Inhibitors of green peroxidase

Abstract

The present specification relates generally to compounds of formulae (I), (Ia) and (Ib) and their pharmaceutically acceptable salts wherein X, Y1, Y2, Y3, Y4 and Y5 and X1, X2, r and q have any of the meanings defined herein, compositions containing them and their use in therapy. These compounds are inhibitors of the MPO enzyme, and thus are particularly useful in the treatment or prevention of diseases or conditions in which modulation of green peroxidase (MPO) activity is desired, including diseases with inflammatory, cardiovascular, respiratory, kidney, liver and / or neural components, as well as neutrophil-driven diseases. # imgabs0 #

Description

[0001] Related applications

[0002] This application claims the benefit of priority to U.S. application No. 63 / 398,939, filed on August 18, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Green peroxidase (MPO) is a heme-containing enzyme expressed primarily in neutrophils (neutrophils). MPO is a member of the diverse mammalian peroxidase protein family, which also includes eosinophil peroxidase (EPX), lactoperoxidase (LPO), thyroid peroxidase (TPO), etc. MPO is activated by hydrogen peroxide, the sources of which can be NADPH-derived superoxide anions catalyzed by superoxide dismutase (SOD) and xanthine oxidase-derived superoxide anions, as well as hydrogen peroxide formed during purine oxidation. MPO catalyzes the two-electron oxidation of halides (primarily chloride) and pseudohalides (such as thiocyanate) to form the microbicidal hypohalous acids hypochlorous acid (bleach) and hypothiocyanic acid. These can, in turn, act on a variety of protein, lipid, and nucleic acid targets, causing dysfunction and further inflammation 1 Furthermore, MPO catalyzes the one-electron oxidation of many electron-rich substrates through the so-called peroxidation cycle, thereby generating free radicals that can themselves be harmful (e.g., urate radicals 2 ), or may interfere with NO-driven physiological functions by directly oxidizing nitric oxide (NO) or generating free radicals that oxidize NO 1 .

[0004] Neutrophils are the major leukocyte population in terms of numbers (50%-70% of human blood leukocytes) and represent a highly dynamic cell population that is part of the first line of defense against stressors (whether microbial or sterile triggers). Within neutrophils, preformed MPO is stored in millimolar concentrations within the granules, which fuse with phagosomes containing engulfed microorganisms, thereby activating MPO and killing the microorganisms. 3 In addition, MPO can be released outside the cell, where its oxidative activity may cause damage to adjacent tissues and lead to dysfunction or modulation of biochemical and cellular processes, such as tissue remodeling and fibrosis. This release can occur through degranulation or NETosis, in which neutrophils release a network of depolymerized DNA that encapsulates intracellular proteins such as MPO, the so-called neutrophil extracellular traps (NETs). 4 In addition, MPO can be released continuously through constitutive 5The enzyme is highly cationic and therefore becomes trapped on negatively charged structures outside cells, such as proteoglycans in the blood vessel walls and the extracellular matrix in the interstitial space. 6 .

[0005] Given the dominant role of neutrophils in inflammatory biology and the abundance of MPO within neutrophils (estimated to be 5% of cell dry weight), it is not difficult to understand why a wide range of disease conditions are thought to be associated with the pathological role of green peroxidase. These conditions encompass not only "traditional" inflammatory diseases such as inflammatory bowel disease and the autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus, but also other common diseases in which inflammation appears as an important pathophysiological component, such as cardiovascular disease, neurodegenerative diseases, renal disease, respiratory disease, metabolic disease, obesity and cancer. 1 .

[0006] Human genetic studies and rodent intervention studies further confirm the pathophysiological role of MPO. 7 and tissue MPO activity 8 A common polymorphism in the MPO promoter has been shown to be associated with coronary microvascular dysfunction. 9 , heart failure mortality 10 , coronary artery disease risk 11 and its prognosis 12 Risk of hepatitis C-related liver fibrosis and cirrhosis 13、14 and risk of hepatocellular carcinoma and death in alcohol-related cirrhosis 15 Selective MPO inhibitors have been reported to be effective in a variety of diseases and / or conditions in rodents and humans in vitro: preservation of cardiac function in a post-myocardial infarction model 16 , stabilize atherosclerotic plaques 17 , improve pulmonary arterial hypertension 18 , glomerulonephritis 19 and cystic fibrosis 20 , reduce liver steatosis and fibrosis 21、22 , attenuating vascular impairment in inflammatory vascular disorders 23 , normalize microvascular function 24 , improve relaxation of human myocardial cells 25 and inhibiting human neutrophil NETosis 26 .

[0007] The effects of MPO on different disease conditions may vary depending on the condition, but several mechanisms may be important for several of these conditions. In addition to MPO-derived reactive oxygen species such as hypochlorous acid 1In addition to the damage and dysfunction caused by MPO, it also appears to play a regulatory role in inflammation by activating neutrophils. 27 and activating proteases that cleave latent forms into active effector proteins (e.g., cytokines 28 ), thereby amplifying the inflammatory response. The mechanistic association between MPO and fibrosis may also be multifactorial, such as: i) secondary to increased inflammation; ii) through the activation of myofibroblasts 29 iii) by increasing collagen secretion itself 30 Finally, active MPO directly (and indirectly) oxidizes NO through the peroxidative cycle, thereby impairing nitric oxide-driven mechanisms such as smooth muscle cell relaxation. 31 The latter mechanism may be particularly important in linking MPO to microvascular dysfunction and the resulting impaired tissue blood supply, as MPO is captured on proteoglycans, transcytotically transported through endothelial cells, and then deposited spatially in the subendothelial compartment between NO-producing endothelial cells and NO-receiving smooth muscle. 32 .

[0008] In summary, there is both a medical need and a strong theoretical rationale for the oral inhibitors of MPO activity for the treatment of chronic inflammatory conditions. To improve the therapeutic index of such drugs, it is essential to obtain MPO inhibitors that are more selective for MPO than for TPO. The thyroid gland is an important regulator of thermogenesis and metabolic function, and TPO plays a central role by iodinating tyrosine residues to form the thyroid hormones T4 and T3. The activation of TPO is controlled by thyrotropin, and T4 and T3 are part of a negative feedback mechanism, so that when TPO is inhibited, T3 and T4 levels decrease, leading to a compensatory increase in thyrotropin. 33 .

[0009] WO2003 / 089430, WO2005 / 037835, WO2007 / 120097, WO2007 / 120098 and WO2007 / 142576 disclose thioxanthene derivatives and their use as MPO inhibitors in therapy.

[0010] WO2006 / 062465 and WO2007 / 142577 disclose 2-thiocarbonyl-1,2,3,4-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one derivatives that are said to be MPO inhibitors. The compounds are said to show selectivity for related enzymes such as TPO.

[0011] WO2009 / 025618 discloses the use of thioxanthene and 2-thiocarbonyl-1,2,3,4-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one derivatives, and MPO inhibitors for the treatment of multiple system atrophy (MSA) and Huntington's disease (HD) and for neuroprotection.

[0012] J. Labelled Compounds and Radiopharmaceuticals, 2012, 55, 393-399 discloses some tritiated 13C- and 14C-labeled thioxanthene derivatives and 14C-labeled pyrrolo[3,2-d]pyrimidin-4-one compounds, which are said to be inactivators of MPO.

[0013] J. Biol. Chem., 2011, 286, 37578-37589 discloses certain thioxanthene derivatives. These compounds are said to inhibit MPO in plasma and reduce protein chloride in mouse models. However, these compounds are said to have poor inhibitory effects on TPO.

[0014] WO 2013 / 068875 discloses thiamidone derivatives which are said to be MPO inhibitors.

[0015] WO 2016 / 087338 discloses thiocarbonylpyrrolidinone derivatives that are said to be MPO inhibitors.

[0016] Therefore, there is a need for new MPO inhibitors that can be used therapeutically.There is also a need for new MPO inhibitors that have improved selectivity for the MPO enzyme over the TPO enzyme, as well as MPO inhibitors with suitable pharmacological properties. DETAILED DESCRIPTION

[0017] This detailed description and its specific examples, while indicating embodiments, are intended for illustrative purposes only. Therefore, there is no limitation on the exemplary embodiments described in this specification. Furthermore, it should be understood that, for the sake of clarity, various features described in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for the sake of brevity, various features described in the context of individual embodiments may also be combined to form subcombinations thereof.

[0018] Listed below are definitions of various terms used in the specification and claims.

[0019] The term "halogen" refers to fluorine, chlorine, bromine and iodine. In one embodiment, halogen is fluorine or chlorine.

[0020] The term "N-heterocycle" refers to a partially or fully saturated hydrocarbon ring system, ie, non-aromatic, in which at least one ring carbon atom is replaced by nitrogen.

[0021] For the avoidance of doubt, it is to be understood that in this specification, when a group is defined by "as defined above", that group encompasses the first occurring and broadest definition as well as each and all other definitions of that group. It is to be understood that any definition, claim, aspect or embodiment of a variable group in a formula disclosed herein may be combined with any other definition, claim, aspect or embodiment herein (unless the context does not permit) to provide further embodiments of the specification.

[0022] Certain embodiments disclosed herein provide compounds, compositions, and methods for inhibiting green peroxidase, as well as methods for treating green peroxidase-associated diseases or disorders.

[0023] Compound

[0024] One embodiment disclosed herein provides a compound of formula (I)

[0025]

[0026] in

[0027] X=CH or N

[0028] Y 1 =CZ 1 or N, Y 2 =CZ 2 or N, Y 3 =CZ 3 or N, Y 4 =CZ 4 or N, and

[0029] Y 5 =CZ 5 or N

[0030] If present, Z 1 、Z 2 、Z 3 、Z 4 and Z 5 are independently H, halogen, CF3, Q or T, provided that Y 1 、Y 2 、Y 3 、Y 4 or Y 5 No more than one of them is N, Y 1 、Y 2 、

[0031] Y 3 、Y 4 or Y 5 At least two of them are CH, Z 1 、Z 2 、Z3 、Z 4 and Z 5 Not more than one of them is a halogen or CF3, and Z 1 、Z 2 、Z 3 、Z 4 and Z 5 One and only one of them is Q or T,

[0032] Q is where m is 0, 1, 2, or 3,

[0033] T is

[0034] p is 0 or 1,

[0035] s is 0, 1, or 2,

[0036] n is 0, 1, or 2,

[0037] A is CH2, CF2, CHF, CHR 2 , CFR 2 NR 3 or O,

[0038] in;

[0039] If present, R 1 and R 2 independently CH2F, CHF2 or CF3

[0040] If present, R 3 are independently H or CH3,

[0041] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

[0042] In one embodiment, a compound of any of Formula (I) is provided.

[0043] In one embodiment, a pharmaceutically acceptable salt of any compound of Formula (I) is provided.

[0044] Another embodiment disclosed herein provides a compound having the structure:

[0045]

[0046] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X, Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined above for formula (I).

[0047] Yet another embodiment disclosed herein provides a compound:

[0048]

[0049] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X, Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined above for formula (I).

[0050] Some embodiments disclosed herein provide compounds having the following structure:

[0051]

[0052] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X, Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined above for formula (I).

[0053] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 1 is N, and Y 2 、Y 3 and Y 4 It is CH.

[0054] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 1 is N, and Y 2 、Y 3 and Y 4 It is CH.

[0055] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 2 is N, and Y 1 、Y 3 and Y 4 It is CH.

[0056] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 2 is N, and Y 1 、Y 3 and Y 4 It is CH.

[0057] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 3 is N, and Y 1 、Y 2 and Y 4 It is CH.

[0058] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 3 is N, and Y 1 、Y 2 and Y 4 It is CH.

[0059] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 4 is N, and Y 1 、Y 2 and Y 3 It is CH.

[0060] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 4 is N, and Y 1 、Y 2 and Y 3 It is CH.

[0061] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 0.

[0062] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 0.

[0063] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 1.

[0064] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 1.

[0065] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 2.

[0066] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 2.

[0067] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 .

[0068] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 .

[0069] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 , and R 3 It is CH3.

[0070] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 , and R 3 It is CH3.

[0071] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 , and R 3 It’s H.

[0072] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 , and R 3 It’s H.

[0073] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II) or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CH2, CF2, CHF, CHR 2 or CFR 2 .

[0074] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III) or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CH2, CF2, CHF, CHR 2 or CFR 2 .

[0075] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CH2.

[0076] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CH2.

[0077] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHF 。

[0078] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHF.

[0079] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CF2.

[0080] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CF2.

[0081] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 .

[0082] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 .

[0083] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 , and R 2 It is CH2F.

[0084] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 , and R 2 It is CH2F.

[0085] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 , and R 2 It is CHF2.

[0086] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 , and R 2 It is CHF2.

[0087] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 , and R 2 It's CF3.

[0088] Some embodiments disclosed herein provide compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 , and R 2 It's CF3.

[0089] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 0.

[0090] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 0.

[0091] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 1.

[0092] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 1.

[0093] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 2.

[0094] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 2.

[0095] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 0.

[0096] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 0.

[0097] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 1.

[0098] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 1.

[0099] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , and Z5 It's T or Q.

[0100] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , and Z 5 It’s T.

[0101] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , and Z 5 is T, and T is

[0102] In a further embodiment, p is 0.

[0103] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , Z 5 is T or Q, and Y 1 、Y 2 、Y 3 and Y 4 is CH. In a further embodiment, Z 5 is T. In yet further embodiments, T is In yet further embodiments, p is 0.

[0104] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , Z 5 is T or Q, and Y 1 、Y 2 、Y 3 and Y 4 One of them is N.

[0105] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , Z 5 is T or Q, and Y 1 、Y 2 、Y 3 and Y 4 The two are CH, Y 1 、Y 2 、Y 3and Y 4 One of them is N, and Y 1 、Y 2 、Y 3 and Y 4 One of them is CCl.

[0106] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z 1 and Z 5 Together with the atoms to which they are attached, they form a five-membered or six-membered N-heterocyclic ring. In a further embodiment, Y 2 、Y 3 and Y 4 It is CH.

[0107] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z 2 and Z 3 Together with the atoms to which they are attached, they form a five-membered or six-membered N-heterocyclic ring. In a further embodiment, Y 1 、Y 4 and Y 5 It is CH.

[0108] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 2 is Q. In a further embodiment, m=1.

[0109] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 3 is Q. In a further embodiment, m=1.

[0110] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 4 is Q. In a further embodiment, m=1.

[0111] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is CH.

[0112] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is N.

[0113] Some embodiments disclosed herein provide a compound selected from the group consisting of:

[0114] 1-(2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0115] (R)-1-(2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0116] (S)-1-(2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0117] 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0118] (R)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0119] (S)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0120] 1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0121] (R)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0122] (S)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0123] 1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0124] (R)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0125] (S)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0126] 3-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one,

[0127] 1-(2-(azepan-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0128] (R)-1-(2-(azepan-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0129] (S)-1-(2-(azepan-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0130] (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one,

[0131] (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one,

[0132] (R)-1-(2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0133] (S)-1-(2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0134] 1-(2-(4-methylpiperazin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0135] Racemic-2-thiocarbonyl-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0136] 2-thiocarbonyl-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0137] 2-thiocarbonyl-1-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0138] 2-thiocarbonyl-1-(2-(5-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0139] 1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0140] (R)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0141] (S)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0142] Racemic-2-thiocarbonyl-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0143] 2-thiocarbonyl-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0144] 2-thiocarbonyl-3-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0145] 3-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one,

[0146] 3-(2-(5-fluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one,

[0147] 2-thiocarbonyl-1-((2-(-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0148] Racemic-2-thiocarbonyl-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0149] 2-thiocarbonyl-1-((2-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0150] 2-thiocarbonyl-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0151] 2-thiocarbonyl-1-((2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0152] Racemic-2-thiocarbonyl-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0153] 2-thiocarbonyl-1-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0154] 2-thiocarbonyl-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0155] 2-thiocarbonyl-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0156] Racemic-2-thiocarbonyl-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0157] 2-thiocarbonyl-3-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0158] 2-thiocarbonyl-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0159] 2-thiocarbonyl-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

[0160] Racemic-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0161] 1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0162] 1-(2-((2S,4R)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0163] 1-((2-(piperidin-2-yl)pyridin-3-yl)methyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0164] Racemic-2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0165] 2-thiocarbonyl-1-((3-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0166] 2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0167] 2-thiocarbonyl-1-((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0168] Racemic-2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0169] 2-thiocarbonyl-1-((3-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0170] 2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0171] 2-thiocarbonyl-1-((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0172] 1-(4-(1-aminocyclobutyl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0173] 1-(3-(1-aminocyclobutyl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0174] 1-(2-(piperidin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0175] 1-(2-(morpholin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0176] (R)-1-(2-(morpholin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0177] (S)-1-(2-(morpholin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0178] 1-(2-(piperidin-4-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0179] Racemic-2-thiocarbonyl-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0180] 2-thiocarbonyl-1-((2-((trans)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0181] 2-thiocarbonyl-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0182] 2-thiocarbonyl-1-((2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and

[0183] their pharmaceutically acceptable salts.

[0184] Another embodiment disclosed herein provides a compound of formula (Ia)

[0185]

[0186] in,

[0187] X 1 =CH or N,

[0188] Each X 2 are independently CH, CF or CCl, and

[0189] r and q are 0, 1 or 2, provided that r+q=2 or 3,

[0190] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

[0191] Another embodiment disclosed herein provides a compound of formula (Ib)

[0192]

[0193] in,

[0194] X 1 =CH or N,

[0195] Each X 2 are independently CH, CF or CCl, and

[0196] r and q are 0, 1 or 2, provided that r+q=2 or 3,

[0197] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

[0198] Some embodiments disclosed herein provide a compound of Formula (Ia) or (Ib) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein each X 2 It is CH.

[0199] Some embodiments disclosed herein provide a compound of Formula (Ia) or (Ib) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein r is 1, and q is 1.

[0200] Some embodiments disclosed herein provide a compound of Formula (Ia) or (Ib), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein r is 1 and q is 2 or r is 2 and q is 1.

[0201] Some embodiments disclosed herein provide a compound of Formula (Ia) or (Ib), or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein r is 0 and q is 2 or r is 2 and q is 0.

[0202] Some embodiments disclosed herein provide a compound of Formula (Ia) or (Ib) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X 1 It is CH.

[0203] Some embodiments disclosed herein provide a compound of Formula (Ia) or (Ib) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X 1 It's N.

[0204] Some embodiments disclosed herein provide a compound selected from the group consisting of:

[0205] 1-((1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0206] 1-(isoindolin-5-ylmethyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

[0207] 1-(isoindolin-4-ylmethyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and

[0208] their pharmaceutically acceptable salts.

[0209] Some embodiments disclosed herein provide compounds having the following structure:

[0210] Among them, X, Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined above for formula (II).

[0211] One embodiment disclosed herein provides a compound having the structure:

[0212] where Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined above for formula (III).

[0213] One embodiment disclosed herein provides a compound having the structure:

[0214] where Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined above for formula (IV).

[0215] It should be noted that any of these specific compounds may be excluded from any of the embodiments mentioned herein.

[0216] In some embodiments, methods for preparing compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), compounds disclosed herein, and pharmaceutically acceptable salts thereof, and intermediates therefor are provided.

[0217] Some embodiments disclosed herein provide products obtainable by any of the methods or examples disclosed herein.

[0218] Furthermore, since the absolute configurations of the enantiomers of the compounds disclosed herein are determined by spectroscopic studies rather than by, for example, X-ray studies, it will be understood that if for any reason the results of the spectroscopic studies prove to be erroneous, the corresponding R and S configuration designations will be reversed.

[0219] Medical and pharmaceutical uses

[0220] Compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), compounds disclosed herein, and pharmaceutically acceptable salts thereof, are useful because they have pharmacological activity as MPO enzyme inhibitors.

[0221] Compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), compounds disclosed herein, and pharmaceutically acceptable salts thereof, are useful for treating or preventing diseases or conditions requiring modulation of chloroperoxidase (MPO) activity. In particular, the link between MPO activity and disease has been implicated in a number of diseases, including those with inflammatory, cardiovascular, respiratory, renal, hepatic, and / or neurological components, as well as neutrophil-driven diseases.

[0222] The disclosed compounds are useful for treating or preventing inflammatory diseases or conditions responsive to inhibition of MPO, or diseases or conditions having an inflammatory component, in mammals, including humans. Such diseases or disorders include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, and type 2 diabetes.

[0223] The disclosed compounds are suitable for treating or preventing cardiovascular diseases or conditions that are responsive to inhibition of MPO in mammals, including humans. Such cardiovascular diseases or conditions include, but are not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.

[0224] The disclosed compounds are also useful for treating or preventing neurological diseases and disorders in mammals, including humans, in which microvascular dysfunction is prominent.

[0225] The disclosed compounds are also suitable for treating or preventing neurological diseases and conditions in mammals (including humans) that are responsive to inhibition of MPO. Such diseases and conditions include, but are not limited to, diseases with a neuroinflammatory response. These diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy.

[0226] The disclosed compounds are also suitable for treating or preventing neutrophil-driven diseases and conditions in mammals, including humans. Such diseases and conditions include, but are not limited to, chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophil asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pneumonia, and acute respiratory distress syndrome (ARDS).

[0227] The disclosed compounds are useful for treating or preventing inflammatory diseases or conditions responsive to inhibition of MPO, or diseases or conditions having an inflammatory component, in mammals, including humans. Such diseases or conditions include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end-stage renal disease (ESKD), immunoglobulin A vasculitis (Henoch-Schonlein Purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

[0228] The disclosed compounds are useful for treating or preventing cardiovascular diseases or conditions responsive to inhibition of MPO in mammals, including humans. Such cardiovascular diseases or conditions include, but are not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to recurrence of atrial fibrillation / flutter after cardioversion / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), preventing the progression and / or promoting regression of atherosclerosis, COVID-19 (or SARS CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal crosstalk, primary or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction.

[0229] The disclosed compounds are also suitable for treating or preventing neurological diseases and conditions in mammals (including humans) that respond to inhibition of MPO. Such diseases and conditions include, but are not limited to, diseases with a neuroinflammatory response. These diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and / or subarachnoid hemorrhage.

[0230] The disclosed compounds are useful in the treatment of cancer.

[0231] Preventative treatment is expected to be particularly useful for treating individuals who have previously developed the disease or condition in question, or who are otherwise considered to be at increased risk for developing the disease or condition. Individuals at risk for developing a particular disease or condition generally include those with a family history of the disease or condition, those who have been identified through genetic testing or screening, or those who have been identified as being particularly susceptible to developing the disease or condition by specific biomarker patterns.

[0232] For the above-mentioned therapeutic indications, the dosage administered will of course vary depending on the compound used, the mode of administration and the treatment required. However, in general, satisfactory results are achieved when the compound is administered in a solid form at a dosage of between 1 mg and 2000 mg per day.

[0233] The compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or the compounds disclosed herein, and pharmaceutically acceptable derivatives thereof, can be used alone or in the form of suitable pharmaceutical compositions, wherein the compounds or derivatives are mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Accordingly, another aspect relates to a pharmaceutical composition comprising a novel compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Thus, another aspect relates to a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Administration may be, but is not limited to, enteral (including oral, sublingual, or rectal), intranasal, inhalation, intravenous, topical, or other parenteral routes. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in Pharmaceuticals—The Science of Dosage Form Designs, ME Aulton, Churchill Livingstone, 2 nd Ed.2002.

[0234] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in therapy, particularly for the prevention or treatment of one or more conditions or diseases in which inhibition of MPO would be beneficial.

[0235] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating one or more conditions or diseases with an inflammatory component in a mammal, particularly a human, in which inhibition of MPO would be beneficial.

[0236] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment, particularly for the prevention or treatment, of one or more cardiovascular diseases in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0237] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating one or more neurological diseases in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0238] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in therapy, particularly for the prevention or treatment of one or more neutrophil-driven diseases in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0239] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating an inflammatory disease or disorder or a disease or disorder with an inflammatory component in a mammal, particularly a human, such as, but not limited to, autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetes mellitus, or a combination thereof. Diabetic nephropathy, cardiorenal syndrome (CRS), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, or type 2 diabetes mellitus.

[0240] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating a cardiovascular disease or condition in a mammal, particularly a human, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.

[0241] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating a cardiovascular disease or condition in a mammal, particularly a human, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.

[0242] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating neurological diseases and disorders in mammals, particularly humans, including but not limited to diseases with a neuroinflammatory response, such as, but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy.

[0243] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating one or more neutrophil-driven diseases in a mammal, particularly a human, such as, but not limited to, chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pneumonia, and acute respiratory distress syndrome (ARDS).

[0244] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating an inflammatory disease or disorder or a disease or disorder with an inflammatory component in a mammal, particularly a human, such as, but not limited to, autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome, or the like. CRS, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes mellitus, bronchiectasis, COVID-19 (or SARS CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end-stage renal disease (ESKD), immunoglobulin A vasculitis (Henschoff purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

[0245] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating a cardiovascular disease or condition in a mammal, particularly a human, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, or Myopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to recurrence of atrial fibrillation / flutter after cardioversion / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), preventing the progression and / or promoting regression of atherosclerosis, COVID-19 (or SARS) CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal crosstalk, primary or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction.

[0246] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating neurological diseases and disorders in mammals, particularly humans, including but not limited to diseases with a neuroinflammatory response, such as, but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and / or subarachnoid hemorrhage.

[0247] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer in a mammal, particularly a human.

[0248] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating coronary artery disease in a mammal, particularly a human.

[0249] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating acute coronary syndrome in a mammal, particularly a human.

[0250] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating heart failure in a mammal, particularly a human.

[0251] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating heart failure with reduced ejection fraction in a mammal, particularly a human.

[0252] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating heart failure with preserved ejection fraction in a mammal, particularly a human.

[0253] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating chronic kidney disease (CKD) in a mammal, particularly a human.

[0254] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating cardiorenal syndrome (CRS) in a mammal, particularly a human.

[0255] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.

[0256] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating arrhythmias in mammals, particularly humans.

[0257] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.

[0258] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating sickle cell disease in a mammal, particularly a human.

[0259] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating acute kidney injury (AKI) in a mammal, particularly a human.

[0260] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating non-cystic fibrosis bronchiectasis (NCFB) in a mammal, particularly a human.

[0261] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis in a mammal, particularly a human.

[0262] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating Alzheimer's disease in a mammal, particularly a human.

[0263] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating Parkinson's disease in a mammal, particularly a human.

[0264] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating nephritis in a mammal, particularly a human.

[0265] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating inflammatory bowel disease (IBD) in a mammal, particularly a human.

[0266] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is provided for use in preventing or treating irritable bowel syndrome (IBS) in a mammal, particularly a human.

