-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinonitrile TFA salt (0.20 g, 0.42 mmol) in THF (3.0 mL) was added K2CO3 (0.17 g, 1.26 mmol) at rt and stirred for 10 min. Cyanogen bromide (0.04 g, 0.42 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into ice-cold water (50 mL). The precipitated solid was collected through a Buchner funnel, washed with n-hexane (3 x 30 mL), and dried under reduced pressure to yield 4-(3-((37?,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-<7]pyrimidin-6-yl)picolinonitrile (0.02 g, 0.05 mmol, 17% yield over two steps).

[1507] LCMS: Method D, 2.60 min, MS: ES+ 388.4; ’H NMR (400 MHz, DMSO-6) 5 ppm: 9.24 (s, 1H), 8.86 - 8.89 (m, 2H), 8.82 (s, 1H), 8.52 - 8.54 (m, 2H), 5.25 - 5.31 (m, 1H), 4.19 - 4.24 (m, 1H), 3.85 -3.89 (m, 1H), 3.77 - 3.80 (m, 1H), 3.45 - 3.54 (m, 2H), 3.38 (s, 3H), 2.44 - 2.50 (m, 1H), 2.20 - 2.27 (m, 1H); chiral SFC: Method Q, 6.49 min.

[1508] Example 39

[1509] 2-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)isonicotinonitrile

[1510]

[1511] Step (i)

[1512] tert-Butyl (2R,3R)-3-(6-(4-cyanopyridin-2-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpyrrolidine-l-carboxylate

[1513] A stirred solution of tert-butyl (2 / .3 / )-3-(6-chloro-4-oxopyrido|3.4-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.25 g, 0.68 mmol) and 2-(trimethylstannyl)isonicotinonitrile (0.22 g, 0.82 mmol) in THF (2.5 m ) was purged with N2 gas for 10 min, followed by addition of (2 -dicyclohexylphosphino-2', 4', 6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,l '-biphenyl)]-palladium(II) methanesulfonate (Xphos Pd G3) (0.06 g, 0.07 mmol). The mixture was heated at 100 °C for 16 h, then poured into water (50 m ) and extracted with EtOAc (2x 15 mb). The combined organic phases were dried over anhydrous NajSOr. filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 53% EtOAc in w-hexane) to yield tert-butyl (2 / ?.3 / ?)-3-(6-(4-cyanopyridin-2-yl)-4-oxopyrido|3.4-t / |pyrimidin-3(4 / / )-yl)-2-methylpyrrolidine-1 -carboxylate (0.07 g, 0.16 mmol, 24% yield).

[1514] ECMS: Method A, 1.76 min, MS: ES+ 433.4.

[1515] Step (ii)

[1516] 2-(3-((2R,3R)-2-Methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)isonicotinonitrile TFA salt

[1517] To a stirred solution of tert-butyl (2 / ?.3 / ?)-3-(6-(4-cyanopyridin-2-yl)-4-oxopyrido|3.4-t / |pyrimidin-3 (4H)-yl)-2-mcthylpyrrolidinc- 1 -carboxylate (0.07 g, 0.16 mmol) in DCM (0.7 mb) was added TFA (0.21 mb, 3 vol) dropwise at 0 °C. The mixture was allowed to warm to rt and stirred for 1 h, then concentrated under reduced pressure to yield 2-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido[3,4-<7]pyrimidin-6-yl)isonicotinonitrile TFA salt (0.08 g, quantitative yield).

[1518] ECMS: Method E, 2.14 min, MS: ES+ 333.3.

[1519] Step (iii)

[1520] 2-(3-((2R,3R)-l-Cyano-2-methylpyrrolidin-3-yl)-4-oxo-3, 4-dihydropyrido[3, 4-d]pyrimidin-6-yl)isonicotinonitrile

[1521] To a stirred solution of 2-(3-((2 / ?.3 / ?)-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydropyrido|3.4 / |-pyrimidin-6-yl)isonicotinonitrile TFA salt (0.08 g, 0.18 mmol) in THF (0.8 mL) was added K2CO3 (0.07 g, 0.53 mmol) at rt and stirred for 5 min. Cyanogen bromide (0.02 g, 0.18 mmol) was added into the reaction mixture at 0 °C. The mixture was stirred at rt for 1 h, then poured into water (50 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 53% EtOAc in w-hexane) to yield 2-(3-((2 / ?.3 / ?)-l-cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,4-d] py rim idin-6-y 1 )i sonicotinoni tri le (0.02 g, 0.06 mmol, 35% yield over two steps).