[0267] In some embodiments, a method of treating, preventing, or reducing the risk of one or more diseases or conditions in which inhibition of the MPO enzyme is beneficial is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, a method of treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, a method of treating, preventing, or reducing the risk of one or more neutrophil-driven diseases or conditions is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, Liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, or type 2 diabetes, the method comprising administering to a human suffering from or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, a method of treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity, is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions, such as, but not limited to, diseases with a neuroinflammatory response, such as, but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy, is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, a method of treating, preventing, or reducing the risk of one or more neutrophil-driven diseases or conditions, such as, but not limited to, chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more diseases or conditions with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2), CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end stage renal disease (ESKD), immunoglobulin A vasculitis (Henschoff purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD and / or obesity associated with CKD, the method comprising administering to a human suffering from or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonged time to recurrence of atrial fibrillation / flutter after cardioversion / prevention of recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arresting progression and / or promoting regression of atherosclerosis, COVID-19 (or SARS CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced heart failure, CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal cross-lesions, initial or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction, the method comprising administering to a person suffering from or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb) or a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, a method of treating, preventing, or reducing the risk of one or more neurological diseases or conditions, such as, but not limited to, diseases with a neuroinflammatory response, such as, but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and / or subarachnoid hemorrhage, is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, a method of treating cancer is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, a method of treating, preventing, or reducing the risk of coronary artery disease is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, a method of treating, preventing, or reducing the risk of acute coronary syndrome is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, a method of treating, preventing, or reducing the risk of heart failure is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, a method of treating, preventing, or reducing the risk of heart failure with reduced ejection fraction is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, a method of treating, preventing, or reducing the risk of heart failure with preserved ejection fraction is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, a method of treating, preventing, or reducing the risk of chronic kidney disease (CKD) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, a method of treating, preventing, or reducing the risk of cardiorenal syndrome (CRS) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, a method of treating, preventing, or reducing the risk of non-alcoholic steatohepatitis (NASH) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, a method of treating, preventing, or reducing the risk of a cardiac arrhythmia is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, a method of treating, preventing, or reducing the risk of chronic obstructive pulmonary disease (COPD) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, a method of treating, preventing, or reducing the risk of sickle cell disease is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, a method of treating, preventing, or reducing the risk of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, a method of treating, preventing, or reducing the risk of acute kidney injury (AKI) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, a method of treating, preventing, or reducing the risk of non-cystic fibrosis bronchiectasis (NCFB) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, a method of treating, preventing, or reducing the risk of Alzheimer's disease is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, a method of treating, preventing, or reducing the risk of Parkinson's disease is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, a method of treating, preventing, or reducing the risk of nephritis is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, a method of treating, preventing, or reducing the risk of inflammatory bowel disease (IBD) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, a method of treating, preventing, or reducing the risk of irritable bowel syndrome (IBS) is provided, comprising administering to a human having or at risk of the disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing a disease or condition requiring modulation of chloroperoxidase (MPO) activity.

[0301] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing a disease or disorder having an inflammatory, cardiovascular, and / or neural component, and / or a neutrophil-driven disease.

[0302] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), Non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, and / or type 2 diabetes mellitus.

[0303] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for the treatment or prevention of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and / or chemotherapy-induced cardiotoxicity.

[0304] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and / or epilepsy.

[0305] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for the treatment or prevention of chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pneumonia, and acute respiratory distress syndrome (ARDS).

[0306] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb) or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), nonalcoholic steatohepatitis, (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end-stage renal disease (ESKD), immunoglobulin A vasculitis (Henschoff purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

[0307] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary hypertension, PAH, pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging time to recurrence of atrial fibrillation / flutter after cardioversion / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), preventing progression and / or promoting regression of atherosclerosis, COVID-19 (or SARS-CoV-2)-induced heart failure, COVID-19 (or SARS-CoV-2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal crosstalk, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction.

[0308] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (II), (IIa), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for treating or preventing Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and / or subarachnoid hemorrhage.

[0309] In some embodiments, provided are compounds of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, for use in the preparation of a medicament for the treatment of cancer.

[0310] In some embodiments, a pharmaceutical formulation is provided comprising a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, and / or inert carrier.

[0311] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in therapy, particularly for the prevention or treatment of one or more conditions or diseases in which inhibition of MPO would be beneficial.

[0312] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in therapy, particularly for the prevention or treatment of one or more conditions or diseases in which inhibition of MPO would be beneficial.

[0313] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating one or more conditions or diseases with an inflammatory component in a mammal, particularly a human, in which inhibition of MPO would be beneficial.

[0314] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in the treatment, particularly for the prevention or treatment, of one or more cardiovascular diseases in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0315] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating one or more neurological diseases in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0316] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in therapy, particularly for the prevention or treatment of one or more neutrophil-driven diseases in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0317] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (Iva), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating an inflammatory disease or disorder, or a disease or disorder with an inflammatory component, in a mammal, particularly a human, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), nephritis, glomerulonephritis, or renal failure. Interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, or type 2 diabetes mellitus.

[0318] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (la), (lb), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (IVa), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating cardiovascular diseases or conditions in mammals, particularly humans, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HfrEF), heart failure with preserved ejection fraction (HfpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.

[0319] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating cardiovascular diseases or conditions in mammals, particularly humans, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.

[0320] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating neurological diseases and disorders in mammals, particularly humans, including but not limited to diseases with a neuroinflammatory response, such as, but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and epilepsy.

[0321] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating one or more neutrophil-driven diseases in mammals, particularly humans, such as, but not limited to, chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pneumonia, and acute respiratory distress syndrome (ARDS).

[0322] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (Iia), (Iib), (III), (IIIa), (IIIb), (IV), (IVa), or (Ivb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating an inflammatory disease or condition, or a disease or condition with an inflammatory component, in a mammal, particularly a human, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, or a combination thereof. Nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS) CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end-stage renal disease (ESKD), immunoglobulin A vasculitis (Henschoff purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

[0323] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating cardiovascular diseases or conditions in mammals, particularly humans, such as, but not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), or F), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging time to recurrence of atrial fibrillation / flutter after cardioversion / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), preventing progression and / or promoting regression of atherosclerosis, COVID-19 (or SARS CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal crosstalk, primary or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction.

[0324] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating neurological diseases and disorders in mammals, particularly humans, including but not limited to diseases with a neuroinflammatory response, such as, but not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke, and / or subarachnoid hemorrhage.

[0325] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in treating cancer in a mammal, particularly a human.

[0326] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating coronary artery disease in a mammal, particularly a human.

[0327] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating acute coronary syndrome in a mammal, particularly a human.

[0328] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating heart failure in a mammal, particularly a human.

[0329] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating heart failure with reduced ejection fraction in a mammal, particularly a human.

[0330] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating heart failure with preserved ejection fraction in a mammal, particularly a human.

[0331] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating chronic kidney disease (CKD) in a mammal, particularly a human.

[0332] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating cardiorenal syndrome (CRS) in a mammal, particularly a human.

[0333] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.

[0334] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating cardiac arrhythmias in mammals, particularly humans.

[0335] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.

[0336] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating sickle cell disease in a mammal, particularly a human.

[0337] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis in a mammal, particularly a human.

[0338] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating Alzheimer's disease in a mammal, particularly a human.

[0339] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating Parkinson's disease in a mammal, particularly a human.

[0340] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating nephritis in a mammal, particularly a human.

[0341] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating inflammatory bowel disease (IBD) in a mammal, particularly a human.

[0342] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier for use in preventing or treating irritable bowel syndrome (IBS) in a mammal, particularly a human.

[0343] In some embodiments, plasma urate levels can be used as a stratification tool and pharmacodynamic biomarker for MPO inhibitor treatment using a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0344] In yet further embodiments, methods of identifying patients suitable for treatment with an MPO inhibitor using a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, are provided, encompassing measuring plasma urate levels.

[0345] In some embodiments, predictive biomarkers (i.e., characteristics or variables that reflect the involvement of MPO in disease pathology) can be used as stratification tools and pharmacodynamic biomarkers for MPO inhibitor treatment using a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Such biomarkers include, but are not limited to, biomarkers of neutrophil activation (MPO, NGAL, sTNFR1, sTNFR2, calprotectin, UPAR, blood neutrophil count or percentage, blood neutrophil / lymphocyte ratio), other inflammatory prognostic biomarkers (GDF15, FGF23, sTRAIL-R2), biomarkers of systemic inflammation (IL6, C-reactive protein or other acute phase proteins), biomarkers of increased purine catabolism (urate) and purine oxidation (allantoin), biomarkers of iron deficiency (transferrin saturation, ferritin, hemoglobin), biomarkers of extracellular matrix remodeling (MMP7, TIMP4, osteopontin), biomarkers of renal dysfunction (eGFR, UACR, cystatin C), biomarkers of nitric oxide production (SDMA, ADMA, Arg, cGMP). Several of these biomarkers can be quantified from blood, plasma, serum, urine, feces, or saliva.

[0346] In yet further embodiments, methods of identifying patients suitable for treatment with an MPO inhibitor using a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, are provided, encompassing measuring such predictive biomarkers as disclosed herein.

[0347] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, has an IC of 0.001 when tested in an MPO binding assay (e.g., Test A described below). 50 Less than 10μM.

[0348] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, has an IC of 0.001 when tested in an MPO binding assay (e.g., Test A described below). 50 Less than 5μM.

[0349] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, has an IC of 0.001 when tested in an MPO binding assay (e.g., Test A described below). 50 Less than 1μM.

[0350] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, has an IC of 0.001 when tested in an MPO binding assay (e.g., Test A described below). 50 Less than 0.5μM.

[0351] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, has an IC of 0.001 when tested in an MPO binding assay (e.g., Test A described below). 50 Less than 0.2μM.

[0352] The compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, also exhibit favorable pharmacological properties by discriminating between desired and undesired effects in vivo.

[0353] These and other embodiments are described in more detail below, wherein additional aspects will become apparent to those skilled in the art from reading this specification.

[0354] Pharmacological properties

[0355] Compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, are believed to be useful in preventing or treating a variety of conditions requiring modulation of chloroperoxidase (MPO) activity, including, but not limited to, diseases with inflammatory, cardiovascular, and / or neurological components, and neutrophil-driven diseases.

[0356] For the avoidance of doubt, as used herein, the term "treatment" includes therapeutic and / or prophylactic treatment.

[0357] When the compounds or salts described herein are used to treat a disorder, a "therapeutically effective amount" refers to an amount sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder, cure the disorder, reverse, completely stop or slow the progression of the disorder, or reduce the risk of the disorder worsening.

[0358] Therefore, the compounds described herein are useful in the therapeutic and / or prophylactic treatment of these disorders.

[0359] The compounds described herein have the following advantages over compounds known in the prior art: they may be more effective, less toxic, more selective, more potent, produce fewer side effects, be more readily absorbed, and / or have better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance).

[0360] Combination therapy

[0361] The compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may also be administered in combination with other compounds used to treat the above-mentioned conditions.

[0362] In some embodiments, there are combination therapies in which a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially, or in admixture with a second active ingredient for the treatment of one or more of the conditions listed above. Such combinations may be used in combination with one or more other active ingredients.

[0363] The compounds described herein can be used in combination with the following agents to treat cardiovascular, metabolic, and renal diseases:

[0364] Cardiac therapy,

[0365] Antihypertensive drugs,

[0366] Diuretics,

[0367] Peripheral vasodilators,

[0368] Lipid modifiers,

[0369] Antidiabetic drugs,

[0370] Anti-inflammatory drugs or

[0371] Anticoagulants.

[0372] Examples of such substances include, but are not limited to, digitalis glycosides, antiarrhythmics, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers (e.g., valsartan), endothelin receptor blockers, beta-blockers, thiazide diuretics, loop diuretics, cholesterol synthesis inhibitors such as statins (e.g., rosuvastatin), cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, antidiabetic agents such as insulin and analogs, GLP-1 analogs, sulfonamides, dipeptidyl peptidase 4 inhibitors, thiazolidinediones, SGLT-2 inhibitors and anti-inflammatory drugs such as NSAIDs and CCR2 antagonists, anticoagulants such as heparin, thrombin inhibitors and factor Xa inhibitors, platelet aggregation inhibitors, P2X7 antagonists and neprilysin inhibitors (e.g., sacubitril).

[0373] When used in combination therapy, it is contemplated that a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and the other active ingredient(s) may be administered in a single composition, in completely separate compositions, or in a combination thereof. It is also contemplated that the active ingredients may be administered simultaneously, concurrently, sequentially, or separately. The specific composition and frequency of administration of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the type of patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to an animal patient, and a variety of other factors known to physicians (in the case of human patients), veterinarians (in the case of non-human patients), and others skilled in the art.

[0374] Pharmaceutical composition

[0375] The present invention provides methods for treating conditions requiring inhibition of MPO, comprising administering to a human suffering from or susceptible to such a condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0376] The compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, will typically be administered orally, topically, parenterally, intravenously, intramuscularly, subcutaneously or by other injectable means, buccal, rectal, vaginal, transdermal, and / or nasal routes, and / or via inhalation, in the form of pharmaceutical formulations comprising the active ingredient or a pharmaceutically acceptable salt thereof. Depending on the condition and patient to be treated, and the route of administration, these compositions may be administered in varying doses. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in Pharmaceuticals—The Science of Dosage Form Designs, ME Aulton, Churchill Livingstone, 2 nd Ed.2002.

[0377] The optimal dose and frequency of administration will depend on the specific condition being treated and its severity; the species of patient; the age, sex, size and weight, diet and general physical condition of the specific patient; the brain / body weight ratio; other medications the patient may be taking; the route of administration; the formulation; and a variety of other factors known to physicians and other persons skilled in the art.

[0378] In some embodiments, a pharmaceutical formulation is provided comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, and / or carrier.

[0379] A compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be present in the pharmaceutical formulation at a concentration of 0.1% to 99.5% (such as 0.5% to 95%) by weight of the total formulation.

[0380] Some embodiments encompass pharmaceutically acceptable salts of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb).

[0381] Some embodiments encompass pharmaceutically acceptable salts of the compounds disclosed herein.

[0382] Such salts may have advantages due to one or more of their chemical or physical properties, such as stability under varying temperatures and humidities, or desired solubility in H2O, oils, or other solvents. In some cases, salts can be used to aid in the isolation or purification of compounds. In some embodiments (particularly when the salt is intended for administration to an animal (e.g., a human) or is an agent for preparing a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable.

[0383] The term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) that is suitable for use in the context of sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects can include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0384] When the compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.

[0385] For a review of suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, PHStahl, PG Vermuth, IUPAC, Wiley-VCH, 2002.

[0386] When the acidic coformer is a solid at room temperature and there is no proton transfer or only partial proton transfer between a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb) or a compound disclosed herein and such an acidic coformer, a co-crystal of the coformer and the compound may be produced rather than a salt. All such co-crystal forms of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb) or a compound disclosed herein are contemplated herein.

[0387] It will also be understood that certain compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or certain compounds disclosed herein, may exist in solvated forms, such as hydrates, including solvates of pharmaceutically acceptable salts of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or compounds disclosed herein.

[0388] In some embodiments, certain compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or certain compounds disclosed herein, may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and diastereomeric mixtures. Certain compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or certain compounds disclosed herein, may also contain a linker (e.g., a carbon-carbon bond, a carbon-nitrogen bond such as an amide bond) wherein bond rotation about that particular linker is restricted, for example, due to the presence of a ring bond or a double bond. Stereoisomers may be separated using conventional techniques, such as chromatography or fractional crystallization, or they may be prepared by stereoselective synthesis.

[0389] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), the compounds disclosed herein, and pharmaceutically acceptable salts thereof encompass any isotopically labeled (or "radiolabeled") derivatives of such compounds. Such derivatives are derivatives of the compounds in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated include 2 H (also written as "D" for deuterium).

[0390] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb) and the compounds disclosed herein can be administered in the form of a prodrug or a pharmaceutically acceptable salt thereof, which breaks down in the human or animal body to yield the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb) or the compounds disclosed herein.

[0391] Various forms of prodrugs are known in the art. Examples of prodrug derivatives are described in Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein.

[0392] Intermediate compounds may also exist in enantiomeric forms and can be used as purified enantiomers, diastereomers, racemates, or mixtures.

[0393] Example

[0394] The following abbreviations are used:

[0395] Abs Absolute value

[0396] AcOH acetic acid

[0397] Aq water based

[0398] Boc tert-Butoxycarbonyl

[0399] Boc2O Di-tert-butyl dicarbonate

[0400] BnOH phenylmethanol

[0401] Butyl

[0402] n-Butyllithium 1-Butyllithium

[0403] n-Butanol 1-Butanol

[0404] tert-Butanol tert-Butanol

[0405] Brine saturated sodium chloride aqueous solution

[0406] Calcd

[0407] CataXCium A Di(adamantan-1-yl)(butyl)phosphine (CAS Reg. No. 321921-71-5)

[0408] Cbz benzyloxycarbonyl

[0409] CPME amyl methyl ether

[0410] DAST N,N-diethyl-1,1,1-trifluoro-l 4 -sulfonamide

[0411] DCE dichloroethane

[0412] DCM dichloromethane

[0413] DEA Diethylamine

[0414] DIPEA N-ethyl-N-isopropyl-propan-2-amine

[0415] DMAP N,N-dimethylpyridin-4-amine

[0416] DMF N,N-dimethylformamide

[0417] DMP 3-oxo-1l 5 -Benzo[d][1,2]iodidefuran-1,1,1(3H)-triyl-triacetate

[0418] DMSO dimethyl sulfoxide

[0419] DPPA diphenylphosphoryl azide

[0420] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0421] EDC 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine

[0422] ESI electrospray ionization

[0423] Et ethyl

[0424] Et2O ether

[0425] EtOAc

[0426] EtOH

[0427] FA Formic acid

[0428] Fmoc (9H-fluoren-9-yl)methylcarbonyl

[0429] g grams

[0430] G3 3rd Generation

[0431] h hour

[0432] HPLC high-performance liquid chromatography

[0433] HOAc acetic acid

[0434] IPA 2-Propanol

[0435] iPr Isopropyl

[0436] HRMS High Resolution Mass Spectrometry

[0437] L liter

[0438] LiHMDS Lithium bis(trimethylsilyl)amide

[0439] LC liquid chromatography

[0440] M Moore

[0441] Me methyl

[0442] MeCN Acetonitrile

[0443] mL milliliters

[0444] mL microliter

[0445] MeOH methanol

[0446] Min minutes

[0447] Mmol millimole

[0448] MS

[0449] MTBE methyl tert-butyl ether

[0450] NIS 1-iodopyrrolidine-2,5-dione

[0451] NMR Nuclear Magnetic Resonance

[0452] OAc acetate

[0453] OEt Ethoxy

[0454] Pd-C activated carbon supported palladium

[0455] Ph Phenyl

[0456] Rt Room temperature

[0457] Sat Saturated

[0458] SFC Supercritical Fluid Chromatography

[0459] TEA triethylamine

[0460] TFA trifluoroacetic acid

[0461] THF Tetrahydrofuran

[0462] TMEDA N 1 ,N 1 ,N2 ,N 2 -Tetramethylethane-1,2-diamine

[0463] TLC thin layer chromatography

[0464] Ts p-toluenesulfonyl or 4-methylbenzenesulfonyl

[0465] TsOH 4-Methylbenzenesulfonic acid

[0466] General Conditions (i) operating at room temperature (rt) (i.e., in the range of 17° C. to 28° C.) and, if necessary, under an atmosphere of an inert gas such as N 2 ;

[0467] (ii) where the reaction involves degassing or purging, this can be carried out, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 to 10 minutes) or by repeatedly evacuating the vessel and backfilling with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g));

[0468] (iii) where the reaction involves the use of a microwave reactor, one of the following microwave reactors is used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry SmithCreator, or CEM Explorer;

[0469] (iv) In general, the progress of the reaction is followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) often coupled to a mass spectrometer (LCMS).

[0470] (v) If necessary, the organic solution is dried over anhydrous MgSO4 or Na2SO4, or by using The organic layer is dried in a phase separator and subjected to post-processing using conventional phase separation techniques. When a drying agent such as MgSO4 or Na2SO4 is used to dry the organic layer, it should be understood that the organic layer is filtered before concentrating the organic layer.

[0471] (vi) evaporation by vacuum rotary evaporation or by Genevac HT-4 / EZ-2 or Biotage V10;

[0472] (vii) Unless otherwise stated, flash column chromatography was performed on straight phase silica using Merck silica gel (Art. 9385) or pre-packed cartridges such as SNAP cartridge (40μm-63μm silica, 4g-330g), Silica HC D cartridge (20 μm, 10 g-100 g), Interchim puriFlash TM Small columns (25 μm, 4 g-120 g), Interchim puriFlash TM Small column (50μm, 25g-330g), Grace TM GraceResolv TM Silica flash cartridges (4 g–120 g) or Agela flash silica-CS cartridges (80 g–330 g) were used, or Grace was used on reversed-phase silica using Agela Technologies C-18 spherical cartridges (20 μm–35 μm, 100 Å, 80 g–330 g). X2 Rapid System or similar system, manually or automatically;

[0473] (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instrumentation, respectively, equipped with MS and / or UV-triggered fraction collection instrumentation, using isocratic or gradient mobile phases as described in the experimental section.

[0474] The relevant fractions are collected, combined and freeze-dried or evaporated to give the purified compound, or the relevant fractions are collected, combined and concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase is dried over Na2SO4 or by using a phase separator and then concentrated under reduced pressure to give the purified compound.

[0475] (ix) chiral preparative chromatography using HPLC or SFC on standard HPLC or SFC instruments, respectively, using isocratic or gradient runs with mobile phases as described in the experimental section;

[0476] (x) the yield, where any, is not necessarily the maximum obtainable and, when necessary, the reaction is repeated if a larger amount of the reaction product is desired;

[0477] (xi) In the case of certain compounds obtained as acid addition salts (e.g., monohydrochloride or dihydrochloride), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and it is generally not possible to determine the exact stoichiometry of the salt, for example, from elemental analysis data;

[0478] (xii) In general, the structures of the final products of the compounds described herein were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; Bruker Avance III 300, 400, 500, and 600 spectrometers (operating at 300 MHz, 400 MHz, 500 MHz, and 600 MHz, respectively) were used. 1H frequency) are operated on the δ scale to measure proton NMR chemical shift values. Experiments are typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as an internal standard. Protons on heteroatoms such as NH and OH protons are reported only when detected in the NMR and may therefore be missing. In some cases, protons may be obscured or partially obscured by solvent peaks and are therefore either missing and not reported or reported as multiplets overlapping with the solvent. The following abbreviations (and their derivatives, such as dd, doublet, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. In some cases, the structure of the final product of the compound disclosed herein may appear as a rotamer in the NMR spectrum, in which case only the peak of the major rotamer is reported. Electrospray ionization mass spectrometry data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar device, acquiring both positive and negative ion data, and generally only ions associated with the parent structure are reported. High-resolution electrospray ionization mass spectrometry data were obtained using a Waters XEVO qToF mass spectrometer coupled to a Waters Acquity UPLC or similar device, acquiring both positive and negative ion data, and generally only ions associated with the parent structure are reported.

[0479] (xiii) The intermediates are not necessarily completely purified, but their structure and purity are assessed by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry;

[0480] (xiv) Unless otherwise stated, compounds containing asymmetric carbon and / or sulfur atoms were not resolved;

[0481] (xv) In general, the examples and intermediate compounds were named using ChemDraw Professional version 20.1.1.125 from PerkinElmer. ChemDraw Professional version 20.1.1.125 uses the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate names for chemical structures and adheres as closely as possible to IUPAC rules when generating chemical names. Stereoisomers are distinguished from each other by the stereodescriptors cited in the names and are assigned according to the CIP rules.

[0482] ChemDraw optionally uses symbols such as '&' and 'or' in representations of stereocenters to describe the configuration of stereochemical centers present in the structure.

[0483] In general, chemical structures of embodiments and intermediates containing the designation '&' at a stereocenter mean that the configuration of such embodiment or intermediate at that stereocenter is a mixture of both (R) and (S); and the designation 'or' means that the configuration of such embodiment or intermediate at that stereocenter is either (S) or (R). Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure.

[0484] In general, the 'and' and 'or' markings at each stereocenter present in the structure can also include numbers. These numbers represent that the stereocenters can change independently of each other or do not change independently, so that if two or more stereocenters do not change independently of each other, i.e., are fixed relative to each other, they have the same number, but if they change independently of each other, they have different numbers. For example, if a compound has two stereocenters that are independent of each other in a ring, one stereocenter is marked as "or 1" (or "&1") and the other stereocenter is marked as "or 2" (or "&2"), and if a compound has two stereocenters in a ring and they are fixed relative to each other and do not change independently of each other, the two stereocenters are marked as "or 1" (or "&1"), and if a compound has two stereocenters that are fixed relative to each other and a third stereocenter that changes independently of the aforementioned stereocenters, the first two stereocenters are both marked as "or 1" (or "&1") and the third stereocenter is marked as "or 2" (or "&2").

[0485] Note also that as an artifact of this automatic labeling from ChemDraw, in some examples, the two isomers are represented side by side, with the stereocenter in Isomer 1 labeled with "Or 1," and the stereocenter in Isomer 2 labeled with "Or 2." It is understood that these two compounds are considered to be isomers of one another, as evidenced by different properties, such as different elution times on chiral HPLC.

[0486] In general, for chemical structures of examples and intermediates in which all stereocenters present are racemic, no labels are assigned to the stereocenters, and the structures are drawn with direct bonds at each stereocenter.

[0487] In general, for structures of embodiments and intermediates in which all stereocenters are designated as '&', the structures are named with a "racemic-" prefix. For structures of embodiments and intermediates in which all stereocenters are designated as 'or', the structures are named with a "rel-" prefix.

[0488] In general, the label "Isomer 1" corresponds to the first eluting isomer and "Isomer 2" corresponds to the second eluting isomer on a given chiral HPLC column and eluent, and is used to distinguish between two isomers containing one or more stereocenters and of absolutely unknown configuration.

[0489] In general, for examples or intermediates containing more than one stereocenter, the configurational descriptors 'S' and 'R' for the stereocenters are used to describe the relative stereochemistry and the name is preceded by a "rac-" or "rel-" prefix.

[0490] It should be understood that examples or intermediates named with the prefix "rel-" are single isomers, and that although the stereocenter in that isomer has been designated as "R" or "S," the actual stereochemistry of that particular isomer may be reversed from the designation. For example, although Example 12a (Isomer 1) is named "rel-(R)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one," Example 12a may be "(S)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one." For example, although Example 18b (Isomer 1) is named "rel-2-thiocarbonyl-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one", Example 18b can be "rel-2-thiocarbonyl-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one".

[0491] It is understood that the examples or intermediates named with the prefix "rac-" are mixtures of isomers, and that although the relative stereochemistry of the stereocenters in that isomer has been designated with the descriptor "R" or "S," the actual stereochemistry of that particular isomeric mixture also encompasses the opposite of that descriptor. For example, although Example 17b is named "rac-2-thiocarbonyl-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one," Example 17b also encompasses "2-thiocarbonyl-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one."

[0492] Preparation of compounds

[0493] General approach

[0494] In another aspect, there is provided a process for preparing a compound of formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, the process comprising:

[0495] a) Where Y 1 、Y 2 Y 3 、Y 4 、Y 5 and X are as defined above, the compound of formula (I) may be prepared by making Y 1 、Y 2 、Y 3 、Y 4 Y 5 and X is as defined in formula (I) and LG1 is a suitable leaving group (such as (C1-C4) alkoxy (such as OEt) or NH2) of formula (V)

[0496]

[0497] The reaction is carried out in a suitable organic solvent such as MeOH or EtOH at a temperature generally ranging from 20°C to 80°C for an extended period of time (eg, 3 to 24 hours).

[0498] If necessary, the obtained compound of formula (I) can be converted into a pharmaceutically acceptable salt of formula (I), and if desired, the obtained compound of formula (I) can be separated into its individual optical isomers.

[0499] The compound of formula (V) can be prepared by making Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and X is as defined in formula (I) and LG1 is as defined above, a compound of formula (VI)

[0500]

[0501] With isothiocyanate benzoyl ester (1 equivalent to 3 equivalents) reaction to prepare.This reaction is usually carried out in inert organic solvent such as DCM or MeCN at room temperature for 1 hour to 24 hours.Optionally, this reaction can be carried out in the presence of organic base such as DIPEA.

[0502] The compound of formula (VI) above can be prepared by making Y 1 、Y 2 、Y 3 、Y 4 and Y5 The reaction is carried out by reacting a compound of formula (VII) as defined in formula (I) with a compound of formula (VIII) wherein X and LG1 are as defined above.

[0503]

[0504] The condition is to form an NC bond between the nitrogen-atom of the compound of formula (VIII) and the carbon atom of the aldehyde group of the compound of formula (VII) by reducing alkylation. The reaction conditions are conventional reducing alkylation conditions. Typically, in an organic solvent such as EtOH, MeOH, DCM or DCE, in the presence of the aldehyde compound of formula (VII), the amine compound in the form of hydrochloride is treated with DIPEA or TEA and HOAc. After the mixture is stirred for a period of time, for example at room temperature, a reducing agent such as NaBH is added CN, NaBH or NaBH (OAc) , and the resulting mixture is stirred at a temperature range of generally 20 DEG C to 80 DEG C, until the reaction is complete, for example, for 1 hour to 20 hours, to obtain a compound of formula (VI). (See, for example, J.Org.Chem 1996, 61, 3849).

[0505] where Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Certain compounds of formula (VII) as defined in formula (I) can be prepared from compounds of formula (IX), (X), (XI) and (XII) according to the methods illustrated in Scheme TA1 and the description below and by methods analogous to those described in the Examples.

[0506] Plan TA1

[0507]

[0508] Method a1 The compound according to formula (VII) can be obtained by reacting the compound of formula (IX) with pyridine x SO (e.g. 2 equivalents) in the presence of TEA (e.g. 3.5 equivalents) in DMSO at room temperature until the reaction is complete (1 to 17 hours). (Parikh-Doering conditions, J. Am. Chem. Soc. 1967, 89, 5505).

[0509] Method a2:Compounds according to formula (VII) can be obtained by reacting compounds of formula (IX) with pyridinium chlorochromate (PCC) (eg 1.5 equivalents) in an inert organic solvent such as DCM at room temperature for a prolonged period of time (eg 1 to 2 hours) (Synthesis, 1982, 245).

[0510] Method a3: Compounds according to formula (VII) can be obtained by reacting compounds of formula (IX) with DMP (e.g. 1.1 to 2 equivalents) in an inert organic solvent such as DCM at a temperature typically in the range of 0°C to 30°C for a prolonged period of time (e.g. 1 hour). (J. Am. Chem. Soc. 1991, 113, 7277).

[0511] Method a4: Compounds according to formula (VII) can be obtained by reacting compounds of formula (IX) with excess activated MnO2 (e.g. 5 to 7 equivalents) in an inert organic solvent such as DCM at room temperature for a prolonged period of time (e.g. 48 hours) (Synthesis, 1976, 65).

[0512] Method b1: The compound according to formula (VII) can be obtained by treating the compound of formula (X) with synthesis gas (H2 / CO, 1 / 1) in the presence of a catalyst, which can be, for example, a mixture of palladium diacetate, di((3S,5S,7S)-adamantan-1-yl)(butyl)-phosphine and tetramethylethylenediamine in an organic solvent such as toluene. Typically, the reaction is carried out at about 5 bar and about 100°C for about 6 to 21 hours. (Angew. Chem. Int. ed. 2006, 45, 154).

[0513] Method b2: Compounds according to formula (VII) can be obtained by treating compounds of formula (X) with a strong base such as butyllithium in an inert solvent such as THF, followed by treating the resulting mixture with DMF. The reaction can be carried out at low temperatures such as -78°C to -60°C.

[0514] Method c1: Compounds according to formula (VII) can be obtained by treating compounds of formula (XI) with nitric acid (4 to 8 equivalents) in an inert organic solvent such as DCM. The reaction is typically carried out at room temperature for extended periods of time (24 to 72 hours).

[0515] Method d1: Compounds according to formula (VII) can be prepared by treating the mixture wherein PG is present with an acid such as TsOH (eg 0.1 eq to 0.2 eq) in a water / acetone mixture at a temperature typically in the range of 25°C to 60°C. 1 and PG 2The compound of formula (XII) containing protecting groups is obtained over a longer period of time (usually overnight), these protecting groups can be the same as each other (e.g. methyl or ethyl), and they can be unconnected or connected to each other to form a ring (e.g. -CH2-CH2- or -CH2-CH2-CH2-).

[0516] Method d2: Compounds according to formula (VII) can be prepared by treating PG with excess aqueous HCl in MeCN at a temperature typically in the range of 25°C to 90°C. 1 and PG 2 Compounds of formula (XII) as defined above are obtained by annealing for a longer period of time (usually overnight).

[0517] Compounds of formula (VIII) wherein X and LG1 are as defined above are commercially available, known in the art or can be prepared in a conventional manner known to those skilled in the art.

[0518] Compounds of formula (IX), (X), (XI) and (XII) are commercially available, known in the art or can be prepared by methods analogous to those described in the examples and in the following description or in conventional manner known to those skilled in the art.

[0519] where Y 1 、Y 2 、Y 3 、Y 4 X, A, R 1 , n, p and s are as defined above in formula (II) and the compound of formula (II) can be prepared by making Y 1 、Y 2 、Y 3 、Y 4 X, A, R 1 Compound of formula (XIII) wherein n, p and s are as defined above and LG1 is as defined above

[0520]

[0521] With base such as CsCO, NaOH, NH or NHOH reaction to form.Usually, this reaction is carried out for a long time (3 hours to 24 hours) in a suitable organic solvent such as MeOH or EtOH at a temperature range of generally 20 ℃ to 80 ℃.If necessary, the resulting compound of formula (II) can be converted into a pharmaceutically acceptable salt of formula (II), and when necessary, the resulting compound of formula (II) can be separated into its individual optical isomers.

[0522] The compound of formula (XIII) can be prepared by making Y 1 、Y 2 、Y 3、Y 4 ,X,A,R 1 Compounds of formula (XIV) wherein n, p and s are as defined above in formula (II) and LG1 is as defined above

[0523]

[0524] With isothiocyanate benzoyl ester (1 equivalent to 3 equivalents) reaction to prepare.This reaction is usually carried out in inert organic solvent such as DCM or MeCN at room temperature for 1 hour to 24 hours.Optionally, this reaction can be carried out in the presence of organic base such as DIPEA.

[0525] The compound of the above formula (XIV) can be prepared by making Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 The reaction can be carried out by reacting a compound of formula (XV) wherein X, n, p and s are as defined in formula (I) with a compound of formula (VIII) wherein X and LG1 are as defined above.

[0526]

[0527] The condition is to make the reduction alkylation of formula (VIII) compound form NC bond between the nitrogen-atom of formula (VIII) compound and the carbon atom of the aldehyde group of formula (XV) compound.Reaction conditions are conventional reduction alkylation conditions.Generally, in an organic solvent such as EtOH, MeOH, DCM or DCE, in the presence of the aldehyde compound of formula (XV), the amine compound in the form of hydrochloride is treated with DIPEA or TEA and HOAc.After the mixture is stirred for a period of time, for example at room temperature, a reducing agent such as NaBH is added CN, NaBH or NaBH (OAc) , and the resulting mixture is stirred at a temperature range of generally 20 DEG C to 80 DEG C, until the reaction is complete, for example, for 1 hour to 20 hours, to obtain formula (XIV) compound.(See, for example, J.Org.Chem 1996, 61, 3849).

[0528] Compounds of formula (VIII) wherein X and LG1 are as defined above are commercially available, known in the art or can be prepared in a conventional manner known to those skilled in the art.

[0529] where Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1Certain compounds of formula (XV) wherein n, p and s are as defined in formula (I) can be prepared from compounds of formula (XVI), (XVII), (XVIII) and (XIX) according to the methods illustrated in Scheme TA2 and the description below and by methods analogous to those described in the Examples.

[0530] Plan TA2

[0531]

[0532] Method a1 The compound according to formula (XV) can be obtained by reacting the compound of formula (XVI) with pyridine x SO (e.g., 2 equivalents) in the presence of TEA (e.g., 3.5 equivalents) in DMSO at room temperature until the reaction is complete (1 to 17 hours). (Parikh-Doering conditions, J. Am. Chem. Soc. 1967, 89, 5505).

[0533] Method a2: Compounds according to formula (XV) can be obtained by reacting compounds of formula (XVI) with pyridinium chlorochromate (PCC) (eg 1.5 equivalents) in an inert organic solvent such as DCM at room temperature for a prolonged period of time (eg 1 to 2 hours) (Synthesis, 1982, 245).

[0534] Method a3: Compounds according to formula (XV) can be obtained by reacting compounds of formula (XVI) with DMP (e.g. 1.1 to 2 equivalents) in an inert organic solvent such as DCM at a temperature typically in the range of 0°C to 30°C for a prolonged period of time (e.g. 1 hour). (J. Am. Chem. Soc. 1991, 113, 7277).

[0535] Method a4: Compounds according to formula (XV) can be obtained by reacting compounds of formula (XVI) with excess activated MnO2 (e.g. 5 to 7 equivalents) in an inert organic solvent such as DCM at room temperature for a prolonged period of time (e.g. 48 hours) (Synthesis, 1976, 65).

[0536] Method b1:The compound according to formula (XV) can be obtained by treating the compound of formula (XVII) with synthesis gas (H2 / CO, 1 / 1) in the presence of a catalyst, which catalyst can be, for example, a mixture of palladium diacetate, di((3S,5S,7S)-adamantan-1-yl)(butyl)-phosphine and tetramethylethylenediamine in an organic solvent such as toluene. Typically, the reaction is carried out at about 5 bar and about 100°C for about 6 to 21 hours. (Angew. Chem. Int. ed. 2006, 45, 154).

[0537] Method b2: Compounds according to formula (XV) can be obtained by treating compounds of formula (XVII) with a strong base such as butyllithium in an inert solvent such as THF, followed by treating the resulting mixture with DMF. The reaction can be carried out at low temperatures such as -78°C to -60°C.

[0538] Method c1: Compounds according to formula (XV) can be obtained by treating compounds of formula (XVIII) with nitric acid (4 to 8 equivalents) in an inert organic solvent such as DCM. The reaction is typically carried out at room temperature for extended periods of time (24 to 72 hours).

[0539] Method d1: Compounds according to formula (XV) can be prepared by treating wherein PG with an acid such as TsOH (eg 0.1 eq to 0.2 eq) in a water / acetone mixture at a temperature typically in the range of 25°C to 60°C. 1 and PG 2 Compounds of formula (XIX) as defined above are obtained by drying for a longer period of time (usually overnight).

[0540] Method d2: Compounds according to formula (XV) can be prepared by treating PG with excess aqueous HCl in MeCN at a temperature typically in the range of 25°C to 90°C. 1 and PG 2 Compounds of formula (XIX) as defined above are obtained by drying for a longer period of time (usually overnight).

[0541] Compounds of formula (VIII) wherein X and LG1 are as defined above are commercially available, known in the art or can be prepared in a conventional manner known to those skilled in the art.

[0542] Compounds of formula (XVI), (XVII), (XVIII) and (XIX) are commercially available, known in the art or can be prepared by methods analogous to those described in the examples and in the description below or in conventional manner known to a person skilled in the art.

[0543] where Y 1 、Y 2、Y 3 、Y 4 A.R. 1 n, p and s are as defined in formula (I) and FG 1 is CH2OH, Br, CH2-OMe or CH(OPG) 1 (OPG) 2 (PG 1 and PG 2 Certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) as defined above) can be prepared according to the method illustrated in Scheme TA3.

[0544] Plan TA3

[0545]

[0546] Step 1: Where Y 1 、Y 2 、Y 3 、Y 4 and FG 1 Compounds according to formula (XXI) as defined above and wherein M is Li can be prepared by treating wherein Y 1 、Y 2 、Y 3 、Y 4 and FG 1 The compound of formula (XX) is obtained as defined above. The reaction can be carried out at low temperature (such as -78°C) and under an inert atmosphere (eg nitrogen).

[0547] Step 2: Where Y 1 、Y 2 、Y 3 、Y 4 and FG 1 Compounds according to formula (XXI) as defined above and wherein M is Mg can be prepared by treating wherein Y with iPrMgCl x LiCl (Turbo Grignard) in an inert organic solvent such as THF. 1 、Y 2 、Y 3 、Y 4 and FG 1 The compound of formula (XX) as defined above is obtained. The reaction can be carried out at a temperature range of -40°C to room temperature under an inert atmosphere such as nitrogen, depending on the substrate used. (Chem. Eur. J. 2019, 25, 2695).

[0548] Step 3: Where Y 1 、Y 2 、Y3 、Y 4 ,A,R 1 , n, p and s are as defined in formula (I) and FG 1 The compounds according to formula (XXIII) as defined above may be prepared by making the compound wherein Y 1 、Y 2 、Y 3 、Y 4 and FG 1 As defined above, a compound of formula (XXI) wherein M is Mg or Li is obtained by reacting a compound of formula (XXII) in an inert organic solvent such as THF. The reaction can be carried out at a temperature ranging from -78°C to room temperature and under an inert atmosphere such as nitrogen, depending on the substrate used.

[0549] Step 4: Where Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined in formula (I) and FG 1 Compounds according to formula (XXIV) (enamine) and / or formula (XXV) (imine) as defined above can be obtained by treating a compound of formula (XXIII) with a strong acid such as TFA or HCl. The reaction is carried out in an inert organic solvent such as DCM or MeOH at a temperature ranging from 20° C. to 100° C. According to the method described in step 5, compounds of formula (XXIV) and formula (XXV) can be separated before reduction, or the compound of formula (XXV) can be reduced in situ.

[0550] Step 5: Where Y 1 、Y 2 、Y 3 、Y 4 ,A,R 1 , n, p and s are as defined in formula (I) and FG 1 Certain compounds according to formula (XVI), (XVII), (XVIII) and (XIX) as defined above can be obtained by any one of the methods described below in i) to iii):

[0551] i) treating a compound of formula (XXV) as defined above with a reducing agent such as NaBH4, NaBH(OAc)3 or NaBH3CN. The reaction is carried out in an inert organic solvent such as MeOH, DCM or THF at room temperature, or

[0552] ii) treating a compound of formula (XXIV) as defined above with a metal catalyst such as Pd / C, Pd(OH)2 / C or PtO2 under a hydrogen atmosphere at about room temperature for a prolonged period of time. The reaction is carried out in an inert organic solvent such as HOAc, MeOH, EtOAc or a HOAc / MeOH mixture. Optionally, the reaction can be carried out in the presence of an organic base such as DIPEA, or

[0553] iii) reacting a compound of formula (XXIV) as defined above with LiBHEt3 in an inert organic solvent such as THF at about 0°C to about room temperature.

[0554] where Y 1 、Y 2 、Y 3 、Y 4 and n are as defined in formula (I) and FG 1 Certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) wherein s is 0, p is 0 and A is CH2 as defined above can be prepared according to the method illustrated in Scheme TA4.

[0555] Solution TA4

[0556]

[0557] Step 1: Where Y 1 、Y 2 、Y 3 、Y 4 and FG 1 Compounds according to formula (XXVII) as defined above and wherein x is 0, 1 or 2 can be prepared by reacting a compound of formula (XXVI) with a Grignard reagent CH2=CH-(CH2) x -MgBr (wherein x is 0, 1 or 2) is optionally obtained by reacting in an inert solvent such as THF or DCM at about -78°C in the presence of CeCl3, and optionally separating the obtained intermediate into its diastereomers by conventional methods (such as silica gel chromatography). (Chem. Rev. 2010, 110, 3600).

[0558] Step 2: Where Y 1 、Y 2 、Y 3 、Y 4 and FG 1 Compounds according to formula (XXVIII) as defined above wherein x is 0, 1 or 2 can be obtained by reacting a compound of formula (XXVII) as defined above with allyl bromide in the presence of a strong base such as LiHMDS or NaH in an inert organic solvent such as THF at about room temperature to 60°C.

[0559] Step 3: Where Y 1 、Y 2 、Y 3 、Y 4 and FG 1 As defined above, compounds according to formula (XXIX) where x is 0, 1 or 2 can be obtained by reacting a compound of formula (XXVIII) as defined above with a metathesis catalyst such as a Grubbs II catalyst. The reaction is carried out in an inert organic solvent such as DCM at about room temperature to 40°C for a long reaction time. Optionally, the N-sulfinyl group is removed by treatment with a strong acid such as HCl in an organic solvent such as MeOH. (Chem. Soc. Rev. 2018, 47, 4510).

[0560] Step 4: Where Y 1 、Y 2 、Y 3 、Y 4 and n are as defined in formula (I) and FG 1 As defined above, s is 0, p is 0 and A is CH certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) can be obtained by reducing the compound of formula (XXIX) as defined by formula (I) with a metal catalyst such as Pd / C under a hydrogen atmosphere and room temperature for a long time. The reaction is carried out in an inert organic solvent such as MeOH, THF or EtOAc.

[0561] where Y 1 、Y 2 、Y 3 and Y 4 is CH, C-halogen or C-CF3, n is 1, p is 0 or 1, s is 0, A is CH2 is CH-R 2 , R 1 and R 2 As defined in formula (I) and FG 2 is CH2OH, CH2OMe or CH(OPG) 1 (OPG) 2 (PG 1 and PG 2 Certain compounds of formula (XVI), (XVIII) and (XIX) as defined above) can be prepared according to the method illustrated in Scheme TA5.

[0562] Solution TA5

[0563]

[0564] Step 1:

[0565] Compounds of formula (XVI), (XVIII) or (XIX) as defined in Scheme TA5 can be prepared by treating them with a metal catalyst such as PtO2 under a hydrogen atmosphere (1 bar to 5 bar) at about room temperature wherein Y 1 、Y 2 、Y 3 and Y 4 is CH, C-halogen or C-CF3, p is 0 or 1, R 1 As defined in formula (I) and FG 2 is CH2OH, CH2OMe or CH(OPG 1 )(OPG 2 )(PG 1 and PG 2 The compound of formula (XXX) is obtained in a longer time. The reaction can be carried out under acidic conditions, for example in HOAc or in HCl / MeOH or HCl / EtOH mixtures.

[0566] where Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I), n is 0, 1 or 2, p is 0 or 1, s is 0, A is CH2 or CH-R 2 And R 1 and R 2 As defined in formula (I) and FG 2 Certain compounds of formula (XVI), (XVIII) and (XIX) as defined above can be prepared according to the method illustrated in Scheme TA6.

[0567] Solution TA6

[0568]

[0569] Step 1: Where Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I), p is 0 or 1, R 1 As defined in formula (I) and FG 2 The compounds according to formula (XXXIII) as defined above may be prepared by making the compound wherein p is 0 or 1 and R 1 The compound of formula (XXXI) as defined in formula (I) and wherein Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I) and FG 2The compound of formula (XXXII) as defined above is obtained by reacting. The reaction is carried out in an inert organic solvent such as THF at a relatively low temperature, for example, about -78°C and under a nitrogen atmosphere, until the reaction is complete. The compound of formula (XXXII) can be prepared from the corresponding bromide according to the method described in Scheme TA3 (step 1). The compound of formula (XXXI) can be prepared by reacting the corresponding pyridine compound with benzyl bromide using conditions known to those skilled in the art.

[0570] Step 2: Where Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I), n is 0, 1 or 2, p is 0 or 1, s is 0, A is CH2 or CH-R 2 And R 1 and R 2 As defined in formula (I) and FG 2 Certain compounds of formula (XVI), (XVIII) and (XIX) as defined above can be obtained by reducing a compound of formula (XXXIII) as defined above with a metal catalyst such as Pd / C or Pd(OH) / C under a hydrogen atmosphere and room temperature for a longer period of time. The reaction is carried out in an inert organic solvent such as MeOH.

[0571] Step 3: Where Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I), p is 0 or 1, n is 0, 1 or 2, R 1 As defined in formula (I) and FG 2 The compounds according to formula (XXXVI) as defined above may be prepared by making wherein p is 0 or 1, n is 0, 1 or 2 and R 1 The compound of formula (XXXV) as defined in formula (I) and wherein Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I) and FG 2 The compound of formula (XXXIV) as defined above is obtained by reacting. The reaction is carried out in the presence of a palladium catalyst such as CataCXium A-Pd-G3 and a base such as K2CO3 or Cs2CO3 in an organic solvent such as a mixture of dioxane and water at a slightly elevated temperature, for example, 60°C to 100°C, for a relatively long reaction time. The compound of formula (XXXV) can also be prepared according to the method described in, for example, J.Org.Chem 2005, 70, 7324.

[0572] Step 4: Where Y 1 、Y2 、Y 3 and Y 4 As defined in formula (I), n is 0, 1 or 2, p is 0 or 1, s is 0, A is CH2 or CH-R 2 And R 1 and R 2 As defined in formula (I) and FG 2 Certain compounds of formula (XVI), (XVIII) and (XIX) as defined above can be obtained by reducing compounds of formula (XXXVI) as defined above with a metal catalyst such as Pd / C or Pd(OH) / C under a hydrogen atmosphere and room temperature for a long time. The reaction can be carried out in an inert organic solvent such as MeOH, optionally in the presence of an acid such as HOAc.

[0573] where Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I), n is 1, p is 0, s is 0 and A is O, FG 1 Certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) as defined above can be prepared according to the method illustrated in Scheme TA7.

[0574] Solution TA7

[0575]

[0576] Step 1: Make the Y 1 、Y 2 、Y 3 and Y 4 As defined in formula (I) and FG 1 The compound of formula (XXXVII) as defined above is reacted with a compound of formula (XXXVIII). The reaction is carried out in an inert organic solvent such as DCM in the presence of an organic amine base such as TEA (2 to 3 equivalents) at a temperature ranging from 0°C to 40°C (Angew. Chem. Int. Ed. Engl. 2008, 47, 3784).

[0577] where Y 3 and Y 4 As defined in formula (I) and Y 1 、Y 2 or Y 5 One of them is CQ (wherein Q and m are as defined in formula (I)) and FG 1 Certain compounds of formula (IX), (X), (XI) and (XII) as defined above can be prepared according to the method illustrated in Scheme TA8.

[0578] Solution TA8

[0579]

[0580] Step 1: Where Y 3 and Y 4 As defined in formula (I) and Y 1 、Y 2 or Y 5 The compound according to formula (XLI) wherein one of the components is CQ (wherein Q and m are as defined in formula (I)) can be prepared by making m as defined above, LG 3 and LG 4 The compound of formula (XXXIX) is obtained by reacting a compound of formula (XL) as defined above with a suitable leaving group, which may be the same or different, such as Cl, Br, I, OMs or OTs. The reaction is carried out in an inert organic solvent such as DMF in the presence of a strong base such as NaH at a temperature ranging from 0°C to 40°C.

[0581] Step 2: Where Y 3 and Y 4 As defined in formula (I) and Y 1 、Y 2 or Y 5 A compound according to formula (XLII) wherein one of the compounds is CQ (wherein Q and m are as defined in formula (I)) can be obtained by hydrolyzing a compound of formula (XLI) as defined above. The reaction is carried out in an alcoholic organic solvent such as n-butanol or the like, in the presence of a strong base such as NaOH or KOH, at a temperature ranging from 40° C. to 120° C. Optionally, the reaction can be carried out in the presence of water.

[0582] Step 3: Where Y 3 and Y 4 As defined in formula (I) and Y 1 、Y 2 or Y 5 One of them is CQ (wherein Q and m are as defined in formula (I)) and FG 1 Certain compounds of formula (IX), (X), (XI) and (XII) as defined above can be prepared by Curtius rearrangement of compounds of formula (XLII). The reaction can be carried out by treating with DPPA in an inert organic solvent such as THF, toluene, MeCN, acetone or the like in the presence of an alcohol (such as tert-butyl alcohol or BnOH) and an organic base (such as TEA or DIPEA) at a temperature range of about 20°C to 120°C. Standard conditions can then be used to deprotect the amine (e.g., Boc or Cbz). (ChemMedChem. 2018, 13, 2351).

[0583] where Y 1 、Y 2 、Y 3 and Y 4 is CH, C-halogen or C-CF3, Y 5 is CT (wherein T is as defined in formula (I)) and n is 1, p is 0 or 1, s is 0, A is CH2 or CH-R 2 , R 1 and R 2 As defined in formula (I) and FG 2 Certain compounds of formula (IX), (XI) and (XII) as defined above can be prepared according to the method illustrated in Scheme TA9.

[0584] Solution TA9

[0585]

[0586] Step 1: Place Y 1 、Y 2 、Y 3 and Y 4 is CH, C-halogen or C-CF3, p is 0 or 1, R 1 As defined in formula (I) and FG 2 Compounds of formula (XLIII) as defined above are treated with metal catalysts such as PtO under a hydrogen atmosphere (1 bar to 5 bar) and about room temperature for a long reaction time. The reaction can be carried out under acidic conditions, for example in HOAc or in a HCl / MeOH or HCl / EtOH mixture.

[0587] It should also be understood that in some reactions mentioned herein, any sensitive group in the protection compound may be needed / expected. In the case of needs or expectation protection, suitable protection method is well known to those skilled in the art. Conventional blocking groups can be used according to standard operation (for example, referring to " Protective groups in Organic Chemistry ", edited by J WF McOmie, Plenum Press (1973) and " Protective Groups in Organic Synthesis ", the 4th edition, TW Greene&P.GM Wutz, Wiley-Interscince (2007)). Therefore, if reactant includes group such as amino, aldehyde, carboxyl or hydroxyl, then it may be desired to protect this group in some reactions mentioned herein.