[1522] LCMS: Method E, 2.66 min, MS: ES+ 358.2;1HNMR(400 MHz, DMSO-6) 5 ppm: 9.24 (s, 1H), 9.00 (d, J= 5.2 Hz, 1H), 8.97 (s, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 7.97 (d, J= 4.8 Hz, 1H), 5.34 - 5.37 (m, 1H), 4.03 - 4.06 (m, 1H), 3.87 - 3.93 (m, 1H), 3.48 - 3.54 (m, 1H), 2.47 - 2.49 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H); chiral SFC: Method Q, 5.81 min.

[1523] Example 40

[1524] (2S, 4R)-4-( 6-(3-Cyanophenyl)-4-oxopyr...

Claims

Claims1. A compound of formula (I):x3x2a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:(a) X1is CR4aand X2is N, or(b) X1is N and X2is CR4b;X3, X4and X5are each independently selected from N, CR4c, CR4dand CR4e;R1is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)fluoroalkyl, CH2O(Ci-C4)alkyl, CH2N((Ci-C4)alkyl)2, CFb-N-linkcd pyrazolyl and CFb-N-linkcd triazolyl; wherein the pyrazolyl and triazolyl rings are optionally substituted by one to three methyl groups;R2is selected from hydrogen, (Ci-C4)alkyl, cyclopropyl and (Ci-C4)fluoroalkyl;R3is selected from hydrogen, halo, (Ci-C4)alkyl, cyclopropyl and (Ci-C4)alkoxy;R4a, R4b, R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, CN, hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy and (C1-C6)alkoxy(C1-C6)alkyl;ring A is selected from:(i) phenyl;(ii) a 5 to 6-membered monocyclic heteroaryl ring comprising one to four heteroatoms, each independently selected from N, O and S; and(iii) a 9 to 10-membered bicyclic heteroaryl ring comprising 1 to 4 heteroatoms, each independently selected from N, O and S;ring A is either unsubstituted or substituted by one to five substituents selected from R5, R6, R7, R8and R9; and R5, R6, R7, R8and R9are each independently selected from halo, CN, hydroxy, NH2, (Ci-Cg)alkyl, (Ci-Cg)alkoxy, halo(Ci-Cg)alkyl, halo(Ci-Cg)alkoxy, hydroxy(Ci-Cg)alkyl, hydroxy(C2-Cg)alkoxy, (C3-Cg)cycloalkyl, halo(C3-Cg)cycloalkyl, hydroxy(C3-Cg)cycloalkyl, (C3-Cg)cycloalkoxy, halo(C3-Cg)cycloalkoxy, hydroxy(C3-Cg)cycloalkoxy, (Ci-Cg)alkoxy(Ci-Cg)alkyl, (Ci-Cg)alkoxy(Ci-Cg)alkoxy, (Ci-Cg)alkoxy(C3-Cg)cycloalkyl, (Ci-Cg)alkoxy(C3-Cg)cycloalkoxy, (C3-Cg)cycloalkoxy(Ci-Cg)alkyl, (C3-Cg)cycloalkoxy(Ci-Cg)alkoxy, oxetanyl, oxetanyloxy, NH(Ci-Cg)alkyl, N((C1-Cg)alkyl)2, NH(C3-Cg)cycloalkyl, N((C3-Cg)cycloalkyl)2, N((Ci-Cg)alkyl)((C3-Cg)cycloalkyl)), C(O)NH(Ci-Cg)alkyl, C(O)N((C1-Cg)alkyl)2, NHC(O)(Ci-Cg)alkyl, N(C1-Cg)alkyl)C(O)(C1-Cg)alkyl), C(O)(Ci-Cg)alkyl, C(O)O(Ci-Cg)alkyl, CO2H, CONH2, SO2NH(Ci-Cg)alkyl and SO2N((Ci-Cg)alkyl)2.