[0588] Suitable protecting groups for hydroxyl groups include optionally substituted and / or unsaturated alkyl groups (e.g., methyl, allyl, benzyl, or tert-butyl). Suitable protecting groups for carboxylic acids include (C1-C6) alkyl or benzyl esters. Suitable protecting groups for amino groups include allyl, tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, 9-fluorenylmethoxycarbonyl, 4-methylbenzenesulfinyl, tert-butylsulfinyl, or p-methoxybenzyl. Suitable protecting groups for aldehydes include acetals, such as dimethoxy, 1,3-dioxolane, or 1,3-dioxane.

[0589] Protecting groups can be removed at any convenient stage of the synthesis using conventional techniques well known in the chemical arts. Those skilled in the art will understand how to deprotect compounds comprising such groups (see "Protective groups in Organic Chemistry," edited by J.W. F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis," 4th edition, T.W. Greene & P. ​​G.M. Wutz, Wiley-Interscince (2007)).

[0590] It will be understood by those skilled in the art that certain compounds of the above formulae (V) to (XLIII) may also be referred to as "protected derivatives".

[0591] It will be appreciated by those skilled in the art that, in order to obtain the compounds disclosed herein in alternative and, in some cases, more convenient ways, the various process steps mentioned above may be performed in a different order and / or the various reactions may be performed at different stages in the overall route (i.e., substituents may be added to and / or chemically transformed in various intermediates than those mentioned above in connection with the specific reactions). This may obviate the need for protecting groups or necessitate such a need.

[0592] It will be understood by those skilled in the art that chiral isomers of the compounds herein can be resolved at any stage of the synthesis process using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatographic methods described in the literature and known to those skilled in the art, or as further described in the examples. Stereocenters can also be introduced by asymmetric synthesis. All stereoisomers are included within the scope of this disclosure.

[0593] Those skilled in the art will appreciate that a fluorinating agent such as DAST, XtalFluor-E, XtalFluor-M, or Deoxo-Fluor can be used to transfer a -C=O, -CHO, or C-OH group to -CF2, -CF2H, or CF, respectively (J. Org. Chem. 2010, 75, 3401).

[0594] It will be appreciated by those skilled in the art that the starting materials for any of the above methods are, in some cases, commercially available.

[0595] Those skilled in the art should understand that for some of the above raw materials, their preparation methods may be common knowledge.

[0596] It is also understood that some of the compounds described in the above methods may exhibit tautomerism and that the above methods encompass any tautomeric forms.

[0597] In another aspect, an intermediate disclosed herein is provided. In another aspect, an intermediate or salt or any stereoisomer thereof or a pharmaceutically acceptable salt thereof is provided. In another aspect, an intermediate or a salt thereof, such as a pharmaceutically acceptable salt thereof, is provided.

[0598] intermediates

[0599] Intermediate 1

[0600] 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl) tert-Butyl phenyl)piperidine-1-carboxylate

[0601]

[0602] Step A. (2-(Pyridin-2-yl)phenyl)methanol

[0603]

[0604] Benzo[c][1,2]oxaborolane-1(3H)-ol (50.4 g, 375.96 mmol) and 2M Na2CO3 aqueous solution (216 mL, 410.14 mmol) were added to a mixture of Pd(Ph3P)4 (3.95 g, 3.42 mmol) and 2-bromopyridine (32.6 mL, 341.78 mmol) in toluene (500 mL), and the mixture was stirred at 90 ° C until the reaction was complete (checked by LC-MS). The reaction was cooled to room temperature, the organic matter was separated and washed with water (600 mL). The product was extracted into HCl aqueous solution (1 M, 300 mL). The pH of the aqueous phase was adjusted to 10 with NaOH aqueous solution (3.8 M), and the product was stripped into EtOAc. The organic matter was dried (Na2SO4) and evaporated to dryness to give the crude product (53.9 g, 85%) as a yellow oil. MS (ESI): m / z [M+H] + 186.

[0605] Step B. (2-(Piperidin-2-yl)phenyl)methanol

[0606]

[0607] A solution of (2-(pyridin-2-yl)phenyl)methanol (168g, 907mmol) in AcOH (1200mL) was degassed with N2(g) for 30 minutes, followed by addition of platinum (IV) oxide (4.48g, 18.14mmol), the slurry transferred to a 3L hydrogenation reactor, and hydrogenated at 5 bar until the reduction was complete. The reaction mixture was filtered, most of the AcOH evaporated, and when the residue weighed approximately 380g, water (1L) was added, and the aqueous phase was washed twice with DCM (1L and 300mL). The combined DCM phases were washed with water (200mL), and the combined acidic aqueous phases were alkalized to pH 12-13 with a 50% NaOH aqueous solution to obtain a precipitate. The solid was filtered off, washed with water (3 x 500mL), and dried under vacuum at 45°C for 90 hours to give the title compound (148g, 87%) as a solid. 1 H NMR(400MHz,DMSO)d 1.3-1.61(4H,m),1.69(1H,d),1.83(1H,d),2.26(1H,s),2.59-2.74(1H,m),3.01(1H,d),3.7 1-3.82(1H,m),4.56(2H,dd),5.67(1H,s),7.16-7.26(2H,m),7.33(1H,dd),7.43-7.5(1H,m).

[0608] Step C. tert-Butyl 2-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate

[0609]

[0610] Boc2O (12.44 g, 57.0 mmol) dissolved in DCM (40 mL) was added to a solution of (2-(piperidin-2-yl)phenyl)methanol (10.9 g, 57.0 mmol) and DIPEA (19.91 mL, 114 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature overnight. The reaction was washed with water (2×100 mL), dried (through a phase separator) and evaporated in vacuo to give 26 g of crude product, which was purified by flash chromatography using a gradient of 0% to 25% EtOAc in heptane as the mobile phase to give the title compound (15.2 g, 92%) as a clear oil. MS (ESI): m / z [M+H] + 292.

[0611] Step D. tert-Butyl 2-(2-formylphenyl)piperidine-1-carboxylate

[0612]

[0613] Sulfur trioxide pyridine complex (7.37 g, 46.33 mmol) dissolved in DMSO (21 mL) was added dropwise to a cold mixture of tert-butyl 2-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate (6.75 g, 23.2 mmol), TEA (11.2 mL, 81.1 mmol) and DMSO (14 mL) (approximately 14°C, the internal temperature never exceeded 25°C). The resulting mixture was stirred at room temperature for 2 hours. MTBE (250 mL) and saturated aqueous NaHCO3 solution (150 mL) were added, the organic phase was separated, and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered, and evaporated to give the crude title compound (6.60 g, 98%) as an amber oil. MS (ESI): m / z [M+H] + 290.

[0614] Step E. 2-(2-(((2-(Ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)piperidine-1-carboxylic acid tert-Butyl ester

[0615]

[0616] NaBH3CN (1.564g, 24.88mmol) is added to a mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (4.35g, 22.81mmol), DIPEA (3.97mL, 22.81mmol), 2-(2-formylphenyl)piperidine-1-carboxylic acid tert-butyl ester (6.0g, 20.7mmol), AcOH (2.39mL, 41.5mmol) and EtOH (99.5%) (60mL) in five batches (exothermic) to give a brown mixture. The reaction is stirred at room temperature overnight, quenched with water and evaporated. The crude product is absorbed in a mixture of DCM and saturated NaHCO3 aqueous solution. The DCM phase is dried and evaporated through a phase separator to give a crude product (12.07g) as an amber oil. MS (ESI): m / z[M+H] + 428.

[0617] Step F. 2-(2-((3-Benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)benzene tert-Butyl)piperidine-1-carboxylate

[0618]

[0619] Benzoyl isothiocyanate (0.164 mL, 1.22 mmol) was added to a solution of tert-butyl 2-(2-((2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)methyl)phenyl)piperidine-1-carboxylate (0.52 g, 1.22 mmol) in DCM (5 mL) and stirred at room temperature overnight. The solvent was removed in vacuo to give the crude title compound (0.730 g, 102%) as an orange solid, which was used in the next step without purification. MS (ESI): m / z [M+H] + 591.

[0620] Step G. 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-1- tert-Butyl)methyl)phenyl)piperidine-1-carboxylate.

[0621] A mixture of tert-butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)piperidine-1-carboxylate (15.8 g, 26.75 mmol) in MeOH (80 mL) was treated with CsCO (17.43 g, 53.49 mmol) and stirred at 50° C. under an atmosphere of N(g) for 3 hours. The solvent was removed in vacuo and the residue was dissolved in water (150 mL). The pH was adjusted to about 6 with AcOH and extracted with EtOAc (3×150 mL). The solid particles formed were filtered off to give (3.63 g) of the crude title compound. The organics were dried (MgSO₄) and evaporated in vacuo to give an additional (10.21 g) of the crude title compound as a yellow oil. MS (ESI): m / z[M+H] + 441.

[0622] Intermediate 2

[0623] 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin 4-pyridinone

[0624]

[0625] Step A. tert-Butyl 2-(5-chloro-2-(hydroxymethyl)phenyl)piperidine-1-carboxylate

[0626]

[0627] A solution of (4-chloro-2-(piperidin-2-yl)phenyl)methanol hydrochloride (5 g, 19.07 mmol, free base CAS Reg. No. 1447109-22-9), DIPEA (6.64 mL, 38.14 mmol) and Boc2O (4.82 mL, 20.98 mmol) in DCM (100 mL) was stirred at room temperature for 5 hours. The mixture was washed with water (2 x 200 mL), dried over MgSO4 and evaporated. The crude product was purified by flash chromatography using 100% EtOAc as the mobile phase to give (5.61 g, 90%) of the title compound. MS (ESI): m / z [M+H] + 326.

[0628] Step B. tert-Butyl 2-(5-chloro-2-formylphenyl)piperidine-1-carboxylate

[0629]

[0630] A mixture of tert-butyl 2-(5-chloro-2-(hydroxymethyl)phenyl)piperidine-1-carboxylate (5.5 g, 16.88 mmol) and pyridinium chlorochromate (5.46 g, 25.32 mmol) in DCM (200 mL) was stirred at room temperature for 1 hour. Celite (10 g) was added, followed by Et2O (100 mL) to give a black precipitate. The precipitated crude product was purified by flash chromatography using 100% EtOAc as the mobile phase, followed by a second flash chromatography using 10% EtOAc in heptane as the mobile phase to give (3.64 g, 67%) of the title compound. MS (ESI): m / z[M+H] + 324.

[0631] Step C. 2-(5-chloro-2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)piperidine- 1- tert-Butyl carboxylate

[0632]

[0633] NaCNBH (233 mg, 3.71 mmol) was added to a solution of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (648 mg, 3.40 mmol), DIPEA (0.592 mL, 3.40 mmol), 2-(5-chloro-2-formylphenyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.09 mmol) and AcOH (0.357 mL, 6.18 mmol) in EtOH (100 mL). The reaction was stirred at room temperature for 3 hours, quenched with water and evaporated. The crude product was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a 30%-95% MeCN gradient of H O / MeCN / FA (95 / 5 / 0.2) buffer system as the mobile phase to give (771 mg, 58%) of the title compound. 1 HNMR(400MHz,CDCl3)d 1.22–1.4(m,12H),1.52–1.8(m,4H),1.8–2.02(m,2H),3.03–3.34(m,1H),3.94–4.11(m,1H),4.16–4.5 7(m,4H),5.21(t,1H),5.63(t,1H),6.68(s,1H),7.16(dd,1H),7.28(dd,1H),7.36(d,1H),8.18(s,1H).

[0634] Step D. 2-(2-((3-Benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)- tert-Butyl 5-chlorophenyl)piperidine-1-carboxylate

[0635]

[0636] Benzoyl isothiocyanate (0.110 mL, 0.82 mmol) was added to a solution of tert-butyl 2-(5-chloro-2-((2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)methyl)phenyl)piperidine-1-carboxylate (315 mg, 0.68 mmol) in DCM (50 mL), and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo to give (426 mg, 100%) of the crude product as an orange gum which was used without purification. MS (ESI): m / z [M+H] + 626.

[0637] Step E. 2-(5-chloro-2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidinyl) ... tert-Butyl)piperidin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0638]

[0639] CsCO (1.605 g, 4.93 mmol) was added to a solution of tert-butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)-5-chlorophenyl)piperidine-1-carboxylate (1.54 g, 2.46 mmol) in MeOH (7 mL) and the reaction was stirred at 50° C. under an N(g) atmosphere for 3 hours. The solvent was removed in vacuo and the residue was dissolved in water (25 mL), the pH adjusted to about 6 with AcOH, and then extracted with EtOAc (3×50 mL). The combined organic phases were dried (MgSO ), filtered, and evaporated in vacuo. The crude product was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×50 mm ID) using a 20% to 70% MeCN gradient in H 2 O / MeCN / FA (95 / 5 / 0.2) as the mobile phase to afford (1.0 g, 85%) the title compound as a yellow / white solid which was used in the next step without purification. MS (ESI): m / z [M+H] + 475.

[0640] Step F. 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3, 2-d]pyrimidin-4-one

[0641] tert-Butyl 2-(5-chloro-2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate (215 mg, 0.45 mmol) was added to a mixture of DCM (8 mL) and TFA (2 mL) to give a colorless solution. The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the crude product was taken up in EtOAc, washed with water, filtered through a phase separator and evaporated to give the title compound in quantitative yield as a white solid. MS (ESI): m / z[M+H] + 375.

[0642] Intermediate 3

[0643] 2-(5-chloro-2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl) tert-Butyl)methyl)phenyl)pyrrolidine-1-carboxylate

[0644]

[0645] Step A. tert-Butyl 2-(5-chloro-2-(hydroxymethyl)phenyl)pyrrolidine-1-carboxylate

[0646]

[0647] DCM (50 mL) and TEA (6.35 mL, 45.83 mmol) were added to a mixture of (4-chloro-2-(pyrrolidin-2-yl)phenyl)methanol (CAS Reg. No. 1391024-08-0) (4.62 g, 21.82 mmol) and Boc2O (5.00 g, 22.92 mmol), and the reaction mixture was stirred at room temperature overnight. DCM (100 ml) was added, and the organic phase was washed with water (40 mL), dried through a phase separator and evaporated to give the crude title compound in quantitative yield, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 312.

[0648] Step B. tert-Butyl 2-(5-chloro-2-formylphenyl)pyrrolidine-1-carboxylate

[0649]

[0650] Sulfur trioxide pyridine complex (611 mg, 3.84 mmol) was added in batches to a mixture of tert-butyl 2-(5-chloro-2-(hydroxymethyl)phenyl)pyrrolidine-1-carboxylate (598 mg, 1.92 mmol) and TEA (0.930 mL, 6.71 mmol) in DMSO (5 mL), and the reaction was stirred at room temperature for 1.5 hours. The mixture was diluted with MTBE (100 ml), washed with saturated NaHCO3 aqueous solution (40 mL) and water (40 mL) and dried (MgSO4). Filtration and subsequent evaporation of the solvent gave (559 mg, 94%) of the title compound. MS (ESI): m / z[M+H] + 310.

[0651] Step C. 3-((2-(1-(tert-Butyloxycarbonyl)pyrrolidin-2-yl)-4-chlorobenzyl)amino)-1H-pyrrole-2-carboxylic acid Ethyl acetate

[0652]

[0653] By 2-(5-chloro-2-formylphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.552g, 1.78mmol), 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.375g, 1.97mmol) and TEA (0.296mL, 2.14mmol) mixture in MeOH (15mL) stirred 30 minutes.At room temperature add AcOH (0.204mL, 3.56mmol), then add NaCNBH (0.112g, 1.78mmol), and reaction mixture is stirred at room temperature 1 hour.Evaporating solvent, residue is dissolved in DCM (70mL), and washed with water (30mL), by phase separator drying. Evaporation of the solvent gave the crude product (0.85 g), which was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 ID mm) using a 30% to 70% MeCN gradient in H 2 O / MeCN / NH 3 (95 / 5 / 0.2) as the mobile phase to afford (380 mg, 48%) the title compound. MS (ESI): m / z [M+H] + 448.

[0654] Step D. 3-(3-Benzoyl-1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-chlorobenzyl)thiourea (Methyl)-1H-pyrrole-2-carboxylate

[0655]

[0656] Benzoyl isothiocyanate (0.11 mL, 0.81 mmol) was added to a solution of ethyl 3-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-chlorobenzylamino)-1H-pyrrole-2-carboxylate (365 mg, 0.81 mmol) in DCM (5 mL), and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated to give the crude product (499 mg, 100%), which was used in the next step without purification. MS (ESI): m / z [M+H] + 611.

[0657] Step E. 2-(5-chloro-2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidinyl) ... tert-Butyl)pyridin-1-yl)methyl)phenyl)pyrrolidine-1-carboxylate

[0658] A mixture of ethyl 3-(3-benzoyl-1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-chlorobenzyl)thioureido)-1H-pyrrole-2-carboxylate (4.20 g, 6.88 mmol) and Cs2CO3 (4.48 g, 13.76 mmol) in MeOH (50 mL) was heated to 65°C for 4 hours. The solvent was evaporated, water (80 mL) was added to the residue, and the pH was adjusted to 6 with AcOH and extracted with EtOAc (4×50 mL). The organic phase was separated and dried (MgSO4). The solvent was evaporated to give the crude product (3.7 g), which was slurried in DMSO / water. The precipitate was filtered and washed with water and a small amount of MeOH to give (3.2 g, 100%) of the title compound. MS (ESI): m / z[M+H] + 461.

[0659] Intermediate 4

[0660] 3-(5-chloro-2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl) tert-Butyl)methyl)phenyl)morpholine-4-carboxylate

[0661]

[0662] Step A. 1-((Allyloxy)methyl)-2-bromo-4-chlorobenzene

[0663]

[0664] NaH (0.542 g, 22.6 mmol) was added in portions to a solution of (2-bromo-4-chlorophenyl)methanol (CAS registration number 143888-84-0) (5 g, 22.6 mmol) and 3-bromoprop-1-ene (2.05 mL, 23.7 mmol) in toluene (50 mL) and THF (50 mL), and the reaction was stirred at room temperature for 4 hours. Additional NaH (0.30 g, 12.5 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with EtOAc (200 mL) and washed with 0.25 M HCl aqueous solution (100 mL) and brine (100 mL). The organic phase was dried (MgSO4) and evaporated to give (5.60 g) of crude product which was purified by flash chromatography using 20% ​​EtOAc in heptane as the mobile phase followed by a second flash chromatography using 10% EtOAc in heptane as the mobile phase to give (4.36 g, 74%) of the title compound. 1H NMR (500MHz, CDCl3) δ4.08–4.13(2H,m),4.54(2H,s),5.21–5.27(1H,m),5.31–5.39(1H,m),5.97(1H,ddt),7.30(1H,dd),7.44(1H,dt),7.55(1H,d).

[0665] Step B. (2-((Allyloxy)methyl)-5-chlorophenyl)magnesium chloride

[0666]

[0667] Under N2(g) atmosphere, iPrMgCl×LiCl (1.3M, 18.99mL, 24.69mmol) was added to a cold (0°C) solution of 1-(allyloxymethyl)-2-bromo-4-chlorobenzene (5.87g, 22.44mmol) in THF (50mL). The reaction mixture was allowed to reach room temperature over 5 hours and then stirred at room temperature for 16 hours. Prior to use, the solution was stored at -20°C under N2(g) atmosphere.

[0668] Step C. tert-Butyl 3-oxomorpholine-4-carboxylate

[0669]

[0670] The Boc that is dissolved in anhydrous THF (30mL) O (11.87g, 54.40mmol) is added in anhydrous THF (60mL) solution of morpholine-3-one (CAS registration number 109-11-5) (5g, 49.45mmol) and DMAP (6.65g, 54.40mmol), and reaction mixture is at room temperature stirred 3 hours.Evaporation removes solvent, and crude product is absorbed among the EtOAc, uses NaHCO The aqueous solution and water washing.With organic phase drying (MgSO ), and evaporation removes solvent, obtains crude product, it is passed through purified by flash chromatography, uses the heptane solution that gradient is 10%-80% EtOAc as mobile phase, obtains (8.37g, 84%) title compound, is white solid. 1 H NMR (400MHz, CDCl3) δ1.55(s,9H),3.68-3.81(m,2H),3.83-3.95(m,2H),4.23(s,2H).

[0671] Step D. (2-(2-(2-((allyloxy)methyl)-5-chlorophenyl)-2-oxoethoxy)ethyl)carbamic acid tert-Butyl ester

[0672]

[0673] (2-((allyloxy)methyl)-5-chlorophenyl)magnesium chloride (41.3mL, 12.35mmol) was cooled to -30°C and introduced into a solution of tert-butyl 3-oxomorpholine-4-carboxylate (2.58g, 12.84mmol) in THF (30mL) also at -30°C. The reaction mixture was allowed to reach room temperature and spent overnight, diluted with DCM (200mL), and washed with saturated NH4Cl aqueous solution (80mL) and brine (80mL). The organic phase was dried with a phase separator and evaporated. The crude product was purified by flash chromatography using a gradient of 0%-40% EtOAc in heptane as the mobile phase to give (3.70g, 78%) of the title compound as a yellow oil. MS (ESI): m / z[M+H] + 384.

[0674] Step E. 3-(2-((allyloxy)methyl)-5-chlorophenyl)morpholine

[0675]

[0676] Acetyl chloride (20.1 mL, 282 mmol) was added dropwise to a cold (0 ° C) solution of tert-butyl (2-(2-(2-((allyloxy)methyl)-5-chlorophenyl)-2-oxoethoxy)ethyl)carbamate (5.41 g, 14.09 mmol) in MeOH (120 mL). After stirring at 0 ° C for 10 minutes, the reaction was allowed to reach room temperature and stirred for 2 hours. Additional acetyl chloride (11.1 g, 140 mmol) was added and the reaction was stirred until LCMS showed that the imine was completely formed in situ. NaBH3CN (8.86 g, 141 mmol) was added and the reaction was stirred for 30 minutes. The reaction was quenched with water, the pH was adjusted to 8 with saturated aqueous NaHCO3, and the reaction mixture was extracted with DCM. The organic phase was dried using a phase separator and concentrated to give (3.58 g, 95%) of the title compound as a yellow oil. MS (ESI): m / z [M+H] + 268.

[0677] Step F. tert-Butyl 3-(2-((allyloxy)methyl)-5-chlorophenyl)morpholine-4-carboxylate

[0678]

[0679] BocO (3.81 g, 17.44 mmol) was added to a solution of 3-(2-((allyloxy)methyl)-5-chlorophenyl)morpholine (4.245 g, 15.85 mmol) in DCM (100 mL), followed by the addition of TEA (4.62 mL, 33.29 mmol), and the reaction was stirred at room temperature overnight. DCM (50 mL) was added, the organic phase was washed with salt water (20 mL) and dried over a phase separator. The solvent was evaporated to give the crude product, which was purified by flash chromatography using a gradient of 0%-40% EtOAc in heptane as the mobile phase to give (2.70 g, 46%) of the title compound as a yellow solid. 1 H NMR(400MHz, CDCl3)δ1.35(9H,s),3.4-3.5(1H,m),3.68(1H,td),3.73-3.79(1H,m),3.87(1H,dd),3.95-4.03(4H,m),4.37(1H,d) ,4.74(1H,d),5.05-5.09(1H,m),5.17-5.22(1H,m),5.26-5.32(1H,m),5.87-5.98(1H,m),7.23(1H,dd),7.31(1H,d),7.66(1H,d).

[0680] Step G. tert-Butyl 3-(5-chloro-2-(hydroxymethyl)phenyl)morpholine-4-carboxylate

[0681]

[0682] A mixture of tert-butyl 3-(2-(allyloxymethyl)-5-chlorophenyl)morpholine-4-carboxylate (1.226 g, 3.33 mmol), PdCl2 (0.812 g, 4.58 mmol) and NaOAc (0.902 g, 11.00 mmol) was heated in AcOH (20 mL) and water (80 μl) at 50° C. for 3 hours. The reaction was diluted with DCM (150 mL) and washed with saturated aqueous NaHCO3 (3×30 mL). The organic phase was dried using a phase separator and evaporated. The crude product was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 ID mm) using a 20%-60% MeCN gradient in H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase to give (816 mg, 75%) of the title compound. MS (ESI): m / z [MH] + 326.

[0683] Step H. tert-Butyl 3-(5-chloro-2-formylphenyl)morpholine-4-carboxylate

[0684]

[0685] Sulfur trioxide pyridine complex (792 mg, 4.98 mmol) dissolved in DMSO (3 mL) was added dropwise to a solution of tert-butyl 3-(5-chloro-2-(hydroxymethyl)phenyl)morpholine-4-carboxylate (816 mg, 2.49 mmol) and TEA (1.208 mL, 8.71 mmol) in DMSO (2 mL) at 17° C., and the mixture was stirred for 16 hours. The reaction mixture was diluted with MTBE (100 mL), washed with saturated aqueous NaHCO 3 solution (40 mL), water (40 mL) and dried (MgSO 4 ). The solvent was evaporated to give (770 mg, 95%) of the title compound. MS (ESI): m / z [M+H] + 326.

[0686] Step I. 3-(5-chloro-2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)morpholine- 4- tert-Butyl carboxylate

[0687]

[0688] 3-(5-chloro-2-formylphenyl)morpholine-4-carboxylic acid tert-butyl ester (770mg, 2.36mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (451mg, 2.36mmol) are dissolved in MeOH (15mL) and TEA (0.393mL, 2.84mmol), and the mixture is stirred at room temperature for 10 minutes.Add AcOH (0.271mL, 4.73mmol), and the mixture is stirred at room temperature for another 10 minutes.Add NaBH3CN (149mg, 2.36mmol), and the mixture is stirred at room temperature for 4 hours.Evaporating solvent, residue is diluted with DCM (100mL), washed with water (40mL), and dried with phase separator. Evaporation gave the crude product (1.2 g), which was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 ID mm) using a 35% to 75% MeCN gradient in H 2 O / MeCN / NH 3 (95 / 5 / 0.2) buffer as the mobile phase to afford (600 mg, 55%) the title compound. MS (ESI): m / z [M+H] + 464.

[0689] Step J. 3-(2-((3-Benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)- tert-Butyl 5-chlorophenyl)morpholine-4-carboxylate

[0690]

[0691] Benzoyl isothiocyanate (0.173 mL, 1.28 mmol) was added to a solution of tert-butyl 3-(5-chloro-2-((2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)methyl)phenyl)morpholine-4-carboxylate (595 mg, 1.28 mmol) in DCM (12 mL), and the reaction was stirred at room temperature for 3 hours. The solvent was evaporated to give the title compound (998 mg). MS (ESI): m / z [M+H] + 627.

[0692] Step K. 3-(5-chloro-2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidinyl) ... tert-Butyl)pyridin-1-yl)methyl)phenyl)morpholine-4-carboxylate

[0693] Cs2CO3 (834 mg, 2.56 mmol) was added to a solution of tert-butyl 3-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)-5-chlorophenyl)morpholine-4-carboxylate (803 mg, 1.28 mmol) in MeOH (10 mL), and the mixture was heated at 65°C for 6 hours. The solvent was evaporated, water (50 mL) was added to the residue, and the aqueous phase was acidified to pH 4 with AcOH and extracted with EtOAc (3×50 mL). The organic phase was dried (MgSO4) and evaporated to give (836 mg) of the crude title compound. MS (ESI): m / z[M+H] + 477.

[0694] Intermediate 5

[0695] 3-(5-chloro-2-((6-oxo-2-thiocarbonyl-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)phenyl) tert-Butyl 4-Methyl-1-piperidin-4-carboxylate

[0696]

[0697] Step A. 3-(2-(((5-Carbamoyl-1H-imidazol-4-yl)amino)methyl)-5-chlorophenyl)morpholine-4-carboxylic acid Tert-butyl ester

[0698]

[0699] AcOH (0.054 mL, 0.94 mmol) is added to a solution of tert-butyl 3-(5-chloro-2-formylphenyl)morpholine-4-carboxylate intermediate 4 step H (305 mg, 0.94 mmol) and 4-amino-1H-imidazole-5-carboxamide (CAS registration number 21299-72-9) (118 mg, 0.94 mmol) in EtOH (10 mL), and the reaction is heated at 70 ° C for 16 hours. The solvent is evaporated, and the residue is dissolved in MeOH (20 mL) and cooled on an ice bath. NaBH3CN (35.4 mg, 0.94 mmol) is added, the reaction is stirred at 0 ° C for 2 hours, and stirred at room temperature for 16 hours. Additional EtOH (20 mL) is added, followed by NaBH3CN (15 mg, 0.40 mmol), and stirring is continued at room temperature for 3 hours. The solvent was evaporated and the residue was partitioned between DCM (40 mL) and brine / saturated NH4Cl solution (1 / 1) (40 mL). The aqueous layer was extracted with DCM (2×30 ml) and the combined organic phases were evaporated. The crude product was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 ID mm) using a gradient of 15% to 60% MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) buffer as the mobile phase to give (343 mg, 84%) of the title compound. MS (ESI): m / z [M+H] + 436.

[0700] Step B. 3-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thiourea)methyl)-5- tert-Butyl (chlorophenyl)morpholine-4-carboxylate

[0701]

[0702] Benzoyl isothiocyanate (0.337 mL, 2.51 mmol) was added to a solution of tert-butyl 3-(2-((5-carbamoyl-1H-imidazol-4-ylamino)methyl)-5-chlorophenyl)morpholine-4-carboxylate (910 mg, 2.09 mmol) in MeCN (30 mL), and the reaction was stirred at room temperature for 18 hours. The solvent was evaporated to give the crude product, which was used in the next step without purification. MS (ESI): m / z [M+H] + 599.

[0703] Step C. 3-(5-chloro-2-((6-oxo-2-thiocarbonyl-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)benzene tert-Butyl morpholine-4-carboxylate

[0704] Tert-butyl 3-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)-5-chlorophenyl)morpholine-4-carboxylate (1252 mg, 2.09 mmol) was dissolved in a mixture of EtOH (40 mL) and 1 M NaOH (6.27 mL, 6.27 mmol), and the mixture was heated at 78 ° C for 16 hours. The reaction was quenched with 1 M HCl (5 mL) and concentrated. The crude product was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 ID mm) using a gradient of 5% to 50% MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) buffer as the mobile phase to give (566 mg, 57%) of the title compound. MS (ESI): m / z[M+H] + 478.

[0705] Intermediate 6

[0706] 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl) tert-Butyl phenyl)azepane-1-carboxylate

[0707]

[0708] Step A. (2-((Allyloxy)methyl)phenyl)magnesium chloride

[0709]

[0710] iPrMgCl×LiCl (1.3 M, 130 mL, 169.5 mmol) was added to a cold (0° C.) solution of 1-(allyloxymethyl)-2-bromobenzene (CAS Reg. No. 1447109-22-9) (35 g, 154.1 mmol) in THF (100 mL). The reaction mixture was allowed to reach room temperature over 5 hours and then stirred at room temperature for 16 hours. This reagent was used as is in the next step.

[0711] Step B. tert-Butyl (6-(2-((allyloxy)methyl)phenyl)-6-oxohexyl)carbamate

[0712]

[0713] (2-((allyloxy)methyl)phenyl)magnesium chloride (25 g, 145.77 mmol) (the above reaction mixture) was cooled to -5°C and introduced into a solution of tert-butyl 2-oxoazepane-1-carboxylate (CAS Reg. No. 106412-36-6) (40.4 g, 189.51 mmol) in THF (100 mL) at -5°C, and the temperature must not exceed -3°C. The reaction mixture was allowed to reach room temperature over 6 hours and then stirred at room temperature for 16 hours. The reaction was quenched by the addition of aqueous NH4Cl solution (20 mL). EtOAc (200 mL) was added and the phases were separated. The organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by flash chromatography using a gradient of 5%-20% EtOAc in heptane as the mobile phase to give (16 g, 30%) of the title compound. MS (ESI): m / z[M+H] + 362.

[0714] Step C. 2-(2-((Allyloxy)methyl)phenyl)azepane

[0715]

[0716] TFA (2.131mL, 27.66mmol) is added to a DCM (10mL) solution of tert-butyl 6-(2-(allyloxymethyl)phenyl)-6-oxohexylcarbamate (1g, 2.77mmol), and the mixture is stirred at room temperature for 30 minutes. The solvent is removed by evaporation and co-evaporated with toluene (3×50mL). The residue is absorbed in MeOH (10mL) and NaBH3CN (0.191g, 3.04mmol) is added. The mixture is stirred at room temperature for 20 hours. DIPEA (0.580mL, 3.32mmol) is added, and the mixture is stirred for another 20 hours. Only the intermediate imine is observed in LCMS. H2SO4 (0.147mL, 2.77mmol) is added dropwise, effervescence occurs, and the reaction is completed in 30 minutes. The crude product was purified by flash chromatography using a gradient of heptane / EtOAc / saturated NH3 in MeOH (50 / 50 / 0 to 0 / 90 / 10) to give (0.52 g, 77%) of the title compound as a colorless oil. MS (ESI): m / z [M+H] + 246.

[0717] Step D. tert-Butyl 2-(2-((allyloxy)methyl)phenyl)azepane-1-carboxylate

[0718]

[0719] To a solution of 2-(2-(allyloxymethyl)phenyl)azepane (1.08 g, 4.40 mmol) and DIPEA (0.923 mL, 5.28 mmol) in DCM (10 mL) was added Boc2O (1.06 g, 4.84 mmol) at 0°C and the mixture was allowed to reach room temperature over 30 minutes. The reaction mixture was concentrated and the crude product was purified by flash chromatography using a gradient of 10% to 70% EtOAc in heptane as the mobile phase to afford (0.96 g, 63%) of the title compound. MS (ESI): m / z [M+H] + 346.

[0720] Step E. tert-Butyl 2-(2-(hydroxymethyl)phenyl)azepane-1-carboxylate

[0721]

[0722] PdCl2 (2.66 g, 15.02 mmol) and NaOAc (2.71 g, 33.05 mmol) were added to a solution of tert-butyl 2-(2-(allyloxymethyl)phenyl)azepane-1-carboxylate (3.46 g, 10.02 mmol) in AcOH (20 mL) and 20 drops of water. The mixture was stirred at 50 ° C for 2 hours. DCM (130 mL) was added and the organic phase was washed with saturated NaHCO3 aqueous solution (3×30 mL). The organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by flash chromatography using a gradient of 10%-90% EtOAc in heptane as the mobile phase to give (2.26 g, 74%) of the title compound. MS (ESI): m / z[M+H] + 306.

[0723] Step F. tert-Butyl 2-(2-formylphenyl)azepane-1-carboxylate

[0724]

[0725] DIPEA (4.38ml, 25.05mmol) is added to a solution of tert-butyl 2-(2-(hydroxymethyl)phenyl)azepane-1-carboxylate (2.186g, 7.16mmol) in DMSO (4.4mL), followed by dropwise addition (5 minutes) of a sulfur trioxide pyridine complex (2.278g, 14.32mmol) dissolved in DMSO (6.7mL). The mixture is stirred at room temperature for 2 hours. MTBE (100mL) is added, and the organic phase is washed with saturated NaHCO aqueous solution (40mL) and water (40mL). The organic phase is dried (MgSO4) and evaporated to give (82.6g) of the thick title compound.

[0726] Step G. 2-(2-(((2-(Ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)azepane- tert-Butyl 1-carboxylate

[0727]

[0728] A mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (1.960g, 10.28mmol), DIPEA (1.79mL, 10.3mmol), AcOH (1.09mL, 18.85mmol) in 99.5% EtOH (20mL) was added to 2-(2-formylphenyl) azepane-1-carboxylic acid tert-butyl ester (2.6g, 8.57mmol) to obtain a brown solution. The solution was stirred for 15 minutes, and then NaBH was added within 5 minutes. CN (0.727g, 11.57mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30mL) and MTBE (100mL) was added. The layers were separated and the organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using a heptane solution of 10%-80% EtOAc as a mobile phase to obtain (2.58g, 68%) title compound. MS (ESI): m / z [M+H] + 441.

[0729] Step H. 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)benzene tert-Butyl)azepane-1-carboxylate

[0730]

[0731] Benzoyl isothiocyanate (0.947 mL, 7.05 mmol) was added to a solution of tert-butyl 2-(2-((2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)methyl)phenyl)azepane-1-carboxylate (2.58 g, 5.84 mmol) in DCM (50 mL), and the reaction was stirred at room temperature for 4 hours. The solvent was removed in vacuo to give (3.5 g, 99%) of the crude product, which was used in the next step without purification. MS (ESI): m / z [M+H] + 605.

[0732] Step I. 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-1- tert-Butyl)methyl)phenyl)azepane-1-carboxylate

[0733] CsCO (2.263 g, 6.94 mmol) was added (slightly exothermic) to a solution of tert-butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)azepane-1-carboxylate (3.5 g, 5.79 mmol) in MeOH (100 mL), and the reaction was stirred at 50° C. under an N(g) atmosphere for 3 hours. The mixture was concentrated in vacuo, and the crude product was purified by flash chromatography using a gradient of 10% to 80% EtOAc in heptane to give (1.70 g, 65%) of the title compound. MS (ESI): m / z [M+H] + 455.

[0734] Intermediate 7

[0735] (R)-2-(5-chloro-2-((6-oxo-2-thiocarbonyl-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)benzene tert-Butyl)azepane-1-carboxylate

[0736]

[0737] Step A. (S,E)-N-(2-bromo-5-chlorobenzylidene)-2-methylpropane-2-sulfenamide

[0738]

[0739] (S)-2-Methylpropane-2-sulfenamide (5.63 g, 46.48 mmol) was added to a solution of 2-bromo-5-chlorobenzaldehyde (10 g, 45.57 mmol) in DCM (300 mL), followed by the addition of CsCO (14.85 g, 45.57 mmol). The mixture was refluxed until LC-MS showed complete conversion. The mixture was diluted with brine and DCM. The DCM layer was dried through a phase separator and then evaporated to give (14.77 g, 100%) of the title compound as a yellow oil. MS (ESI): m / z [M+H] + 322.

[0740] Step B. (S)-N-(1-(2-Bromo-5-chlorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfenamide

[0741]

[0742] Flask 1: Cerium (III) chloride (99 mg, 0.40 mmol) was added to a round-bottom flask and then dried under vacuum with a heat gun. THF (4 mL) was added and the mixture was cooled to -78°C. But-3-enyl magnesium bromide (2.42 mL, 1.21 mmol) was added dropwise over 15 minutes (a white suspension was observed). The mixture was stirred at -78°C for 30 minutes and then allowed to reach room temperature.

[0743] Flask 2: (S,E)-N-(2-bromo-5-chlorobenzylidene)-2-methylpropane-2-sulfenamide (100 mg, 0.29 mmol) was dissolved in THF (1 mL) and cooled to -78°C. The solution from flask 1 was added in one portion. The resulting mixture was stirred at -78°C for 2 minutes. The reaction was quenched with saturated aqueous NH4Cl in an ice bath and extracted with EtOAc. The solvent was evaporated and the residue was co-evaporated with DCM to give (110 mg, 94%) of the title compound as a colorless oil (mixture of diastereomers). MS (ESI): m / z [M+H] + 378.

[0744] Step C. (S)-N-allyl-N-(1-(2-bromo-5-chlorophenyl)pent-4-en-1-yl)-2-methylpropane-2-ylene Sulfonamide

[0745]

[0746] Allyl bromide (6.85 mL, 79.21 mmol) was added to a solution of (S)-N-(1-(2-bromo-5-chlorophenyl)pent-4-enyl)-2-methylpropane-2-sulfinamide (6.0 g, 15.84 mmol) in THF (40 mL), followed by the addition of LiHMDS (63.4 mL, 63.37 mmol), and the reaction was stirred at room temperature overnight and then heated at 40 ° C overnight. The reaction was cooled in an ice bath and quenched with saturated aqueous NH4Cl. The mixture was extracted with DCM and evaporated. The crude product was purified by flash chromatography using a gradient of 0% to 20% EtOAc in heptane as the mobile phase to give (4.0 g, 60%) of the title compound (mixture of diastereomers). MS (ESI): m / z [M+H] + 418.

[0747] Step D. (R)-2-(2-Bromo-5-chlorophenyl)-1-((S)-tert-butylsulfinyl)-2,3,4,7-tetrahydro-1H-nitrogen Miscellaneous

[0748]

[0749] Under N2(g) atmosphere, GrubbsII catalyst (0.231 g, 0.27 mmol, CAS Reg. No. 246047-72-3) was added to a solution of (S)-N-allyl-N-(1-(2-bromo-5-chlorophenyl)pent-4-enyl)-2-methylpropane-2-sulfinamide (3.8 g, 9.07 mmol) in DCM (800 ml). The reaction mixture was refluxed for 6 hours, and the solvent was evaporated to leave the crude title compound as a light brown oil (a mixture of two diastereomers). The crude product was purified by flash chromatography using a gradient of 0%-25% EtOAc in heptane to give the second eluting compound (R)-2-(2-bromo-5-chlorophenyl)-1-((S)-tert-butylsulfinyl)-2,3,4,7-tetrahydro-1H-azepine as an oil (1.47 g, 42%). MS (ESI): m / z [M+H] + 390.

[0750] Step E. (R)-2-(2-Bromo-5-chlorophenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride

[0751]

[0752] A 4M solution of HCl in dioxane (8.83 mL, 35.32 mmol) was added to a solution of (R)-2-(2-bromo-5-chlorophenyl)-1-((S)-tert-butylsulfinyl)-2,3,4,7-tetrahydro-1H-azepine (1.38 g, 3.53 mmol) in MeOH (10 mL), and the resulting mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give the crude title compound (1.26 g) as a light brown solid. MS (ESI): m / z [M+H] + 286.

[0753] Step F. (R)-tert-Butyl 2-(2-bromo-5-chlorophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate

[0754]

[0755] BocO (1.54 g, 7.06 mmol) and TEA (1.52 mL, 10.94 mmol) were added to a solution of (R)-2-(2-bromo-5-chlorophenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride (1.14 g, 3.53 mmol) in DCM (25 mL), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with brine, and dried through a phase separator. The solvent was evaporated, and the crude product was purified by flash chromatography using a gradient of 0%-20% EtOAc in heptane as the mobile phase. Since unreacted BocO co-eluted on the column, the product mixture was redissolved in DCM (20 mL), and DEA (5 mL) was then added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the crude product was purified by flash chromatography using a gradient of 0% to 10% EtOAc in heptane as the mobile phase to afford (1.31 g, 96%) of the title compound.

[0756] Step G. (R)-tert-Butyl 2-(5-chloro-2-formylphenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate

[0757]

[0758] (R) -2- (2-bromo-5-chlorophenyl) -2,3,4,7-tetrahydro -1H- azepine -1- carboxylic acid tert-butyl ester (100 mg, 0.26 mmol), Pd (OAc) 2 (2.90 mg, 0.01 mmol), CataCXium A (13.91 mg, 0.04 mmol) and TMEDA (0.029 mL, 0.19 mmol) dissolved in toluene (1 mL) were added to a container and placed in an autoclave. The autoclave was purged with CO (g) several times, and then synthesis gas (CO: H2, 1: 1, 5 bar) was filled into the autoclave. The autoclave was heated at 100 ° C for 18 hours in an oil bath. The solvent was evaporated, and the crude product was purified by flash chromatography using a heptane solution with a gradient of 0%-25% EtOAc as the mobile phase to give (80 mg, 92%) of the title compound. MS (ESI): m / z [M + H] + 236.

[0759] Step H. (R)-tert-Butyl 2-(5-chloro-2-formylphenyl)azepane-1-carboxylate

[0760]

[0761] Pd / C (16.31 mg, 0.12 mmol) was added to a solution of (R)-2-(5-chloro-2-formylphenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylic acid tert-butyl ester (390 mg, 1.16 mmol) in MeOH (10 mL), and the resulting mixture was hydrogenated at 1 bar for 2 hours. The catalyst was filtered off through celite and washed with MeOH. The solvent was evaporated. The crude product was redissolved in DCM and the remaining solvent was evaporated to give (400 mg) of the crude title compound as a yellow viscous oil. MS (ESI): m / z[M+H] + 238.

[0762] Step I. (R)-2-(2-(((5-Carbamoyl-1H-imidazol-4-yl)amino)methyl)-5-chlorophenyl)azepine tert-Butyl cycloheptane-1-carboxylate

[0763]

[0764] AcOH (0.068mL, 1.18mmol) is added into EtOH (10mL) solution of (R) -2- (5- chloro- 2- formylphenyl) azepane -1- carboxylic acid tert-butyl esters (400mg, 1.18mmol) and 4- amino -1H- imidazoles -5- formamide (194mg, 1.54mmol), and the reaction is heated at 40 DEG C for 16 hours. The reaction mixture is diluted with EtOH (10mL), NaBH is added at room temperature CN (134mg, 3.55mmol), and the reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched with water (4mL) and concentrated. Residue is diluted with DCM (100ml) and washed with brine (20mL). The crude product was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 ID mm) using a 10% to 70% MeCN gradient in H 2 O / MeCN / NH 3 (95 / 5 / 0.2) as a buffer system to afford (63 mg, 12%) the title compound. MS (ESI): m / z [M+H] + 448.

[0765] Step J. (R)-2-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thiourea)methane tert-Butyl)-5-chlorophenyl)azepane-1-carboxylate

[0766]

[0767] (R)-tert-Butyl 2-(2-(((5-carbamoyl-1H-imidazol-4-yl)amino)methyl)-5-chlorophenyl)azepane-1-carboxylate (63 mg, 0.14 mmol) was dissolved in MeCN (2 mL) and benzoyl isothiocyanate (0.023 mL, 0.17 mmol) was added. The reaction was stirred at room temperature for 18 hours and the solvent was evaporated to give the title compound in quantitative yield. MS (ESI): m / z [M+H] + 611.

[0768] Step K. (R)-2-(5-chloro-2-((6-oxo-2-thioxocarbonyl-1,2,6,7-tetrahydro-3H-purin-3-yl)methane tert-Butyl)phenyl)azepane-1-carboxylate

[0769] (R)-tert-Butyl 2-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)-5-chlorophenyl)azepane-1-carboxylate (86 mg, 0.14 mmol) was dissolved in a mixture of EtOH (2 mL) and 3.8 M aqueous NaOH (0.11 mL, 0.42 mmol), and the mixture was heated at 78° C. for 16 h. The reaction was quenched with 1 M HCl (5 mL) until pH 7, and the solvent was evaporated. The crude product was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×20 ID mm) using a 10%-60% MeCN gradient in H 2 O / MeCN / FA (95 / 5 / 0.2) buffer as the mobile phase to afford (34 mg, 50%) of the title compound. MS (ESI): m / z [M+H] + 488.

[0770] Intermediate 8

[0771] (R)-3-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl) tert-Butyl)methyl)phenyl)morpholine-4-carboxylate

[0772]

[0773] Step A. (S,E)-N-(2-bromobenzylidene)-4-methylbenzenesulfenamide

[0774]

[0775] Ti(OEt)4 (13.3 mL, 64.0 mmol) was added to a solution of 2-bromobenzaldehyde (2.37 g, 12.81 mmol) in anhydrous DCM (150 mL), followed by (S)-4-methylbenzenesulfenamide (2.03 g, 13.1 mmol), and the reactants were refluxed for 4 hours. The reaction was quenched with saturated NH4Cl aqueous solution (300 mL) and stirred for 10 minutes. The reaction mixture was extracted with DCM and dried with a phase separator. The solvent was evaporated, and EtOAc and heptane were added to give a white solid, which was filtered and dried to give (3.29 g, 80%) of the title compound. MS (ESI): m / z[M+H] + 322.

[0776] Step B. (S)-N-((R)-(2-Bromophenyl)(1,3-dithian-2-yl)methyl)-4-methylbenzenesulfenamide

[0777]

[0778] At -20 ° C, n-butyllithium (2.5M) (3.50mL, 8.76mmol) was slowly added to a solution of 1,3-dithiane (1.13g, 9.37mmol) in anhydrous THF (33mL). After 1.5 hours, the resulting solution was cooled to -78 ° C and added to a solution of (S, E)-N-(2-bromobenzylidene)-4-methylbenzenesulfenamide (2.019g, 6.27mmol) in anhydrous THF (39mL) at 78 ° C via a syringe. The reaction was stirred for 20 minutes and quenched at -78 ° C by adding a saturated NH4Cl aqueous solution. The mixture was extracted with EtOAc, and the organic layer was dried (MgSO4) and concentrated. The crude product was purified by flash chromatography using a heptane solution with a gradient of 0%-45% EtOAc as the mobile phase to give (2.011g, 72.5%) of the title compound as a white solid. MS (ESI): m / z [M+H] + 442.

[0779] Step C. (R)-N-(1-(2-bromophenyl)-2-hydroxyethyl)-4-methylbenzenesulfonamide

[0780]

[0781] A solution of (S)-N-((R)-(2-bromophenyl)(1,3-dithian-2-yl)methyl)-4-methylbenzenesulfenamide (3.261 g, 7.37 mmol) in acetone (90 mL) was added dropwise to a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (7.59 g, 26.53 mmol) in 80% acetone (70 mL) at -20 ° C, and the reaction was stirred at -20 ° C for 12 minutes, followed by stirring at room temperature for 10 minutes. The reaction was quenched with Na2SO3 (18 mL) and heptane / DCM (1 / 1, 18 mL). The organic phase was separated and washed with aqueous NaHCO3 (25 mL), water (25 mL) and brine (25 mL), then dried using a phase separator and concentrated to give the intermediate aldehyde. The intermediate aldehyde was dissolved in EtOH (150 mL) and THF (4 mL) and cooled in an ice bath. NaBH4 (1.39 g, 36.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried using a phase separator and concentrated under reduced pressure to give the title compound (1.867 g, 68%). MS (ESI): m / z [M+H] + 370.

[0782] Step D. (R)-3-(2-bromophenyl)-4-p-toluenesulfonylmorpholine

[0783]

[0784] At 0 ° C and N2 (g) atmosphere, TEA (1.414 mL, 10.20 mmol) was added to a stirred solution of (R)-N-(1-(2-bromophenyl)-2-hydroxyethyl)-4-methylbenzenesulfonamide (1.87 g, 5.04 mmol) in DCM (85 mL). After 10 minutes, a solution of diphenyl(vinyl)sulfonium trifluoromethanesulfonate (2.193 g, 6.05 mmol, CAS registration number 247129-29-88) in DCM (45 mL) was added dropwise, and the reaction was stirred at 0 ° C for 3 hours and then stirred at room temperature overnight. The reaction was then quenched with saturated NH4Cl aqueous solution, and the mixture was extracted with DCM. The organic layer was washed with water, dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography using a heptane solution with a gradient of 0%-35% EtOAc as the mobile phase to give (0.676 g, 33.8%) of the title compound. MS (ESI): m / z [M+H] + 396.

[0785] Step E. (R)-3-(2-Bromophenyl)morpholine hydrobromide

[0786]

[0787] A solution of (R)-3-(2-bromophenyl)-4-toluenesulfonylmorpholine (0.676 g, 1.71 mmol), phenol (0.304 ml, 3.41 mmol), and 33% HBr in AcOH (4.9 mL) was stirred at room temperature overnight. The reaction mixture was poured into anhydrous Et2O (13 mL) to give a precipitate. The precipitate was removed by filtration, washed with Et2O, and dried under vacuum to give the title compound (0.452 g, 82%) as a white solid. MS (ESI): m / z [M+H] + 242.

[0788] Step F. (R)-tert-Butyl 3-(2-bromophenyl)morpholine-4-carboxylate

[0789]

[0790] By Boc o (0.336g, 1.54mmol) add in DCM (12mL) solution of (R)-3-(2-bromophenyl)morpholine hydrobromide (0.452g, 1.40mmol), then add TEA (0.601mL, 4.34mmol), and the reaction is stirred at room temperature overnight.DCM is added, and the organic phase is washed with salt water, dried and evaporated with a phase separator.The crude product is purified by flash chromatography using a heptane solution of 0%-30% EtOAc as a gradient to obtain (0.470g, 98%) title compound as a colorless oil. 1 H NMR(400MHz, CDCl3)δ1.31(9H,s),3.55-3.72(2H,m),3.85-3.91(2H,m),3.99-4.05(1H, m),4.08(1H,dd),5.22(1H,dd),7.13(1H,td),7.30(1H,dd),7.40(1H,dd),7.56(1H,dd).

[0791] Step G. (R)-tert-Butyl 3-(2-formylphenyl)morpholine-4-carboxylate

[0792]

[0793] By (R) -3- (2- bromophenyl) morpholine -4- carboxylic acid tert-butyl ester (0.441g, 1.29mmol), Pd (OAc) 2 (0.014g, 0.06mmol), CataCXium A (0.069g, 0.19mmol) and TMEDA (0.145mL, 0.97mmol) are dissolved in toluene (2.5mL) and sealed in an autoclave. The autoclave is filled with synthesis gas (CO:H 2, 1: 1, 5 bar) and heated at 100 ° C in an oil bath for 6 hours. The reactants are concentrated and the crude product is purified by flash chromatography using a heptane solution of 0%-35% EtOAc as a mobile phase to give (0.235g, 62.6%) of the title compound as a yellow oil. MS (ESI): m / z [M-Boc + H] + 192.

[0794] Step H. (R)-3-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)morpholine- 4- tert-Butyl carboxylate

[0795]

[0796] (R) -3- (2- formylphenyl) morpholine -4- carboxylic acid tert-butyl ester (0.220g, 0.76mmol) and 3- amino -1H- pyrrole -2- carboxylic acid ethyl ester hydrochloride (0.144g, 0.76mmol) are dissolved in MeOH (5.5mL) and TEA (0.126mL, 0.91mmol), and the mixture is stirred at room temperature for 10 minutes. AcOH (0.086mL, 1.51mmol) is added, and the mixture is stirred at room temperature for 10 minutes. NaBH3CN (0.040mL, 0.76mmol) is added, and the mixture is stirred at room temperature for 4 hours. The solvent is evaporated, and the residue is dissolved in DCM, washed with water, and dried with a phase separator. The solvent is evaporated, and the crude product is purified by flash chromatography using a gradient of 0% -20% EtOAc in DCM as a mobile phase to obtain (0.124g, 38%) title compound. MS (ESI): m / z [M-Boc+H] + 430.