2. The compound according to claim 1, wherein at least one of X3, X4and X5is selected from CR4c, CR4dand CR4e.

3. The compound according to claim 2, which is selected from formulae (I)(i), (I)(ii), (I)(iii), (I)(iv), (I)(v), (I)(vi) and (I)(vii):(I)(i) (I)(ii)(I)(iii) R4cR4*3(I)(vi)a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

4. The compound according to any one of claims 1 to 3, wherein ring A is selected from phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

5. The compound according to claim 4, wherein ring A is selected from phenyl, IH-pyrazol-l-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and pyrimidinyl.

6. The compound according to claim 5, which is selected from:(i) formulae (I)(A)(i), (I)(B)(i), (I)(C)(i), (I)(D)(i), (I)(E)(i) and (I)(F)(i):(I)(D)(i)(I)(F)(i) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer;(rr) formulae (I)(A)(ii), (I)(B)(ii), (I)(C)(ii), (I)(D)(ii), (I)(E)(rr) and (I)(F)(ii):(I)(F)(n) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer;(iii) formulae (I)(A)(iii), (I)(B)(iii), (I)(C)(iii), (I)(D)(iii), (I)(E)(iii) and (I)(F)(iii):(I)(D)(m)(I)(F)(in) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer;(iv) formulae (I)(A)(iv), (I)(B)(iv), (I)(C)(iv), (I)(D)(iv), (I)(E)(iv) and (I)(F)(iv):(I)(B)(iv)a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer;(v) formulae (I)(A)(v), (I)(B)(v), (I)(C)(v), (I)(D)(v), (I)(E)(v) and (I)(F)(v):R4c(I)(A)(v)a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer;(vi) formulae (I)(A)(vi), (I)(B)(vi), (I)(C)(vi), (I)(D)(vi), (I)(E)(vi) and (I)(F)(vi):R4cR4b(I)(A)(vi)(I)(C)(vi) (I)(D)(vi)(I)(F)(vi) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer; and(vii) formulae (I)(A)(vii), (I)(B)(vii), (I)(C)(vii), (I)(D)(vii), (I)(E)(vii) and (I)(F)(vii):(I)(B)(vii)(I)(C)(vii) (I)(D)(vii)(I)(E)(vii) (I)(F)(vii) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

7. The compound according to any one of claims 1 to 6, wherein R1is selected from hydrogen, methyl, CH2F, CHF2, CF3, CH2OCH3, CH2OCH2CH3, CH2N(CH3)2, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl.

8. The compound according to claim 7, wherein R1is selected from hydrogen, methyl, CH2OCH3, CH2-N-linked pyrazolyl and CH2-N-linked triazolyl.

9. The compound according to claim 8, wherein R1is hydrogen.

10. The compound according to any one of claims 1 to 9, wherein R2is selected from hydrogen, methyl, CF3and cyclopropyl.

11. The compound according to claim 10, wherein R2is methyl.

12. The compound according to any one of claims 1 to 11, wherein R3is hydrogen.

13. The compound according to any one of claims 1 to 12, wherein R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, CN, CF3and OCF3.

14. The compound according to claim 13, wherein R4a, R4b, R4c, R4dand R4eare each independently selected from hydrogen, methyl and CN.

15. The compound according to any one of claims 1 to 14, wherein only one of R4a, R4b, R4c, R4dand R4eis other than hydrogen.

16. The compound according to any one of claims 1 to 15, wherein R5, R6, R7, R8and R9are each independently selected from hydrogen, halo, CN, hydroxy, (Ci-C3)alkyl, (Ci-C3)alkoxy, cyclopropyl, cyclopropoxy, (Ci-C3)alkoxymethyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, oxetanyl and oxetanyloxy.

17. The compound according to claim 16, wherein R5, R6, R7, R8and R9are each independently selected from hydrogen, fluoro, chloro, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclopropoxy, CH2OCH3, CF3, CH2CF3, OCF3, oxetanyl and oxetanyloxy.

18. The compound according to claim 17, wherein R5, R7, R8and R9are each independently selected from hydrogen, CN, cyclopropyl, cyclopropoxy, CF3, CH2CF3and OCF3.