[0797] Step I. (R)-3-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl tert-Butyl)phenyl)morpholine-4-carboxylate

[0798]

[0799] Benzoyl isothiocyanate (0.039 mL, 0.29 mmol) was added to a solution of (R)-tert-butyl 3-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)morpholine-4-carboxylate (0.124 g, 0.29 mmol) in DCM (3 mL), and the reaction was stirred at room temperature overnight. The solvent was evaporated to give the title compound in an assumed quantitative yield. MS (ESI): m / z [M-Boc+H] + 593.

[0800] Step J. (R)-3-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine- tert-Butyl (1-methyl)methyl)phenyl)morpholine-4-carboxylate

[0801] Cs2CO3 (0.188 g, 0.58 mmol) was added to a solution of (R)-tert-butyl 3-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)morpholine-4-carboxylate (0.171 g, 0.29 mmol) in MeOH (2.5 mL), and the mixture was heated at 65°C for 5 hours. The solvent was evaporated, and the residue was diluted with water (10 mL), acidified to pH 4 with AcOH, and extracted with EtOAc (3×10 mL). The organic phase was dried (MgSO4), filtered, and evaporated to give (0.169 g) of the crude title compound. MS (ESI): m / z [M+H] + 443.

[0802] Intermediate 9

[0803] 4-Methyl-2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-1- Benzyl)methyl)phenyl)piperazine-1-carboxylate

[0804]

[0805] Step A. tert-Butyl 3-(2-bromophenyl)piperazine-1-carboxylate

[0806]

[0807] A mixture of 2-(2-bromophenyl)piperazine (CAS registration number 910444-36-9) (4.172 g, 17.30 mmol), Boc2O (3.78 g, 17.30 mmol) and TEA (2.63 mL, 19.00 mmol) in DCM (65 mL) was stirred at room temperature for 1 hour and then partitioned between water and DCM. The organic layer was washed with water, dried over a phase separator and evaporated in vacuo. The crude product was purified by flash chromatography using a DCM / MeOH / NH4OH (99 / 1 / 0.2 to 9 / 1 / 0.2) gradient system to obtain the title compound in quantitative yield as a yellow oil. MS (ESI): m / z[M+H]+ 341.

[0808] Step B. 1-Benzyl 4-(tert-butyl) 2-(2-bromophenyl)piperazine-1,4-dicarboxylate

[0809]

[0810] A mixture of tert-butyl 3-(2-bromophenyl)piperazine-1-carboxylate (2.457 g, 7.2 mmol), benzyl chloroformate (1.71 g, 10.0 mmol) and DIPEA (2.68 mL, 15.4 mmol) in dioxane (40 mL) was heated at 95° C. for 4 hours. After cooling, the reaction mixture was diluted with EtOAc (200 mL) and washed with saturated NaHCO aqueous solution (100 mL) and brine (50 mL). The solvent was evaporated and the crude product was purified by flash chromatography using a gradient of 0% to 55% EtOAc in heptane as the mobile phase to give (2.84 g, 83%) of the title compound as an oil.

[0811] Step C. 1-Benzyl 4-(tert-butyl) 2-(2-formylphenyl)piperazine-1,4-dicarboxylate

[0812]

[0813] 1-Benzyl 4-(tert-butyl)-2-(2-bromophenyl)piperazine-1,4-dicarboxylate (2.69 g, 5.66 mmol), Pd(OAc)2 (0.064 g, 0.28 mmol), CataCXium A (0.304 g, 0.85 mmol), TMEDA (0.64 mL, 4.24 mmol) were dissolved in toluene (11 mL) and sealed in an autoclave. The autoclave was filled with synthesis gas (CO:H2, 1:1, 5 bar) and heated at 100 ° C. in an oil bath for 18 hours. The solvent was evaporated and the crude product was purified by flash chromatography using a gradient of 0%-38% EtOAc in heptane as the mobile phase to give (1.46 g, 61%) of the title compound. MS (ESI): m / z[M+H] + 425.

[0814] Step D. 1-Benzyl 4-(tert-butyl) 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl) phenyl)piperazine-1,4-dicarboxylate

[0815]

[0816] 1-Benzyl 4-(tert-butyl)-2-(2-formylphenyl)piperazine-1,4-dicarboxylate (1.46 g, 3.45 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (0.69 g, 3.62 mmol) and TEA (0.573 mL, 4.14 mmol) were dissolved in EtOH (29 mL). The mixture was stirred at room temperature for 10 minutes. AcOH (0.395 mL, 6.89 mmol) was added and the reaction mixture was heated at 40 ° C for 16 hours. The reaction was cooled to room temperature, NaBH4 (0.287 g, 7.58 mmol) was added in batches, and the reaction was stirred at room temperature for 3.5 hours. Additional NaBH4 (0.287 g, 7.58 mmol) was added and stirring was continued at room temperature for 2 hours. The reaction was quenched with water (5 mL) and concentrated. The residue was diluted with DCM (100 mL) and washed with brine (25 mL). The solvent was evaporated and the crude product was purified by flash chromatography using a gradient of 0% to 18% EtOAc in DCM as the mobile phase to give (0.85 g, 44%) of the title compound. MS (ESI): m / z [M+H] + 563.

[0817] Step E. 1-Benzyl 4-(tert-butyl) 2-(2-((3-benzoyl)-1-(2-(ethoxycarbonyl)-1H-pyrrole-3-yl)- (methyl)thiourea)methyl)phenyl)piperazine-1,4-dicarboxylate

[0818]

[0819] Benzoyl isothiocyanate (0.204 mL, 1.52 mmol) was added to a solution of 1-benzyl 4-(tert-butyl) 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)piperazine-1,4-dicarboxylate (0.853 g, 1.52 mmol) in DCM (16 mL), and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated to give the crude product in an assumed quantitative yield. MS (ESI): m / z [M+H] + 726.

[0820] Step F. 1-Benzyl 4-(tert-butyl) 2-(2-((4-oxo-2-thioxocarbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo [3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1,4-dicarboxylate

[0821]

[0822] Cs2CO3 (0.99 g, 3.03 mmol) was added to a solution of 1-benzyl 4-(tert-butyl) 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)piperazine-1,4-dicarboxylate (1.1 g, 1.52 mmol) in MeOH (12 mL), and the mixture was heated at 65°C for 3.5 hours. The solvent was evaporated, and the residue was diluted with water (10 mL) and acidified to pH 4 with AcOH. The mixture was extracted with EtOAc (×3), and the combined organic layers were dried (MgSO4). The solvent was evaporated to give (0.75 g, 86%) of the title compound. MS (ESI): m / z[M+H] + 574.

[0823] Step G. 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-1- Benzyl)methyl)phenyl)piperazine-1-carboxylate 2,2,2-trifluoroacetate

[0824]

[0825] TFA (3.3 mL) was added to a solution of 1-benzyl 4-(tert-butyl) 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1,4-dicarboxylate (0.746 g, 1.30 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated to give the title compound (0.77 g, 10%). MS (ESI): m / z [M+H] + 476.

[0826] Step H. 4-Methyl-2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidinyl)- Benzyl)piperidin-1-yl)methyl)phenyl)piperazine-1-carboxylate

[0827] Formaldehyde (33 wt% in H2O) (0.668 mL, 6.53 mmol) was added to a solution of benzyl 2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate 2,2,2-trifluoroacetate (0.77 g, 1.31 mmol) in DCM (10 mL) followed by the addition of NaBH(OAc)3 (0.415 g, 1.96 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with DCM and washed with saturated aqueous NaHCO3 and brine. The organic phase was filtered in a phase separator and the solvent was evaporated to give (0.590 g, 92%) of the title compound as a solid. MS (ESI): m / z [M+H] + 490.

[0828] Intermediate 10

[0829] 2-thiocarbonyl-1-(2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5- Tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0830]

[0831] Step A. 2-(2-(Methoxymethyl)phenyl)-4-(trifluoromethyl)pyridine

[0832]

[0833] 2-Chloro-4-(trifluoromethyl)pyridine (12.06 g, 66.4 mmol) was added to a solution of [2-(methoxymethyl)phenyl]boronic acid (10 g, 60.2 mmol) in dioxane-HO (10 / 1) (264 mL), and the flask was purged and maintained under an inert atmosphere of N (g). NaCO (6.36 g, 60.0 mmol) and Pd(dppf)ClxCHCl (1.32 g, 1.44 mmol) were added, and the resulting solution was stirred at 100 ° C for 16 hours. The resulting solid was filtered off and the solvent was removed in vacuo. The crude product was purified by flash chromatography using heptane / EtOAc (9 / 1) as the mobile phase to give (13 g, 75%) of the title compound as a light brown liquid. MS (ESI): m / z[M+H] + 268.

[0834] Step B. 2-(2-(Methoxymethyl)phenyl)-4-(trifluoromethyl)piperidine

[0835]

[0836] Under N2(g) atmosphere, a solution of 2-[2-(methoxymethyl)phenyl]-4-(trifluoromethyl)pyridine (2.3 g, 8.61 mmol) in MeOH (50 mL) was placed in a round-bottom flask, followed by the addition of 12M HCl (2.88 mL) and PtO2 (230 mg, 1.01 mmol). The mixture was evacuated and backfilled with H2(g) (×3), then hydrogenated at 1 bar and room temperature for 3 hours. The reactants were filtered and concentrated in vacuo. The residue was diluted with water (40 mL) and the pH was adjusted to 10 with saturated Na2CO3 aqueous solution. The resulting aqueous solution was extracted with DCM (2×30 mL), and the organic layers were combined and concentrated in vacuo. The crude product was purified by flash chromatography using heptane / EtOAc (6 / 1) as the mobile phase to give (1.2 g, 51%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 274.

[0837] Step C. 2-(2-(Methoxymethyl)phenyl)-1-toluenesulfonyl-4-(trifluoromethyl)piperidine

[0838]

[0839] TsCl (1.68 g, 8.81 mmol, 1.20 equiv) was added to a solution of 2-[2-(methoxymethyl)phenyl]-4-(trifluoromethyl)piperidine (2.0 g, 7.32 mmol) and TEA (2.22 g, 21.9 mmol) in DCM (4.0 mL). The resulting solution was stirred at room temperature for 4 hours and then diluted with DCM (40 mL) and water (40 mL). The organic layer was washed with water (2×40 mL) and brine (40 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by flash chromatography using heptane / EtOAc (6 / 1) as the mobile phase to give (2.95 g, 94%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 274.

[0840] Step D. 2-(2-(Bromomethyl)phenyl)-1-toluenesulfonyl-4-(trifluoromethyl)piperidine

[0841]

[0842] A solution of BBr3 (492 mg, 1.97 mmol) in DCM (1.0 mL) was added dropwise to a solution of 2-[2-(methoxymethyl)phenyl]-1-[(4-methylbenzene)sulfonyl]-4-(trifluoromethyl)piperidine (280 mg, 0.66 mmol) in DCM (4.0 mL) at 0°C. The resulting solution was stirred at 0°C for 30 minutes, then water (2.0 mL) was added dropwise at 0°C. The resulting aqueous solution was extracted with DCM (2×20 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried (Na2SO4), and concentrated in vacuo to afford (250 mg, 80%) of the title compound as a light brown oil. MS (ESI): m / z [M+H] + 476.

[0843] Step E. (2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)phenyl)methanol

[0844]

[0845] KOH (710 mg, 12.6 mmol) was added to a solution of 2-(2-(bromomethyl)phenyl)-1-toluenesulfonyl-4-(trifluoromethyl)piperidine (3.0 g, 6.3 mmol) in dioxane / water (1 / 1) (80 mL) and the resulting solution was stirred at 50° C. for 5 hours and then cooled to room temperature. The reaction was diluted with EtOAc (60 mL) and water (40 mL). The organic layer was washed with water (40 mL) and brine (40 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography using 5% EtOAc in heptane as the mobile phase to give (1.8 g, 69%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 414.

[0846] Step F. 2-(1-p-Toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde

[0847]

[0848] DMP (3.7 g, 8.72 mmol) was added to a solution of (2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)phenyl)methanol (1.8 g, 4.35 mmol) in DCM (40 mL) at 0°C. The resulting solution was stirred at 0°C to 20°C for 2 hours. 1M NaOH aqueous solution was added dropwise at 0°C, and the resulting aqueous solution was diluted with DCM (40 mL) and water (40 mL). The organic layer was washed with water (2×40 mL) and brine (40 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by flash chromatography using 14% EtOAc in heptane as the mobile phase to give (1.75 g, 98%) of the title compound as a red oil. MS (ESI): m / z[M+H] + 412.

[0849] Step G. 3-((2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-pyrrole- 2-Carboxylic acid ethyl ester

[0850]

[0851] AcOH (225mg, 3.76mmol) and NaBH (OAc) (2.71g, 12.79mmol) are added to a DCE (40mL) solution of 2-(1-tosyl-4-(trifluoromethyl) piperidin-2-yl) benzaldehyde (1.75g, 4.25mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (970mg, 6.29mmol). The resulting solution was stirred at room temperature for 16 hours, then quenched with saturated NaHCO3 aqueous solution (20mL). The gained aqueous solution was diluted with DCM (40mL) and water (30mL), and the organic layer was washed with water (40mL) and salt solution (40mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a heptane solution of 17% EtOAc as mobile phase to give (2.0g, 86%) title compound as a white solid. MS (ESI): m / z [M+H] + 550.

[0852] Step H. 3-(3-benzoyl-1-(2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl) Thiourea)-1H-pyrrole-2-carboxylic acid ethyl ester

[0853]

[0854] Benzoyl isothiocyanate (579 mg, 3.55 mmol) was added to a solution of ethyl 3-((2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-pyrrole-2-carboxylate (1.5 g, 2.73 mmol) in MeCN (40 mL). The resulting solution was stirred at room temperature for 4 hours and concentrated in vacuo to afford the crude title compound (2.1 g) as a yellow solid. MS (ESI): m / z [M+H] 713.

[0855] Step I. 2-thiocarbonyl-1-(2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1, 2,3,5-Tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0856] CsCO (1.72 g, 5.28 mmol, 1.94 equiv) was added to a solution of ethyl 3-[[(2-[1-[(4-methylbenzene)sulfonyl]-4-(trifluoromethyl)piperidin-2-yl]phenyl)methyl][(phenylformamido)methylsulfonyl]amino]-1H-pyrrole-2-carboxylate (1.94 g, 2.72 mmol) in MeOH (50 mL) and the reaction was stirred at 50 ° C for 4 hours and then concentrated under reduced pressure. The residue was dissolved in water (80 mL) and AcOH (737 mg). The pH of the solution was adjusted to 6 with 3M aqueous HCl. The resulting aqueous solution was extracted with DCM (2×50 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL). The organic layer was dried (NaSO) and concentrated in vacuo. The crude product was purified by flash chromatography using DCM / MeOH (20 / 1) as mobile phase to afford (1.35 g, 88%) of the title compound as a light yellow solid. MS (ESI): m / z [M+H] + 563.

[0857] Intermediate 11

[0858] 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)phenyl)-5- tert-Butyl (Trifluoromethyl)piperidine-1-carboxylate

[0859]

[0860] Step A. tert-Butyl 2-oxo-5-(trifluoromethyl)piperidine-1-carboxylate

[0861]

[0862] DMAP (1.61 g, 13.2 mmol) and Boc O (3.13 g, 14.36 mmol) were added to a solution of 5-(trifluoromethyl)piperidin-2-one (CAS Reg. No. 50549-24-1) (2 g, 11.97 mmol) in 2-methyltetrahydrofuran (50 mL). The mixture was stirred at room temperature for 2.5 hours. 1 M KHSO (30 mL) was added, the layers were separated, and the aqueous phase was extracted with methyltetrahydrofuran (50 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried (Na SO ) and concentrated in vacuo to give (3.18 g, 99%) of the title compound. 1 H NMR (400MHz, CDCl3) δ1.53(9H,s),1.84–1.98(1H,m),2.13(1H,qd),2.42–2.56(1H,m),2.57–2.74(2H,m),3.74(1H,dd),3.99(1H,ddd).

[0863] Step B. (2-Bromophenyl)magnesium chloride

[0864]

[0865] A solution of 1,2-dibromobenzene (1.204 mL, 10 mmol) in THF (10 mL) was placed in an oven-dried flask and cooled to -40°C under an N2(g) atmosphere. iPrMgCl×LiCl (1.3 M, 7.69 mL, 10.00 mmol) was added dropwise over 2 minutes. The mixture was stirred at -40°C for 10 minutes, and then the reaction was allowed to reach 0°C over 2 hours. The reaction mixture was used directly in the next step.

[0866] Step C. tert-Butyl (5-(2-bromophenyl)-5-oxo-2-(trifluoromethyl)pentyl)carbamate

[0867]

[0868] Under N2 atmosphere, in an oven-dried flask, (2-bromophenyl) magnesium chloride (18.9mL, 10.00mmol) was added dropwise to a solution of tert-butyl 2-oxo-5-(trifluoromethyl) piperidine-1-carboxylate (891mg, 3.33mmol) in anhydrous THF (15mL) at -40°C via a syringe. The mixture was slowly allowed to reach room temperature and stirred for 15 hours. Saturated NH4Cl aqueous solution (30mL) was added and the layers were separated. The aqueous phase was extracted with DCM (30mL), and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give (2.3g) of the title compound. MS (ESI): m / z[M+H] + 324.

[0869] Step D. 2-(2-Bromophenyl)-5-(trifluoromethyl)piperidine

[0870]

[0871] HCl (1.25M in MeOH) (25mL, 31.25mmol) was added to tert-butyl (5-(2-bromophenyl)-5-oxo-2-(trifluoromethyl)pentyl)carbamate (1.41g, 3.33mmol), and the mixture was stirred at room temperature for 1.5 hours, at 65°C for 1 hour, and at 40°C for 16 hours. The mixture was concentrated in vacuo, and the residue was dissolved in MeOH (20mL). NaBH3CN (0.42g, 6.67mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (10mL) was added, and the mixture was concentrated in vacuo. DCM (25mL) was added to the residue, and the organic layer was washed with saturated NaHCO3 aqueous solution (20mL) using a phase separator. The aqueous layer was extracted with DCM (3×25mL), and the combined organic layers were concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 40% to 100% EtOAc in heptane as the mobile phase to afford (0.245 g, 24%) of the title compound. MS (ESI): m / z [M+H] + 308.

[0872] Step E. tert-Butyl 2-(2-bromophenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0873]

[0874] DIPEA (0.17 mL, 0.95 mmol) and Boc O (208 mg, 0.95 mmol) were added to a solution of 2-(2-bromophenyl)-5-(trifluoromethyl)piperidine (245 mg, 0.80 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 22 hours. 1 M KHSO aqueous solution (4 mL) was added, the layers were separated, and the aqueous phase was extracted with DCM (5 mL) using a phase separator. The organic layers were combined, washed with brine (5 mL) and concentrated in vacuo to give (330 mg, 102%) of the title compound, which was used without further purification.

[0875] Step F. tert-Butyl 2-(2-formylphenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0876]

[0877] By tert-butyl 2-(2-bromophenyl)-5-(trifluoromethyl)piperidine-1-carboxylate (330mg, 0.81mmol), Pd(OAc)2(9.07mg, 0.04mmol), CataCXium A(43.5mg, 0.12mmol), TMEDA(0.091mL, 0.61mmol) are dissolved in toluene (1.5mL) and sealed in autoclave.Autoclave is filled with synthesis gas (CO:H2, 1:1, 5 bar).The mixture is stirred at 100 DEG C for 17 hours in an oil bath and then concentrated in vacuo.The crude product is purified by flash chromatography using a heptane solution of 10%-50% EtOAc as a mobile phase to give (127mg, 44%) title compound. 1 HNMR(400MHz, CDCl3)δ1.23(9H,s),1.38–1.58(1H,m),1.66–1.8(1H,m),1.95–2.07(1H,m),2.17–2.35(1H,m),2.48–2.65( 1H,m),3.53(1H,ddd),4.40(1H,dd),5.73(1H,dd),7.38(1H,ddd),7.44(1H,td),7.56(1H,td),7.81(1H,dd),10.17(1H,s).

[0878] Step G. 2-(2-(((2-(Ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)-5-(trifluoromethyl)- tert-Butyl)piperidine-1-carboxylate

[0879]

[0880] DIPEA (0.068mL, 0.39mmol), AcOH (0.041mL, 0.71mmol) and tert-butyl 2-(2-formylphenyl)-5-(trifluoromethyl)piperidine-1-carboxylate (127mg, 0.36mmol) are added to EtOH (10mL) solution of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (74.5mg, 0.39mmol), and the mixture is stirred at 40 DEG C for 15 hours. Disposable addition NaBH3CN (67.0mg, 1.07mmol) is added, and the mixture is stirred at room temperature for 4.5 hours. Additional NaBH3CN (0.037mL, 0.71mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour. Water (10mL) is added, and the reaction mixture is concentrated in vacuo. The residue is dissolved in DCM (10mL), and the resulting mixture is washed with salt water (5mL) using a phase separator. The aqueous layer was washed with DCM (10 mL), and the combined organic layers were concentrated in vacuo. The crude product was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×50 mm ID) using a 40% to 85% MeCN gradient in H O / MeCN / AcOH (95 / 5 / 0.2) as the mobile phase to afford (110 mg, 62%) of the title compound. MS (ESI): m / z [M+H] + 308.

[0881] Step H. 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)benzene tert-Butyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0882]

[0883] Benzoyl isothiocyanate (43.5 mg, 0.27 mmol) was added to a solution of tert-butyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)-5-(trifluoromethyl)piperidine-1-carboxylate (110 mg, 0.22 mmol) in MeCN (5 mL). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to give the title compound. MS (ESI): m / z [M+H] + 496.

[0884] Step I. 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)benzene tert-Butyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0885] Cs2CO3 (144 mg, 0.44 mmol) was added to a solution of tert-butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)phenyl)-5-(trifluoromethyl)piperidine-1-carboxylate (146 mg, 0.22 mmol) in MeOH (2 mL). The mixture was stirred at 65 ° C for 3 hours and then concentrated in vacuo. DCM (5 mL) and water (5 mL) were added to the residue and the layers were separated using a phase separator. 1M HCl was added to the aqueous phase until pH 6-7 was reached and the aqueous phase was extracted with additional DCM (3×5 mL). The combined organic layers were concentrated in vacuo to give (175 mg) of the title compound. MS (ESI): m / z[M+H] + 509.

[0886] Intermediate 12

[0887] 1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2- d]pyrimidin-4-one

[0888]

[0889] Step A. Benzyl 4,4-difluoro-2-(2-(methoxymethyl)phenyl)piperidine-1-carboxylate

[0890]

[0891] DAST (3.3 g, 20.5 mmol) was added to a solution of benzyl 2-[2-(methoxymethyl)phenyl]-4-oxopiperidine-1-carboxylate (1.8 g, 5.09 mmol) in DCM (50 mL) at 0°C. The resulting solution was stirred at room temperature for 48 hours and quenched with aqueous NH4Cl solution (10 mL). The organic layer was washed with water (3×20 mL) and brine (3×20 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-5% EtOAc in petroleum ether to give (800 mg, 42%) of the title compound as a light yellow oil. MS (ESI): m / z[M+H] + 376.

[0892] Step B. Benzyl 4,4-difluoro-2-(2-formylphenyl)piperidine-1-carboxylate

[0893]

[0894] HNO3 (202 mg, 2.20 mmol) was added dropwise to a solution of benzyl 4,4-difluoro-2-[2-(methoxymethyl)phenyl]piperidine-1-carboxylate (300 mg, 0.80 mmol) in DCM (10 mL). The resulting solution was stirred at room temperature for 3 days and diluted with EtOAc (50 mL). The resulting organic layer was washed with water (3 × 20 mL) and brine (3 × 20 mL), dried over anhydrous (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-15% EtOAc in petroleum ether to give (138 mg, 48%) of the title compound as a brown oil. MS (ESI): m / z[M+H] + 360.

[0895] Step C. 2-(2-(((2-(Ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)-4,4-difluoropiperidin Benzyl 1-pyridinecarboxylate

[0896]

[0897] TEA (2.5 g, 24.7 mmol) and NaBH (OAc) 3 (3.2 g, 15.1 mmol) were added to a suspension of benzyl 4,4-difluoro-2-(2-formylphenyl)piperidine-1-carboxylate (1.8 g, 5.01 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (950 mg, 6.16 mmol) in DCM (50 mL). The resulting solution was stirred at room temperature for 48 hours and the reaction was quenched by adding water (20 mL). The resulting aqueous solution was extracted with DCM (3 × 30 mL), washed with brine (2 × 20 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-20% EtOAc in petroleum ether to give (1.9 g, 76%) of the title compound as a brown oil. MS (ESI): m / z[M+H] + 498.

[0898] Step D. 2-(2-((3-Benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)benzene 4,4-difluoropiperidine-1-carboxylic acid benzyl ester

[0899]

[0900] Benzoyl isothiocyanate (2 g, 12.3 mmol) was added dropwise to a solution of benzyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate (2 g, 4.02 mmol) in MeCN (50 mL) at 0°C. The resulting solution was stirred at room temperature for 4 hours and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-20% EtOAc in petroleum ether to give (1.8 g, 68%) of the title compound as a brown oil. MS (ESI): m / z[M+H] + 661.

[0901] Step E. 4,4-difluoro-2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d] Benzyl pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0902]

[0903] Cs2CO3 (1.8 g, 5.54 mmol) was added portionwise to a solution of benzyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate (1.8 g, 2.72 mmol) in MeOH (50 mL). The resulting solution was stirred at 50°C for 2 hours and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 10% MeOH in DCM to give (1.2 g, 86%) of the title compound as a white solid. MS (ESI): m / z [M+Na] + 533.

[0904] Step F. 1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[ ... [3,2-d]pyrimidin-4-one

[0905] Benzyl 4,4-difluoro-2-(2-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate (500 mg, 0.98 mmol) was added to a suspension of HBr in AcOH (40% w / w) (5 mL, 87.8 mmol) and PhOH (460 mg, 4.90 mmol), and the resulting solution was stirred at room temperature for 1 hour, then concentrated in vacuo. The crude product was purified by preparative HPLC on an XBridge C18 OBD column (5 mm, 150×19 mm ID) using a gradient of 0% to 100% MeCN in H 2 O / NH 3 (100 / 0.03) to afford (190 mg, 52%) of the title compound as a white solid.