19. The compound according to any one of claims 1 to 18, wherein one to four of R5, R7, R8and R9are each hydrogen.

20. The compound according to claim 19, wherein R5and R7are each hydrogen, and one or two of R8and R9are hydrogen.

21. The compound according to any one of claims 1 to 20, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein the compound has the absolute stereochemical configuration represented by formula (a):f\R21N — CN(a).

22. The compound according to any one of claims 1 to 20, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein the compound has the absolute stereochemical configuration represented by formula (b):K r — CNFe \* (b).

23. The compound according to claim 1, which is selected from:1 -(3 -((3R,5S)- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3.2 / | py rimidin-6-yl)-lH-pyrazole-4-carbonitrile;1 -(3 -((3R,5S)-1 -cyano-5 -(methoxymethyl)pyrrolidin-3-yl)-2 -methyl -4-oxo-3, 4-dihydropyrido|3.2 / |pyrimidin-6-yl)-l / / -pyrazolc-4-carbonitrilc:2-(3-((3 / ?.

5. S')- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido [3, 2 / |pyrimidin-6-yl)isonicotinonitrile;(2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifliioromcthyl)-l / / -pyrazol-l-yl)pyrido|3.2 / |pyrimidin-3(4 / / )-yl)pyrrolidine- 1 -carbonitrile;1 -(3 -((2R,3R)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2-d] py rim idin-6-y 1 )- 1H-pyrazole-4-carbonitrile;(2R,3R)-3 -(6-(3 -cyanophenyl)-4-oxopyrido [3.2 / | py rimidin-3 (4 / / )-y I )-2-mcthy I py rrol idinc- 1 -carbonitrile;(2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(4-(trifluoromcthyl)- l / / -pyrazol-l-yl)pyrido|3.2-t / |pyrimidin- 3 (4 / / )-y I )py rrol idinc- 1 -carbonitrile;(2R,3R)-2-methyl-3-(4-oxo-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-<7]pyrimidin-3(427)-yl)pyrrolidine- 1 -carbonitrile;(2S,47?)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,2-<7]pyrimidin-3(477)-yl)-2-(methoxymethyl)pyrrolidine- 1 -carbonitrile;(25\4 / ?)-4-(6-(5-cyano-2-cyclopropoxyphcnyl)-4-oxopyrido|3.2-d'|pyrimidin-3(4 / 7)-yl)-2- (methoxymethyl)pyrrolidine- 1 -carbonitrile;(2S,47?)-2-(( 177-py razol - 1 -yl)methyl)-4-(6-(3 -cyanophenyl)-4-oxopyrido [3.2 / | py rimidin-3 (477)-yl)pyrrolidine- 1 -carbonitrile;(2S,47?)-2-(( 177-pyrazol- 1 -yl)methyl)-4-(4-oxo-6-(4-(trifluoromethyl)- 177-pyrazol- 1 -yl)pyrido [3.2-t / | py rimidin-3 (4 / 7)- I (p rrolidine- 1 -carbonitrile;4-(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2-d]pyrimidin-6-yl)picolinonitrile;2-(3-((37?,55)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)-2-methyl-4-oxo-3,4-dihydropyrido[3,2-<7]pyrimidin-6-yl)isonicotinonitrile;2-(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rimidin-6-yl)isonicotinonitrile;4-(3 -((37?, 55)- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2-t / | py rim idin-6-yl)picolinonitrile;(27?,37?)-2-methyl-3-(4-oxo-6-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)pyrido[3,2-<7]pyrimidin-3(477)-yl)pyrrolidine- 1 -carbonitrile;(7?)- 1 -(3 -( 1 -cyanopyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rimidin-6-y I )- 177-pyrazole-4-carbonitrile;5 -(3 -((37?, 55)- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)nicotinonitrile;5 -(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rim idin-6-yl)nicotinonitrile;6 -(3 - ((27?, 37?) - 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,2 / | py rim idin-6-yl)pyrimidine-4-carbonitrile;(27?,37?)-2-methyl-3-(4-oxo-6-(6-(trifluoromethyl)pyrimidin-4-yl)pyrido[3,2-<7]pyrimidin-3(477)-yl)pyrrolidine- 1 -carbonitrile;(2S,47?)-4-(6-(4-cyclopropyl-177-pyrazol-l-yl)-4-oxopyrido[3,2-<7]pyrimidin-3(477)-yl)-2- (methoxymethyl)pyrrolidine- 1 -carbonitrile;(27?, 37?)-2 -methyl-3 -(4-oxo-6-(3 -(trifluoromethoxy )phenyl)quinazolin-3 (477)-yl)pyrrolidine- 1 -carbonitrile;(2S,47?)-2-(methoxymethyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)pyrrolidine-1-carbonitrile;(2R,3R)-3-(6-(3-cyanophenyl)-4-oxoquinazolin-3(4H)-yl)-2-methylpyrrolidine-1-carbonitrile;(2S,47?)-2-((177-l,2,3-triazol-l-yl)methyl)-4-(4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(477)-yl)pyrrolidine- 1 -carbonitrile;(2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifluoromcthoxy)pyridin-2-yl)quinazolin-3(4 / 7)-yl)pyrrolidinc- 1-carbonitrile;(2R,3R)-3 -(6-(3 -cyano-5 -(trifluoromethoxy )phenyl)-4-oxoquinazolin-3 (4 / 7)-yl)-2-mcthylpyrrolidinc- 1 -carbonitrile;(27?,37?)-3-(6-(2-cyano-5-(trifluoromethoxy)phenyl)-4-oxoquinazolin-3(477)-yl)-2-methylpyrrolidine- 1 -carbonitrile;(27?,37?)-2-methyl-3-(2-methyl-4-oxo-6-(3-(trifluoromethoxy)phenyl)quinazolin-3(477)-yl)pyrrolidine- 1 -carbonitrile;3-((2 / ?.3 / ?)-l-cyano-2-mcthylpyrrolidin-3-yl)-6-(2-cyano-5-(trifliioromcthoxy)phcnyl)-4-oxo-3.4-dihydroquinazoline-8-carbonitrile;(2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(4-(trifluoromcthyl)-l / 7-pyrazol-l-yl)pyrido|3.4< / |pyrimidin- 3 (4 / 7)-y I (pyrrol idinc- 1 -carbonitrile;(27?,37?)-2-methyl-3-(4-oxo-6-(3 -(trifluoromethoxy )phenyl)pyrido [3, 4 / |pyrimidin-3 (477)-yl)pyrrolidine- 1 -carbonitrile;1 -(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3.4 / | py rimidin-6-y I )- 177-pyrazole-4-carbonitrile;(27?,37?)-2-methyl-3 -(4-oxo-6-(4-(trifluoromethyl)- 177-pyrazol- 1 -yl)pyrido [3,4-<7]pyrimidin-3 (477)-yl)pyrrolidine- 1 -carbonitrile;4-(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,4 / | py rim idin-6-yl)picolinonitrile;4-(3 -((37?, 55)- 1 -cyano-5 -(methoxymethyl)pyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3.4 / | py rimidin-6-yl)picolinonitrile;2 -(3 - ((27?, 37?) - 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [3,4 / | py rim idin-6-yl)isonicotinonitrile;(2S,4R)-4-(6-(3-cyanophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-2-(methoxymethyl)pyrrolidine-1-carbonitrile;(27?, 37?)-2 -methyl-3 -(4-oxo-6-(3 -(trifluoromethoxy )phenyl)pyrido [2,3 -<7]pyrimidin-3 (477)-yl)pyrrolidine- 1 -carbonitrile;(2S,47?)-2-(methoxymethyl)-4-(4-oxo-6-(4-(trifluoromethyl)-177-pyrazol-l-yl)pyrido[2,3-<7]pyrimidin- 3 (4H)-yl)pyrrolidine- 1 -carbonitrile;1 -(3 -((27?, 37?)- 1 -cyano-2-methylpyrrolidin-3 -yl)-4-oxo-3,4-dihydropyrido [2,3 / | py rim idin-6-y I )- 177-pyrazole-4-carbonitrile;(27?,37?)-2-methyl-3-(4-oxo-6-(4-(trifluoromethyl)-177-pyrazol-l-yl)pyrido[2,3-<7]pyrimidin-3(477)-yl)pyrrolidine- 1 -carbonitrile;4-(3-((2R,3R)-1-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)picolinonitrile;(2. S'.4 / ?)-2-(mcthoxymcthy I )-4-(4-oxo-6-(4-(trifl uoromcthy I )- IH-pyrazol- 1 -yl)pyrimido [5,4-d] py rimidin-3 (4 / / )- I (p rrol idinc- 1 -carbonitrile;(2 / ?.3 / ?)-2-mcthyl-3-(4-oxo-6-(4-(trifliioromcthyl)-l / / -pyrazol-l-yl)pyrimido|5.4 / |pyrimidin-3(4 / / )-yl)pyrrolidine- 1 -carbonitrile;(2S,47?)-2-(methoxymethyl)-4-(l-oxo-7-(3-(trifluoromethoxy)phenyl)phthalazin-2(U7)-yl)pyrrolidine-1 -carbonitrile;l-(3-((3 / .