[0906] Intermediate 13

[0907] 2-thiocarbonyl-3-(2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7- Tetrahydro-6H-purin-6-one

[0908]

[0909] Step A. 4-((2-(1-p-Toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-imidazole- 5-Formamide

[0910]

[0911] AcOH (270 mg, 4.5 mmol) was added to a solution of 2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde Intermediate 10 Step F (3.7 g, 8.99 mmol) and 4-amino-1H-imidazole-5-carboxamide (1.25 g, 9.92 mmol) in EtOH (50 mL). The resulting solution was stirred at 75 ° C overnight and then cooled to 0 ° C. NaBH4 (680 mg, 18.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water (20 mL) and then concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 15% EtOAc in petroleum ether to afford (3.6 g, 77%) of the title compound as a white solid. MS (ESI): m / z [M+Na] + 522.

[0912] Step B. 4-(3-Benzoyl-1-(2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl) Thiourea)-1H-imidazole-5-carboxamide

[0913]

[0914] Benzoyl isothiocyanate (465 mg, 2.85 mmol) was added to a solution of 4-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzylamino)-1H-imidazole-5-carboxamide (1.35 g, 2.59 mmol) in MeCN (40 mL). The resulting solution was stirred at room temperature for 4 hours and concentrated in vacuo to give (1.8 g) of the crude title compound as a yellow solid. MS (ESI): m / z [M+Na] + 685.

[0915] Step C. 2-thiocarbonyl-3-(2-(1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1, 2,3,7-Tetrahydro-6H-purin-6-one

[0916] NaOH (1.72 g, 5.28 mmol) was added to a solution of 4-(3-benzoyl-1-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)thioureido)-1H-imidazole-5-carboxamide (640 mg, 2.72 mmol) in MeOH (50 mL). The resulting solution was stirred at 55 ° C for 8 hours and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 10% MeOH in DCM to give (400 mg, 88%) of the title compound as a light yellow solid. MS (ESI): m / z [M + Na] + 564.

[0917] Intermediate 14

[0918] 2-Thiocarbonyl-3-(2-((2R,4S)-1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)- 1,2,3,7-Tetrahydro-6H-purin-6-one

[0919]

[0920] Step A. 2-((2R,4S)-1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde

[0921]

[0922] HNO3 (10 mL, 75 mmol) was added to a solution of (2R,4S)-2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine (Intermediate 15) (4.0 g, 9.37 mmol) in DCM (80 mL) at 0°C, and the mixture was stirred at 0 to 20°C overnight. The resulting solution was washed with water (2 x 40 mL) and brine (40 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 15% EtOAc in petroleum ether to give (1.36 g, 83%) of the title compound as a yellow solid. MS (ESI): m / z [M+Na] + 412.

[0923] Step B. 4-((2-((2R,4S)-1-p-Toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)- 1H-imidazole-5-carboxamide

[0924]

[0925] AcOH (183 mg, 3.04 mmol) was added to a solution of 2-((2R, 4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde (2.5 g, 6.08 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (920 mg, 7.30 mmol) in EtOH (50 mL). The resulting solution was stirred at 75 ° C overnight and then cooled to room temperature. NaBH4 (460 mg, 12.16 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reactant mixture was concentrated in vacuo and diluted with DCM (50 mL) and water (30 mL). The separated organic layer was washed with water (40 mL) and brine (40 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-15% EtOAc in petroleum ether to obtain (2.5 g, 79%) of the title compound as a white solid. MS (ESI): m / z [M+Na] + 522.

[0926] Step C. 4-(3-Benzoyl-1-(2-((2R,4S)-1-toluenesulfonyl)-4-(trifluoromethyl)piperidin-2-yl)- (4-(2-amino-1H-imidazole)-5-carboxamide)-1H-imidazole-5-carboxamide

[0927]

[0928] Benzoyl isothiocyanate (1.08 g, 6.62 mmol, 1.50) was added to a solution of 4-((2-((2R,4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-imidazole-5-carboxamide (2.3 g, 4.41 mmol) in MeCN (30 mL). The resulting solution was stirred at room temperature for 4 hours and concentrated in vacuo to give (3.3 g, crude) of the crude title compound as a yellow solid. MS (ESI): m / z [M+Na] + 685.

[0929] Step D. 2-Carbothioyl-3-(2-((2R,4S)-1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl) (benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one

[0930] A solution of 4-(3-benzoyl-1-(2-((2R,4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)thioureido)-1H-imidazole-5-carboxamide (3 g, crude) in 33% aqueous NH3 / EtOH (2 / 1, 30 mL) was stirred at 50°C overnight and then concentrated in vacuo. The crude product was purified by flash chromatography using DCM / MeOH (15 / 1) as the mobile phase to give (1.8 g, 72%) of the title compound as a light yellow solid. MS (ESI): m / z [M+Na] + 564.

[0931] Intermediate 15

[0932] (2R,4S)-2-(2-(methoxymethyl)phenyl)-1-toluenesulfonyl-4-(trifluoromethyl)piperidine

[0933]

[0934] Obtained by chiral separation of intermediate 10, step C. [a] D =-87 (c=1g / 100mL, MeCN).

[0935] Intermediate 16

[0936] 2-Thiocarbonyl-3-(2-((2S,4R)-1-toluenesulfonyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)- 1,2,3,7-Tetrahydro-6H-purin-6-one

[0937]

[0938] Prepared as described for Intermediate 14, using Intermediate 17, (2S,4R)-2-(2-(methoxymethyl)phenyl)-1-toluenesulfonyl-4-(trifluoromethyl)piperidine, as starting material. MS (ESI): m / z [M+Na] + 564.

[0939] Intermediate 17

[0940] (2S,4R)-2-(2-(methoxymethyl)phenyl)-1-p-toluenesulfonyl-4-(trifluoromethyl)piperidine.

[0941]

[0942] Obtained by chiral separation of intermediate 10, step C. [a] D =+78 (c=1g / 100mL, MeCN).

[0943] Intermediate 18

[0944] 4,4-Difluoro-2-(2-((6-oxo-2-thiocarbonyl-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)benzene Benzyl)piperidine-1-carboxylate

[0945]

[0946] Step A. 2-(2-(((5-Carbamoyl-1H-imidazol-4-yl)amino)methyl)phenyl)-4,4-difluoropiperidine- 1-Carboxylic acid benzyl ester

[0947]

[0948] AcOH (80 mg, 1.33 mmol) was added to a solution of benzyl 4,4-difluoro-2-(2-formylphenyl)piperidine-1-carboxylate intermediate 12 step B (940 mg, 2.62 mmol) and 4-amino-1H-imidazole-5-carboxamide (330 mg, 2.62 mmol) in EtOH (20 mL), and the resulting solution was stirred at 70 ° C for 16 hours. NaBH4 (100 mg, 2.64 mmol) was added, and the resulting solution was stirred at 20 ° C for another 4 hours, and then the reaction was quenched by adding water. The resulting mixture was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-5% MeOH in DCM to give (790 mg, 66%) of the title compound as a white solid. MS (ESI): m / z [M + Na] + 470

[0949] Step B. 2-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)benzene 4,4-difluoropiperidine-1-carboxylic acid benzyl ester

[0950]

[0951] Benzoyl isothiocyanate (105 mg, 0.64 mmol) was added to a solution of benzyl 2-(2-(((5-carbamoyl-1H-imidazol-4-yl)amino)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate (300 mg, 0.64 mmol) in MeCN (20 mL), and the resulting solution was stirred at 20° C. for 48 hours. The resulting solid was collected by filtration, washed with MeCN (3×1 mL), and dried to give the title compound (230 mg, 57%) as a light yellow solid. MS (ESI): m / z [M+Na] + 633.

[0952] Step C. 4,4-difluoro-2-(2-(6-oxo-2-thiocarbonyl-1,2,6,7-tetrahydro-3H-purin-3-yl)methane Benzyl)phenyl)piperidine-1-carboxylate

[0953] 28% NH3 aqueous solution (2 mL) was added dropwise to a solution of benzyl 2-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate (100 mg, 0.16 mmol) in EtOH (1 mL). The resulting solution was stirred at 50 ° C. for 24 hours and then concentrated in vacuo. The residue was purified by preparative TLC using DCM / MeOH (20 / 1) as the mobile phase to give (80 mg, 98%) of the title compound as an off-white solid. MS (ESI): m / z [M+Na] + 512.

[0954] Intermediate 19

[0955] 3-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro- 6H-Purin-6-one

[0956]

[0957] Step A. Methyl 3-(2-bromophenyl)-3-oxopropanoate

[0958]

[0959] NaH (60 wt %) (24 g, 600 mmol) was added to a solution of 1-(2-bromophenyl)ethan-1-one (100 g, 502.40 mmol) in dimethyl carbonate (600 mL), and the resulting solution was stirred at 90 ° C for 1 hour, cooled to room temperature and diluted with water (700 mL). The pH was adjusted to 4 with 12M HCl, and the resulting acidic aqueous solution was extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (2×800 mL) and brine (800 mL), then dried (Na2SO4) and concentrated in vacuo to give (120 g, 93%) of the crude title compound as a red liquid that was used without further purification. MS (ESI): m / z[M+H] + 257.

[0960] Step B. Methyl 2-(2-bromobenzoyl)pent-4-enoate

[0961]

[0962] NaH (60 wt %) (14 g, 350 mmol) was added portionwise to a solution of methyl 3-(2-bromophenyl)-3-oxopropanoate (70 g, 272 mmol) in THF (600 mL) at 0°C. The mixture was stirred at room temperature for 1 hour. 3-Bromoprop-1-ene (35.7 g, 295 mmol) and NaI (12.67 g, 84.47 mmol) were added, and the resulting solution was stirred at room temperature for 15 hours and then concentrated in vacuo. The residue was diluted with water (600 mL) and the pH was adjusted to 7 with 2M aqueous HCl solution. The resulting aqueous solution was extracted with DCM (3×100 mL), dried (Na2SO4) and concentrated in vacuo to give (78 g, 97%) of the crude title compound as a light brown liquid. MS (ESI): m / z[M+H] + 297.

[0963] Step C. 1-(2-Bromophenyl)pent-4-en-1-one

[0964]

[0965] KOH (37.1 g, 661.8 mmol) was added to a solution of methyl 2-(2-bromobenzoyl)pent-4-enoate (65.52 g, 220.50 mmol) in dioxane / water (1 / 2), and the resulting solution was heated at reflux for 2.5 hours and then cooled to room temperature. The pH of the solution was adjusted to 6 with 4M aqueous HCl. The resulting aqueous solution was extracted with DCM (2×400 mL). The combined organic layers were washed with water (400 mL) and brine (400 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by flash chromatography using 0%-5% EtOAc in petroleum ether to give (36 g, 60% yield over three steps) the title compound as a yellow liquid. MS (ESI): m / z[M+H] + 239.

[0966] Step D. 1-(2-Bromophenyl)-N-(4-methoxybenzyl)pent-4-en-1-amine

[0967]

[0968] TiCl4 (23 g, 121 mmol) was added dropwise to a solution of 1-(2-bromophenyl)pent-4-en-1-one (29 g, 121 mmol), 4-methoxyaniline (19.95 g, 161.99 mmol) and TEA (36.75 g, 363.2 mmol) in THF (400 mL) at -78°C under an N2(g) atmosphere. The mixture was stirred at -78°C to 20°C for 5 hours. A solution of NaBH3CN (33.85 g, 545.9 mmol) in MeOH (150 mL) was added at 0°C. The resulting solution was stirred at 20°C for 15 hours and quenched with saturated aqueous K2CO3 (80 mL). The resulting solution was extracted with Et2O (2 x 400 mL), and the combined organic layers were washed with water (2 x 400 mL) and brine (400 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 10% EtOAc in petroleum ether to afford (27.7 g, 66%) of the title compound as a light yellow oil. MS (ESI): m / z [M+H] + 360.

[0969] Step E. 2-(2-Bromophenyl)-5-iodo-1-(4-methoxybenzyl)piperidine

[0970]

[0971] NIS (17.7 g, 81.6 mmol) was added portionwise to a solution of 1-(2-bromophenyl)-N-(4-methoxybenzyl)pent-4-en-1-amine (28.2 g, 81.6 mmol) in DCM (300 mL) at 0°C. The resulting solution was stirred at 0°C for 30 minutes and quenched with water (100 mL). The resulting organic layer was separated and washed with water (100 mL), brine (100 mL), then dried (Na2SO4) and concentrated in vacuo to give (40 g) of the crude title compound as a black oil. MS (ESI): m / z [M+H] + 486.

[0972] Step F. 6-(2-Bromophenyl)-1-(4-methoxybenzyl)piperidin-3-ol

[0973]

[0974] AgOAc (82.2 g, 492 mmol) was added in batches to a toluene (400 mL) solution of 2- (2- bromophenyl) -5- iodo -1- (4- methoxybenzyl) piperidine (40 g, 82 mmol), and the mixture was stirred at 25 ° C for 1.5 hours. The solid was filtered out and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH (400 mL), K2CO3 (17 g, 123 mmol) was added, and the resulting solution was stirred at room temperature until the reaction was complete. The reaction was quenched by adding saturated NH4Cl aqueous solution (50 mL) and extracted with DCM (2 × 200 mL). The combined organic layer was washed with water (2 × 300 mL) and brine (300 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a petroleum ether solution with a gradient of 0%-20% EtOAc to obtain (9.62 g, 32% yield for two steps) the title compound as a light yellow solid. MS (ESI): m / z [M+H] + 376.

[0975] Step G. 2-(2-Bromophenyl)-5-fluoro-1-(4-methoxybenzyl)piperidine

[0976]

[0977] DAST (1.67 g, 10.37 mmol) was added dropwise to a solution of 6-(2-bromophenyl)-1-(4-methoxybenzyl)piperidin-3-ol (3.0 g, 7.97 mmol) in DCM (50 mL) at 0 ° C. The resulting solution was stirred at 0 ° C. for 4 hours and quenched with water (4 mL). The resulting aqueous solution was diluted with DCM (50 mL), and the organic layer was washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-10% EtOAc in petroleum ether to give (2.45 g, 81%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 378.

[0978] Step H. 2-(5-Fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzaldehyde

[0979]

[0980] At -78 ° C and N2 (g) atmosphere, n-butyllithium solution (2.5M in hexane) (2.34mL, 5.84mmol) was added to a solution of 2-(2-bromophenyl)-5-fluoro-1-(4-methoxybenzyl)piperidine (2.21g, 5.84mmol) in THF (40mL). The mixture was stirred at -78 ° C for 45 minutes, and DMF (1.28g, 3.00 equivalents) was added dropwise at -78 ° C. The resulting solution was stirred at -70 ° C to -60 ° C for 1 hour, and the reaction was quenched with water (2mL). The resulting aqueous solution was extracted with DCM (3 × 100mL), and the combined organic layer was washed with water (2 × 40mL) and brine (40mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 15% EtOAc in petroleum ether to afford (1.6 g, 84%) of the title compound as a light yellow solid. MS (ESI): m / z [M+H] + 328.

[0981] Step I. 4-((2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)amino)-1H-imidazole-5-carboxamide amine

[0982]

[0983] AcOH (293 mg, 4.89 mmol) was added to a solution of 2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzaldehyde (1.6 g, 4.89 mmol) and 4-amino-1H-imidazole-5-carboxamide (616 mg, 4.8 mmol) in EtOH (20 mL). The mixture was stirred at reflux for 6 hours and then cooled to room temperature. The precipitated solid was collected by filtration, dissolved in EtOH (20 mL), and NaBH4 (181 mg, 4.89 mmol) was added in batches. The resulting solution was stirred at room temperature for 1 hour, and the reaction was quenched by adding water (10 mL) dropwise at 0 ° C. The resulting solid was collected by filtration and dried in vacuo to give (2.0 g, 94%) of the title compound as an off-white solid. MS (ESI): m / z[M+H] + 438.

[0984] Step J. 4-(3-Benzoyl-1-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)thiourea 1H-imidazole-5-carboxamide

[0985]

[0986] Benzoyl isothiocyanate (1.12 g, 6.86 mmol) was added to a solution of 4-((2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)amino)-1H-imidazole-5-carboxamide (2.0 g, 4.57 mmol) in DCM (40 mL). The resulting solution was stirred at room temperature for 15 hours and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 5% MeOH in DCM to give (2.24 g, 82%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 601.

[0987] Step K. 3-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,7- Tetrahydro-6H-purin-6-one

[0988] 4M NaOH aqueous solution (4.16 mL, 16.6 mmol) was added to a solution of 4-(3-benzoyl-1-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)thioureido)-1H-imidazole-5-carboxamide (2.0 g, 3.33 mmol) in MeOH (30 mL) and the resulting solution was stirred at 50 ° C for 10 hours, then quenched with AcOH (2.0 mL). The resulting mixture was concentrated in vacuo and diluted with DCM (150 mL), washed with brine (2×70 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0% to 5% MeOH in DCM to give (1.2 g, 75%) of the title compound as an off-white solid. MS (ESI): m / z[M+H]+ 480.

[0989] Intermediate 20

[0990] 2-(3-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl) tert-Butyl pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0991]

[0992] Step A. 2-Bromo-3-(1,3-dioxolan-2-yl)pyridine

[0993]

[0994] TsOH (1.852 g, 10.75 mmol) was added to a solution of 2-bromonicotinaldehyde (10 g, 53.8 mmol) and ethane-1,2-diol (6.67 g, 107.5 mmol) in toluene (80 mL) at room temperature. The resulting solution was stirred at 130 ° C for 15 hours. The solvent was removed under reduced pressure, and the residue was poured into a saturated aqueous NaHCO3 solution (300 mL). The mixture was extracted with EtOAc (3×150 mL), and the combined organic layers were dried (Na2SO4), filtered and evaporated to give (11.00 g, 89%) of the title compound as a yellow solid, which was used directly in the next step without further purification. MS (ESI): m / z[M+H] + 230.

[0995] Step B. (5-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)-5-oxo-3-(trifluoromethyl)pentyl)amine tert-Butyl formate

[0996]

[0997] At -78 ° C and N2g atmosphere, n-butyl lithium (2.5M hexane solution) (12.2mL, 30.4mmol) is added dropwise to a solution of 2-bromo-3-(1,3-dioxolane-2-yl)pyridine (6.36g, 27.6mmol) in THF (180mL), and the mixture is stirred at -78 ° C for 0.5 hours. A solution of tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (CAS registration number 911634-72-5) (7.45g, 27.9mmol) in THF (20mL) is added dropwise while keeping the temperature below -78 ° C. The solution is allowed to reach room temperature and stirred for another 2 hours. The reaction is quenched by adding a saturated NH4Cl aqueous solution (2mL), and the resulting mixture is concentrated in vacuo. The residue was dissolved in DCM (300 mL), washed with water (2×200 mL) and brine (2×300 mL), then dried (Na 2 SO 4 ) and evaporated to dryness. The crude product was purified by flash chromatography using a gradient of 0% to 20% EtOAc in petroleum ether to give (6.87 g, 59%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 419.

[0998] Step C. 3'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-5,6-dihydro-[2,2'-bipyridine]-1 (4H)-tert-Butyl carboxylate

[0999]

[1000] TFA (4.64 g, 40.7 mmol) was added to a solution of tert-butyl (5-(3-(1,3-dioxolane-2-yl)pyridin-2-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate (5.67 g, 13.6 mmol) in DCM (200 mL), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was washed with saturated aqueous NaHCO3 (3×300 mL) and brine (2×200 mL). The combined organic layers were dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash chromatography using a gradient of 0%-10% EtOAc in petroleum ether to give (3.17 g, 58%) of the title compound as a yellow solid. MS (ESI): m / z[M+H] + 401.

[1001] Step D. tert-Butyl 2-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate ester

[1002]

[1003] Under N2(g) atmosphere, Pd / C (10% Pd w / w, 650 mg) was added to a solution of TEA (2.40 g, 23.7 mmol) and 3'-(1,3-dioxolane-2-yl)-4-(trifluoromethyl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylic acid tert-butyl ester (3.17 g, 7.92 mmol) in EtOAc (50 mL). The flask was evacuated and backfilled with H2(g) three times and hydrogenated at room temperature at 1 bar for 36 hours. The catalyst was filtered out and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-20% EtOAc in petroleum ether to give (2.53 g, 79%) of the title compound as a white solid. MS (ESI): m / z[M+H] + 403.

[1004] Step E. tert-Butyl 2-(3-formylpyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[1005]

[1006] A solution of tert-butyl 2-(3-(1,3-dioxolane-2-yl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.6 g, 3.98 mmol), TsOH (0.068 g, 0.40 mmol), and water (1.074 g, 59.64 mmol) in acetone (20 mL) was stirred at 60 ° C for 16 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-20% EtOAc in petroleum ether to give (1.00 g, 70%) of the title compound as a white solid. MS (ESI): m / z [M + H] + 259.

[1007] Step F. 2-(3-(((2-(Ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-2-yl)-4-(tri tert-Butyl (fluoromethyl)piperidine-1-carboxylate

[1008]

[1009] AcOH (215 mg, 3.58 mmol) and NaBH (OAc) 3 (2.28 g, 10.75 mmol) were added to a DCE (10 mL) solution of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (820 mg, 4.30 mmol) and tert-butyl 2-(3-formylpyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.28 g, 3.57 mmol). The resulting solution was stirred at room temperature for 2 hours and the reaction was quenched by adding water (20 mL). The organic layer was separated and washed with brine (2 × 20 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a DCM solution with a gradient of 0%-10% MeOH to give (0.9 g, 79%) of the title compound as an off-white solid. MS (ESI): m / z[M+H] + 497.

[1010] Step G. 2-(3-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)pyrrol tert-Butyl 4-(trifluoromethyl)piperidine-1-carboxylate

[1011]

[1012] Benzoyl isothiocyanate (726 mg, 4.45 mmol) was added to a solution of tert-butyl 2-(3-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.84 g, 3.71 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 16 hours and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-20% EtOAc in petroleum ether to give (2.05 g, 84%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 660.

[1013] Step H. 2-(3-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-1- tert-Butyl (methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[1014] A suspension of tert-butyl 2-(3-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thiourea)methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (2.05 g, 3.11 mmol) and CsCO (2.03 g, 6.21 mmol) in MeOH (20 mL) was stirred at 50 ° C for 16 hours and then cooled to room temperature. AcOH (900 mg, 15.0 mmol) was added and the mixture was diluted with DCM (50 mL) and filtered. The filtrate was concentrated in vacuo and triturated with EtO (100 mL). The resulting solid was collected by filtration and dried in vacuo to give (1.2 g, 76%) of the title compound as a yellow solid. MS (ESI): m / z[M+H] + 510.

[1015] Intermediate 21

[1016] rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5- Tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[1017]

[1018] Step A. tert-Butyl 4-(difluoromethyl)piperidine-1-carboxylate

[1019]

[1020] At 0 ° C, DAST (11.3 g, 49.5 mmol) was added dropwise to a DCM solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g, 23.4 mmol) over 15 minutes. The resulting solution was stirred at 0 ° C for another 15 minutes and quenched by adding an aqueous solution of NaHCO3 (100 mL). The resulting aqueous solution was extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-5% EtOAc in petroleum ether as the mobile phase to give (3.6 g, 65%) of the title compound as an off-white solid. MS (ESI): m / z [M + H] + 180.

[1021] Step B. tert-Butyl 4-(difluoromethyl)-2-oxopiperidine-1-carboxylate

[1022]

[1023] RuO2 (890 mg, 5.24 mmol) was added to a solution of tert-butyl 4-(difluoromethyl)piperidine-1-carboxylate (3.6 g, 15.30 mmol) in EtOAc (63 mL), followed by addition of a solution of NaIO4 (9.84 g, 46.0 mmol) in water (36 mL) in several batches at 0 ° C. The resulting solution was stirred at 25 ° C for 15 hours. The solid was filtered out. The filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-5% EtOAc in petroleum ether as the mobile phase to give (2.5 g, 66%) of the title compound as a white solid. MS (ESI): m / z [M + H] + 194.

[1024] Step C. tert-Butyl (3-(difluoromethyl)-5-(2-(methoxymethyl)phenyl)-5-oxopentyl)carbamate

[1025]

[1026] At -78 DEG C and N2(g) atmosphere, n-Butyllithium (2.2M, 2mL, 4.4mmol) is added dropwise to a solution of 1-bromo-2-(methoxymethyl)benzene (800mg, 4.00mmol) in THF (15mL), and the mixture is stirred at -78 DEG C for 30 minutes. At -100 DEG C, a solution of 4-(difluoromethyl)-2-oxopiperidine-1-carboxylic acid tert-butyl ester (1.0g, 4.01mmol) in THF (5mL) is added dropwise to the reaction mixture, and the resulting solution is stirred at -78 DEG C for 2 hours. The reaction is quenched by adding NH4Cl aqueous solution (15mL). The resulting mixture is extracted with EtOAc (3 × 30mL), and the organic layer is combined and concentrated in vacuo. The crude product is purified by flash chromatography using a DCM solution of 0%-5% MeOH as a mobile phase to obtain (1.0g, 67%) title compound as a light yellow oil. MS (ESI): m / z [M+H] + 372.

[1027] Step D. 4-(Difluoromethyl)-6-(2-(methoxymethyl)phenyl)-1,2,3,4-tetrahydropyridine

[1028]

[1029] TFA (4.0 mL) was added to a solution of tert-butyl (3-(difluoromethyl)-5-(2-(methoxymethyl)phenyl)-5-oxopentyl)carbamate (2.8 g, 7.54 mmol) in DCM (40 mL). The resulting solution was stirred at 100 ° C for 30 minutes in a microwave reactor and concentrated in vacuo. The residue was diluted with DCM (50 mL) and washed with saturated aqueous Na2CO3 (2×70 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give (2.0 g, 70%) of the title compound as a yellow oil. MS (ESI): m / z [M+H] + 254.

[1030] Step E. 4-(Difluoromethyl)-6-(2-(methoxymethyl)phenyl)-1-toluenesulfonyl-1,2,3,4-tetrahydro Pyridine

[1031]

[1032] TsCl (2.24 g, 26.4 mmol) was added portionwise to a solution of 4-(difluoromethyl)-6-[2-(methoxymethyl)phenyl]-1,2,3,4-tetrahydropyridine (1.99 g, 7.84 mmol) and TEA (2.38 g, 23.5 mmol) in DCM (40 mL) at 0 ° C. The resulting solution was stirred at 20 ° C for 20 hours and then diluted with DCM (80 mL). The resulting mixture was washed with water (2×50 mL) and brine (60 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-10% EtOAc in petroleum ether as the mobile phase to give (2.0 g, 63%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 408.

[1033] Step F. 4-(Difluoromethyl)-2-(2-(methoxymethyl)phenyl)-1-toluenesulfonylpiperidine

[1034]

[1035] PtO2 (300 mg, 1.32 mmol) was added to a solution of 4-(difluoromethyl)-6-(2-(methoxymethyl)phenyl)-1-tosyl-1,2,3,4-tetrahydropyridine (2.0 g, 4.91 mmol) in AcOH (40 mL). The reaction flask was evacuated and backfilled with N2(g) twice, then evacuated and backfilled with H2(g) twice, and then stirred at 30°C and H2(g) atmosphere for 2 days. The solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0%-15% EtOAc in petroleum ether as the mobile phase to give (1.1 g, 55%) of the title compound as a light yellow oil. MS (ESI): m / z[M+H]+ 410.