5. S')-l-cyano-5-(mcthox mcth l)pyrrolidin-3- l)-4-oxo-3.4-dihydrophthalazin-6- l(- \H-pyrazole-4-carbonitrile;(2S,47?)-2-(methoxymethyl)-4-(4-methyl-l-oxo-7-(3-(trifluoromethoxy)phenyl)phthalazin-2(U7)-yl)pyrrolidine- 1 -carbonitrile;(2R,3R)-3 -(7-(3 -cyanophenyl)- 1 -oxophthalazin-2( l / / )-yl)-2-mcthylpyrrolidinc- 1 -carbonitrile;(2R,3R)-3 -(7 -(3 -cyanophenyl)-4-methyl- 1 -oxophthalazin-2( 1 H)-y 1 )-2-methy 1 py rrol idine- 1 -carbonitrile;1-(3-((2 / ?.3 / ?)-l-cyano-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydrophthalazin-6-yl)-l / / -pyrazolc-4-carbonitrile;4-(3-((2 / ?.3 / ?)-l-cyano-2-mcthylpyrrolidin-3-yl)-4-oxo-3.4-dihydrophthalazin-6-yl)picolinonitrilc: 2-(3-((27?,37?)-l-cyano-2-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)isonicotinonitrile; (27?, 37?)-2-mcthy 1-3 -(4-oxo-6-(4-(trifluoromethyl)- 177-pyrazol- 1 -yl)pteridin-3 (4 / / )- I (p rrol idinc- 1 -carbonitrile;(2. S'.4 / ?)-2-(mcthoxymcthyl)-4-(4-oxo-6-(4-(trifluoromcthyl)- 177-pyrazol- l-yl)ptcridin-3(4 / / (-yl)pyrrolidine-l -carbonitrile; and(2. S'.4 / ?)-4-(6-(3-cyanophcnyl)-4-oxoptcridin-3(4 / / )-yl)-2-(mcthoxymcthyl)pyrrolidinc-l-carbonitrilc: or a pharmaceutically acceptable salt thereof.

24. A compound according to any one of claims 1 to 23, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, for use as a medicament.

25. A compound according to any one of claims 1 to 23, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, for use in the treatment or prevention of cancer or a condition involving mitochondrial dysfunction.

26. Use of a compound according to any one of claims 1 to 23, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the treatment or prevention of cancer or a condition involving mitochondrial dysfunction.

27. A method for the treatment or prevention of cancer or a condition involving mitochondrial dysfunction, comprising the step of administering an effective amount of a compound according to any one of claims 1 to 23, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, to a patient in need thereof.

28. The compound, use, or method, according to claims 25 to 27, wherein the cancer is selected from breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone, liver, soft tissue, cancers of tissue organs, cancers of the blood cells, CML, AML, mantle cell lymphoma, neuroblastoma, soft tissue sarcoma, liposarcoma, fibroblastic sarcoma, leiomyosarcoma, hepatocellular carcinoma, osteosarcoma, oesophageal cancer, leukaemia, lymphoma, multiple myeloma, metastatic carcinoma, chondosarcoma, Ewing’s sarcoma, nasopharyngeal carcinoma, colorectal cancer, non-small cell lung carcinoma, cancer where apoptotic pathways are dysregulated, and cancer where proteins of the BCL-2 family are mutated, or over or under expressed.

29. The compound, use, or method, according to claims 25 to 27, wherein the condition involving mitochondrial dysfunction is selected from: fibrosis; a CNS disorder; neurodegenerative disease; Parkinson’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis; Huntington’s disease; ischemia; stroke; dementia with Lewy bodies; frontotemporal dementia; multiple sclerosis; mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome; maternally-inherited diabetes and deafness; Leber's hereditary optic neuropathy; cancer; neuropathy, ataxia, retinitis pigmentosa-matemally inherited Leigh syndrome; Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric diseases, schizophrenia; multiple sulfatase deficiency; mucolipidosis II; mucolipidosis III; mucolipidosis IV; GMl-gangliosidosis; neuronal ceroid-lipofuscinoses; Alpers disease; Barth syndrome; beta-oxidation defects; camitine-acyl-camitine deficiency; carnitine deficiency; creatine deficiency syndromes; co-enzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long -chain acyl-CoA dehydrogenase deficiency; Leigh disease or syndrome; Leigh Syndrome Lrench-Canadian variant; lethal infantile cardiomyopathy; Luft disease; medium -chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and ragged-red fiber syndrome; mitochondrial cytopathy; mitochondrial recessive ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastrointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium / short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; and very long-chain acyl-CoA dehydrogenase deficiency; peroxisomal disorders; methylmalonic acidemia; mevalonate kinase deficiency; agedependent decline in cognitive function and muscle strength; muscle structure disorders; and cognitive impairment associated with neurodegenerative and neuropsychiatric disorders.

30. The compound, use, or method, according to claim 29, wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, ischemia, stroke, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia; Parkinson’s disease related tomutations in a-synuclein, parkin, PINK1, GBA, and LRRK2, and autosomal recessive juvenile Parkinson’s disease where parkin is mutated.

31. The compound, use, or method, according to claim 29, wherein the neurodegenerative disease is selected from Leigh syndrome or disease, X-linked Leigh's disease, Leigh Syndrome French-Canadian Variant, and / or the symptoms associated with Leigh’s disease.

32. The compound, use, or method, according to claim 29, wherein the fibrosis is selected from fibrosis or a fibrotic disorder associated with the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia.

33. The compound, use, or method, according to claim 32, wherein the fibrosis is selected from fibrosis, a fibrotic disorder associated with major organ diseases, fibroproliferative disorders, and scarring associated with trauma.

34. The compound, use, or method, according to claim 33, wherein the fibrosis is selected from fibrosis or a fibrotic disorder associated with interstitial lung disease, liver cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, kidney disease, acute kidney injury, chronic kidney disease, delayed kidney graft function, heart or vascular disease, diseases of the eye, systemic and local scleroderma, keloids, hypertrophic scars, atherosclerosis, restenosis, Dupuytren’s contracture, surgical complications, chemotherapeutics drug-induced fibrosis, radiation-induced fibrosis, accidental injury and bums, retroperitoneal fibrosis, and peritoneal fibrosis / peritoneal scarring.

35. The compound, use, or method, according to claim 34, wherein the fibrosis associated with interstitial lung disease is selected from sarcoidosis, silicosis, drug reactions, infections, collagen vascular diseases, rheumatoid arthritis, systemic sclerosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonitis, interstitial lung disease, cryptogenic fibrosing alveolitis, bronchiolitis obliterans, and bronchiectasis.

36. The compound, use, or method, according to claim 34, wherein the kidney disease is acute kidney injury or chronic kidney disease.

37. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 23, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.

38. A compound selected from formulae (II) and (III):wherein PG is a protecting group, and ring A, X1, X2, X3, X4, X5, R1, R2and R3are as defined for the compound of formula (I) in any one of claims 1 to 23, a tautomer thereof, or a salt of said compound or tautomer.

39. A compound according to claim 38 wherein the protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl carbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, -methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, trichloroethoxycarbonyl, 4-nitrobenzenesulfonyl and 2-nitrophenylsulfenyl.

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