[1036] Step G. 2-(4-(Difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzaldehyde

[1037]

[1038] At 0 ℃ by HNO (1.0mL, 22.30mmol) is added dropwise in DCM (20mL) solution of 4-(difluoromethyl)-2-(2-(methoxymethyl) phenyl)-1-tosyl piperidine (1.1g, 2.70mmol).Gained solution is stirred at room temperature 15 hours, and diluted with DCM (60mL).Gained mixture is washed with water (2 × 40mL) and salt solution (40mL), then dried (Na SO ) and concentrated in vacuo.By flash chromatography purification of crude product, using gradient is the petroleum ether solution of 0%-15% EtOAc as mobile phase, obtain (770mg, 72%) title compound, be light yellow solid.

[1039] Step H. 3-((2-(4-(difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzyl)amino)-1H-pyrrole- 2-Carboxylic acid ethyl ester

[1040]

[1041] A solution of 2-(4-(difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzaldehyde (770 mg, 1.96 mmol), ethyl 2-amino-1H-pyrrole-3-carboxylate hydrochloride (411 mg, 2.15 mmol), AcOH (118 mg, 1.96 mmol) and NaBH(OAc)3 (1.25 g, 5.90 mmol) in DCE (30 mL) was stirred at 20 ° C for 15 hours and then diluted with DCM (30 mL). The resulting mixture was washed with water (2×30 mL) and brine (30 mL), then dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc / petroleum ether (1 / 2) as the mobile phase to give (867 mg, 83%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 532.

[1042] Step I. 3-(3-benzoyl-1-(2-(4-(difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzyl) Thiourea)-1H-pyrrole-2-carboxylic acid ethyl ester

[1043]

[1044] Benzoyl isothiocyanate (346 mg, 2.12 mmol) was added to a solution of ethyl 3-((2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzyl)amino)-1H-pyrrole-2-carboxylate (867 mg, 1.63 mmol) in DCM (25 mL), and the resulting solution was stirred at room temperature for 15 hours and then concentrated in vacuo to give (1.2 g) of the crude title compound as a light yellow solid. MS (ESI): m / z [M+H] + 695.

[1045] Step J. 1-(2-(4-(difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzyl)-2-thiocarbonyl-1, 2,3,5-Tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[1046]

[1047] Cs2CO3 (1.12 g, 3.45 mmol) was added to a solution of ethyl 3-(3-benzoyl-1-(2-(4-(difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzyl)thioureido)-1H-pyrrole-2-carboxylate (1.2 g, 1.73 mmol) in MeOH (30 mL), and the resulting solution was stirred at 50°C for 5 hours and then cooled to room temperature. AcOH (4.5 equiv) was added dropwise and the resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL) and water (30 mL), and the pH value of the mixture was adjusted to 6 with 2M HCl. The resulting mixture was extracted with DCM (2×30 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give (680 mg, 72%) of the title compound as a light yellow solid. MS (ESI): m / z[M+H] + 545.

[1048] Step K. rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1, 2,3,5-Tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[1049] Phenol (225 mg, 2.39 mmol) was added to a solution of 1-(2-(4-(difluoromethyl)-1-toluenesulfonylpiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (650 mg, 1.19 mmol) in HBr-AcOH (15 mL), and the resulting solution was stirred at 25°C for 4 hours and then concentrated in vacuo. The crude product was purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 150×19 mm ID) using a 10%-85% MeCN gradient in H2O / NH3 (95 / 5 / 0.03) as the mobile phase to afford (320 mg, 69%) of the title compound as a light yellow solid. MS (ESI): m / z [M+H] +391.

[1050] Intermediate 22

[1051] 2-(3-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl) tert-Butyl pyridin-2-yl)piperidine-1-carboxylate

[1052]

[1053] Step A. tert-Butyl 3'-(1,3-dioxolan-2-yl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate

[1054]

[1055] CataCXium A Pd G3 (CAS Reg. No. 1651823-59-4) (0.317 g, 0.43 mmol) and CataCXium A (0.156 g, 0.43 mmol) were added to a mixture of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (1.0 g, 4.35 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (CAS Reg. No. 865245-32-5) (1.075 g, 3.48 mmol) and Cs2CO3 (3.12 g, 9.56 mmol) in 1,4-dioxane (30 mL) and water (6 mL) at room temperature, and the resulting suspension was stirred at 80°C under N2(g) atmosphere for 15 hours. The reaction mixture was dried (Na2SO4), filtered, and evaporated. The crude product was purified by flash chromatography using a gradient of 5% to 25% EtOAc in petroleum ether to afford (1.0 g, 69%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 333.

[1056] Step B. tert-Butyl 2-(3-(1,3-dioxolan-2-yl)-1,2-dihydropyridin-2-yl)piperidine-1-carboxylate

[1057]

[1058] Pd(OH)2 / C (10% Pd, 1014 mg, 0.72 mmol) was added to a solution of tert-butyl 3'-(1,3-dioxolane-2-yl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate (800 mg, 2.41 mmol) in MeOH (80 mL) at room temperature. The reaction mixture was evaporated and backfilled with H2(g) five times. The resulting suspension was stirred at 25°C under an atmosphere of H2(g) for 16 hours. The reaction mixture was filtered through celite, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give a mixture of tert-butyl 2-(3-(1,3-dioxolan-2-yl)-1,2-dihydropyridin-2-yl)piperidine-1-carboxylate and tert-butyl 2-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate (7:3, 600 mg, 74%) as a light yellow gum, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 337 and 335 respectively.

[1059] Step C. tert-Butyl 2-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate

[1060]

[1061] MnO2 (3.62 g, 41.6 mmol) was added to a mixture of the product (700 mg, 2.08 mmol) obtained in step B in chloroform (20 mL) at room temperature, and the resulting suspension was stirred at 80 ° C for 16 hours. The reaction mixture was filtered through celite, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to obtain a yellow gum. The crude product was purified by preparative TLC (EtOAc: petroleum ether = 1: 5) to obtain the title compound (240 mg, 34%) as a light yellow gum. MS (ESI): m / z [M + H] + 335.

[1062] Step D. tert-Butyl 2-(3-formylpyridin-2-yl)piperidine-1-carboxylate

[1063]

[1064] pTsOH×H2O (25.03 mg, 0.13 mmol) was added to a solution of tert-butyl 2-(3-(1,3-dioxolane-2-yl)pyridin-2-yl)piperidine-1-carboxylate (220 mg, 0.66 mmol) and water (0.178 mL, 9.87 mmol) in acetone (20 mL) at room temperature. The resulting suspension was stirred at 60 ° C for 16 hours. The reaction mixture was poured into brine (100 mL), extracted with EtOAc (3×50 mL), and the organic layer was dried (Na2SO4), filtered and evaporated to give a yellow gum. The crude product was purified by preparative TLC (EtOAc: petroleum ether 1:2) to give (135 mg, 71%) of the title compound as a light yellow gum. MS (ESI): m / z[M+H] + 335.

[1065] Step E. 2-(3-(((2-(Ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-2-yl)piperidine- 1- tert-Butyl carboxylate

[1066]

[1067] AcOH (2.0mL, 34.9mmol) is added to tert-butyl 2-(3-formylpyridin-2-yl)piperidine-1-carboxylate (600mg, 2.07mmol), 3-amino-1H-pyrrole-2-carboxylate ethyl ester hydrochloride (473mg, 2.48mmol) in MeOH (25mL) at room temperature, and the resulting solution is stirred at 60 ° C for 2 hours. NaBH4 (260mg, 4.13mmol) is added to the reaction mixture at room temperature, and the resulting solution is stirred at 60 ° C for 5 hours. The reaction mixture is poured into saturated NaHCO3 aqueous solution (125mL) and extracted with EtOAc (3×75mL). The combined organic layer is dried (Na2SO4), filtered and evaporated to obtain a yellow jelly. The crude product is purified by preparative TLC (EtOAc: petroleum ether 1:3) to obtain (100mg, 11%) title compound as a light yellow jelly. MS (ESI): m / z [M+H] + 429.

[1068] Step F. 2-(3-((4-oxo-2-thiocarbonyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-1- tert-Butyl)methyl)pyridin-2-yl)piperidine-1-carboxylate

[1069] Benzoyl isothiocyanate (76 mg, 0.47 mmol) was added to a solution of tert-butyl 2-(3-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-2-yl)piperidine-1-carboxylate (100 mg, 0.23 mmol) in DCM (10 mL) at 20 ° C. The resulting solution was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in MeOH (10 mL). Cs2CO3 (152 mg, 0.47 mmol) was added, and the resulting solution was stirred at 50 ° C for 15 hours. The solvent was removed under reduced pressure, and the crude product was purified by preparative TLC (EtOAc: petroleum ether=1:2) to give (90 mg, 87%) of the title compound as a light yellow oil that solidified upon standing. MS (ESI): m / z[M+H] + 442.

[1070] Intermediate 23

[1071] (9H-fluoren-9-yl)methyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridine-3- 4-(trifluoromethyl)piperidine-1-carboxylate

[1072]

[1073] Step A. 3-Bromo-2-(1,3-dioxolan-2-yl)pyridine

[1074]

[1075] pTsOH (1.85 g, 10.8 mmol) was added to a solution of 3-bromopyrrolidone (10.0 g, 53.8 mmol) and ethane-1,2-diol (6.67 g, 107.5 mmol) in toluene (80 mL) at room temperature. The resulting solution was stirred at 130 ° C for 15 hours. The solvent was removed under reduced pressure, and the residue was poured into a saturated aqueous NaHCO3 solution (300 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give (9.50 g, 77%) of the title compound as a yellow solid, which was used directly in the next step without further purification. MS (ESI): m / z[M+H] + 230 / 232.

[1076] Step B. (5-(2-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)amine tert-Butyl formate

[1077]

[1078] At -78 ° C, n-butyl lithium (2.5 M in hexane, 3.6 mL, 9.0 mmol) was added to a solution of 3-bromo-2-(1,3-dioxolane-2-yl)pyridine (1.894 g, 8.23 ​​mmol) in THF (10 mL). The resulting solution was stirred at -78 ° C under an N2 (g) atmosphere for 15 minutes. At -78 ° C and an N2 (g) atmosphere, a solution of tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (CAS Reg. No. 911634-72-5) (2.0 g, 7.48 mmol) in THF (10 mL) was added dropwise to the stirred solution. The resulting solution was then stirred at -78 ° C for 1 hour. The reaction mixture was poured into brine (200 mL), extracted with EtOAc (3×100 mL), and the combined organic layers were dried (Na2SO4), filtered, and evaporated to give a yellow gum. The crude product was purified by flash chromatography using a gradient of 10% to 30% EtOAc in petroleum ether as the mobile phase to afford (2.2 g, 70%) of the title compound as a light yellow gum. MS (ESI): m / z [M+H] + 419.

[1079] Step C. 2'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine

[1080]

[1081] TFA (0.81 mL, 10.5 mmol) was added to a solution of tert-butyl (5-(2-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate (2.2 g, 5.26 mmol) in DCM (40 mL) at room temperature, and the resulting solution was stirred for 20 hours. The solvent was removed under reduced pressure, and the residue was poured into brine (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and evaporated to give (1.5 g, 95%) of the title compound as a yellow gum. MS (ESI): m / z [M+H] + 301.

[1082] Step D. 2-(1,3-dioxolan-2-yl)-3-(4-(trifluoromethyl)piperidin-2-yl)pyridine

[1083]

[1084] Pd(OH)2 / C (0.81 g, 0.87 mmol) was added to a solution of 2'-(1,3-dioxolane-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine (1.30 g, 4.33 mmol) in MeOH (20 mL) and AcOH (2.0 mL) at room temperature. The reaction mixture was evacuated and backfilled with H2(g) five times. The resulting suspension was stirred at room temperature under an atmosphere of H2(g) for 8 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure to give (1.0 g, 76%) of the title compound as a yellow gum. MS (ESI): m / z[M+H] + 303.

[1085] Step E. (9H-Fluoren-9-yl)methyl 2-(2-(1,3-dioxolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl) Piperidine-1-carboxylate

[1086]

[1087] Fmoc-Cl (1.03 g, 3.97 mmol) was added to a solution of 2-(1,3-dioxolane-2-yl)-3-(4-(trifluoromethyl)piperidin-2-yl)pyridine (1.0 g, 3.31 mmol) and TEA (1.38 mL, 9.92 mmol) in THF (25 mL) at room temperature, and the resulting solution was stirred for 15 hours. The reaction mixture was poured into brine (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give a yellow gum. The crude product was purified by flash chromatography using a gradient of 5%-50% EtOAc in petroleum ether as the mobile phase to give (1.05 g, 60%) of the title compound as a white solid. MS (ESI): m / z[M+H] + 525.

[1088] Step F. (9H-Fluoren-9-yl)methyl 2-(2-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[1089]

[1090] A 6M aqueous HCl solution (50 mL, 300 mmol) was added to a solution of (9H-fluoren-9-yl)methyl 2-(2-(1,3-dioxolane-2-yl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.05 g, 2.00 mmol) in MeCN (50 mL) at room temperature. The resulting solution was stirred at 90°C for 15 hours. The reaction mixture was poured into a saturated aqueous NaHCO solution (250 mL) and extracted with EtOAc (3 x 125 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to afford (0.7 g, 73%) of the title compound as a brown gum. MS (ESI): m / z [M+H] + 481.

[1091] Step G. (9H-Fluoren-9-yl)methyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl) pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[1092] At room temperature by NaBH (137mg, 2.19mmol) add to (9H-fluorenes-9-yl) methyl 2-(2-formylpyridine-3-yl)-4-(trifluoromethyl) piperidine-1-carboxylate (700mg, 1.46mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (270mg, 1.75mmol) in MeOH (20mL) and AcOH (4.00mL), and gained solution is stirred 3 hours at 60 ℃.Reaction mixture is poured into saturated NaHCO aqueous solution (100mL), and extracted with EtOAc (3 × 50mL).By the organic layer drying (Na 2 SO 4) that merges, filter and evaporate, obtain yellow jelly.By flash chromatography purification of crude product, use gradient be 5%-30% EtOAc petroleum ether solution as mobile phase, obtain (660mg, 73%) title compound, be light yellow oily thing, it solidifies when standing. MS (ESI): m / z [M+H] + 481.

[1093] Intermediate 24

[1094] (9H-fluoren-9-yl)methyl 2-(4-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridine-3- 4-(trifluoromethyl)piperidine-1-carboxylate

[1095]

[1096] Step A. 3-Bromo-4-(1,3-dioxolan-2-yl)pyridine

[1097]

[1098] pTsOH (1.85 g, 10.8 mmol) was added to a solution of 3-bromoisonicotinaldehyde (10 g, 53.8 mmol) and ethane-1,2-diol (6.67 g, 107.5 mmol) in toluene (80 mL) at room temperature, and the mixture was stirred at 130°C for 15 hours. The solvent was removed under reduced pressure, and the residue was poured into a saturated aqueous NaHCO3 solution (300 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give (10.0 g, 81%) of the title compound as a yellow liquid. MS (ESI): m / z [M+H] + 230 / 232.

[1099] Step B. (5-(4-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)amine tert-Butyl formate

[1100]

[1101] At -78 ° C, n-butyl lithium (2.5M in hexane, 9.0 mL, 22.5 mmol) was added to a solution of 3-bromo-4-(1,3-dioxolane-2-yl)pyridine (4.95 g, 21.52 mmol) in THF (30 mL). The resulting solution was stirred at -78 ° C and N2 (g) atmosphere for 15 minutes. At -78 ° C and N2 (g) atmosphere, a solution of tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (5.0 g, 18.71 mmol) in THF (30 mL) was added dropwise to the stirred solution. The resulting solution was stirred at -78 ° C for 1 hour. The reaction mixture was poured into brine (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give a yellow gum. The crude product was purified by flash chromatography using a gradient of 10% to 50% EtOAc in petroleum ether as the mobile phase to afford (4.60 g, 59%) of the title compound as a light yellow gum. MS (ESI): m / z [M+H] + 419.

[1102] Step C. 4'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine

[1103]

[1104] TFA (14.4 mL, 186.9 mmol) was added to a solution of tert-butyl (5-(4-(1,3-dioxolane-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate (4.6 g, 10.99 mmol) in DCM (60 mL) at room temperature and stirred at 20°C for 15 hours. The solvent was removed under reduced pressure. The residue was poured into saturated aqueous NaHCO3 (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give (3.20 g, 97%) of the title compound as a brown color. MS (ESI): m / z[M+H] + 301.

[1105] Step D. 4-(1,3-dioxolan-2-yl)-3-(4-(trifluoromethyl)piperidin-2-yl)pyridine

[1106]

[1107] Lithium triethylborohydride (1M in THF) (22 mL, 22 mmol) was added to a solution of 4'-(1,3-dioxolane-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine (2.2 g, 7.33 mmol) in THF (10 mL) cooled to 0°C. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was poured into saturated aqueous NaHCO3 (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give (2.0 g, 90%) of the title compound as a yellow gum. MS (ESI): m / z[M+H] + 303.

[1108] Step E. (9H-Fluoren-9-yl)methyl 2-(4-(1,3-dioxolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl) Piperidine-1-carboxylate

[1109]

[1110] Fmoc-Cl (2.05 g, 7.94 mmol) was added to a solution of 4-(1,3-dioxolane-2-yl)-3-(4-(trifluoromethyl)piperidin-2-yl)pyridine (2.0 g, 6.62 mmol) and TEA (2.77 mL, 19.85 mmol) in THF (10 mL), and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was poured into brine (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give a yellow gum. The crude product was purified by flash chromatography using a gradient of 5%-50% EtOAc in petroleum ether as the mobile phase to give (1.15 g, 33%) of the title compound as a white solid. MS (ESI): m / z[M+H] + 525.

[1111] Step F. (9H-Fluoren-9-yl)methyl 2-(4-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[1112]

[1113] HCl (6M, aqueous solution) (15 mL, 90.0 mmol) was added to a solution of (9H-fluoren-9-yl)methyl 2-(4-(1,3-dioxolane-2-yl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.1 g, 2.10 mmol) in MeCN (30 mL), and the resulting solution was stirred at 90 ° C for 15 hours. The reaction mixture was poured into saturated NaHCO 3 (250 mL) and extracted with EtOAc (3×125 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and evaporated to give (0.95 g, 94%) of the title compound as a brown gum. MS (ESI): m / z [M+H] + 481.

[1114] Step G. (9H-Fluoren-9-yl)methyl 2-(4-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl) pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[1115] At room temperature by NaBH4(177mg, 2.81mmol) is added to (9H-fluorenes-9-yl) methyl 2-(4-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (900mg, 1.87mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (347mg, 2.25mmol) in MeOH (20mL) and AcOH (4.00mL) solution, and the resulting solution is stirred at 60 DEG C for 3 hours.The reaction mixture is poured into saturated NaHCO3 aqueous solution (100mL) and extracted with EtOAc (3×50mL).The combined organic layer is dried (Na2SO4), filtered and evaporated to obtain a yellow gum.The crude product is purified by preparative TLC (EtOAc: petroleum ether=1:2) to obtain (550mg, 47...

Claims

1. A compound of formula (I) in X=CH or N Y 1 =CZ 1 or N, Y 2 =CZ 2 or N, Y 3 =CZ 3 or N, Y 4 =CZ 4 or N, and Y 5 = CZ 5 or N If present, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently H, halogen, CF3, Q or T, The prerequisite is Y 1 , Y 2 , Y 3 , Y 4 or Y 5 No more than one of them is N, Y 1 , Y 2 , Y 3 , Y 4 or Y 5 At least two of them are CH, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Not more than one of them is a halogen or CF3, and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 One and only one of them is Q or T, Q is where m is 0, 1, 2, or 3, T is p is 0 or 1, s is 0, 1, or 2, n is 0, 1, or 2, A is CH2, CF2, CHF, CHR 2 , CFR 2 NR 3 or O, in; If present, R 1 and R 2 independently CH2F, CHF2 or CF3 If present, R 3 are independently H or CH3, or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which has the following structure: or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, which has the following structure: or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which has the following structure: or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 2 , Y 3 and Y 4 It is CH.

6. The compound according to any one of claims 1 to 4, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 and Y 4 It is CH.

7. The compound according to any one of claims 1 to 4, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 and Y 4 It is CH.

8. The compound according to any one of claims 1 to 7, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 4 is N and Y 1 , Y 2 and Y 3 It is CH.

9. The compound according to any one of claims 1 to 8, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 0.

10. The compound according to any one of claims 1 to 8, wherein n is 1, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 8, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein n is 2.

12. A compound according to any one of claims 1 to 11, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is NR 3 .

13. The compound according to claim 12 or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 3 It is CH3.

14. The compound according to claim 12 or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 3 It's H.

15. The compound according to any one of claims 1 to 11, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CH2, CF2, CHF, CHR 2 or CFR 2 .

16. The compound according to claim 15, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CH2.

17. The compound according to claim 15, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHF.

18. The compound according to claim 15, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CF2.

19. The compound according to claim 15, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein A is CHR 2 .

20. The compound according to claim 19, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein R 2 It is CH2F.

21. The compound according to claim 19 or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 2 It is CHF2.

22. The compound according to claim 19, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein R 2 It's CF3.

23. The compound according to any one of claims 1-22, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 0.

24. The compound according to any one of claims 1-22, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 1.

25. The compound according to any one of claims 1-22, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein s is 2.

26. The compound according to any one of claims 1-25, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 0.

27. The compound according to any one of claims 1-25, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 1.

28. The compound according to claim 1 or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 5 It's CZ 5 , and Z 5 It is T or Q.

29. The compound according to claim 28, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Z 5 It's T.

30. The compound according to claim 29, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein T is 31. The compound according to claim 30, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein p is 0.

32. A compound according to any one of claims 28 to 31, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 1 、 Y 2 , Y 3 and Y 4 It is CH.

33. A compound according to any one of claims 28 to 31, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 1 、 Y 2 , Y 3 and Y 4 One of them is N.

34. A compound according to any one of claims 28 to 31 or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y 1 、 Y 2 , Y 3 and Y 4 The two in it are CH, Y 1 、 Y 2 , Y 3 and Y 4 One of them is N, and Y 1 、 Y 2 , Y 3 and Y 4 One of them is CCl.

35. The compound according to claim 1, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 2 It's Q.

36. The compound according to claim 1, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 3 It's Q.

37. The compound according to claim 1, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein Y 4 It's Q.

38. The compound according to claim 35, 36 or 37, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein m=1.

39. The compound according to any one of claims 28-38, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein X is CH.

40. The compound according to any one of claims 28-38, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein X is N.

41. A compound according to claim 1, selected from: 1-(2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 3-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one, 1-(2-(azepan-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(azepan-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(azepan-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one, (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one, (R)-1-(2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(morpholin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(4-methylpiperazin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-(2-(5-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thiocarbonyl-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thiocarbonyl-3-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 3-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one, 3-(2-(5-fluoropiperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thiocarbonyl-1-((2-(-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((2-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thiocarbonyl-3-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thiocarbonyl-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thiocarbonyl-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, Racemic-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-((2S,4R)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-((2-(piperidin-2-yl)pyridin-3-yl)methyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((3-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((3-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-(1-aminocyclobutyl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(3-(1-aminocyclobutyl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(piperidin-3-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(Morpholin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(morpholin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(morpholin-2-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(piperidin-4-yl)benzyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, Racemic-2-thiocarbonyl-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((2-((trans)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thiocarbonyl-1-((2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and or pharmaceutically acceptable salts thereof.

42. The compound of claim 1, having the structure: or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

43. The compound according to claim 1, having the structure: or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

44. The compound according to claim 1, having the structure: or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

45. A compound of formula (Ia) in, X 1 =CH or N, Each X 2 are independently CH, CF or CCl, and r and q are 0, 1 or 2, provided that r+q=2 or 3, or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

46. ​​A compound of formula (Ib) in, X 1 =CH or N, Each X 2 are independently CH, CF or CCl, and r and q are 0, 1 or 2, provided that r+q=2 or 3, or any stereoisomer thereof or any pharmaceutically acceptable salt thereof.

47. The compound according to claim 45 or 46, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein each X 2 It is CH.

48. A compound according to any one of claims 45-47, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein r is 1 and q is 1.

49. The compound according to any one of claims 45-47, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein r is 1 and q is 2 or r is 2 and q is 1.

50. The compound according to any one of claims 45-47, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein r is 0 and q is 2 or r is 2 and q is 0.

51. A compound according to any one of claims 45-50, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein X 1 It is CH.

52. A compound according to any one of claims 45-50, or any stereoisomer thereof, or any pharmaceutically acceptable salt thereof, wherein X 1 It is N.

53. A compound according to claim 46, selected from: 1-((1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(isoindolin-5-ylmethyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(isoindolin-4-ylmethyl)-2-thiocarbonyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and or pharmaceutically acceptable salts thereof.

54. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

55. A pharmaceutical composition comprising a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof according to any one of claims 45 to 53 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

56. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition requiring modulation of chloroperoxidase (MPO) activity.

57. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder with an inflammatory, cardiovascular and / or neural component, and / or a neutrophil-driven disease.

58. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder having an inflammatory, cardiovascular, respiratory, renal, hepatic and / or neurological component, and / or a neutrophil-driven disease.

59. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 53 for use in treating or preventing an autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2-induced renal failure, diabetic nephropathy (DKD), endometriosis, end stage renal disease (ESKD), immunoglobulin A vasculitis (Henoch-Schonlein Purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

60. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 53 for use in treating or preventing coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to recurrence of atrial fibrillation / flutter after cardioversion / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), preventing the progression of atherosclerosis and / or promoting regression, COVID-19 (or SARSCoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal cross-talk, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction.

61. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke and / or subarachnoid hemorrhage.

62. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pulmonary disease, and acute respiratory distress syndrome (ARDS).

63. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

64. A method of treating, preventing, or reducing the risk of one or more diseases or conditions in which inhibition of the MPO enzyme is beneficial, the method comprising administering to a human suffering from or at risk of the disease or condition a therapeutically effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof.

65. A method of treating, preventing or reducing the risk of one or more diseases or conditions having inflammatory, cardiovascular, respiratory, renal, hepatic and / or neural components, and / or neutrophil-driven diseases, comprising administering to a human suffering from or at risk of the disease or condition a therapeutically effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof.

66. A method of treating, preventing, or reducing the risk of one or more diseases or conditions selected from autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end stage renal disease (ESKD), immunoglobulin A vasculitis (Henschke purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD and / or obesity associated with CKD, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof to a person suffering from or at risk of the disease or condition.

67. A method of treating, preventing or reducing the risk of one or more diseases or conditions selected from the group consisting of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonged time to recurrence of atrial fibrillation / flutter after cardioversion / prevention of recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arresting progression and / or promoting regression of atherosclerosis, COVID-19 (or SARS CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal cross-lesions, initial or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof to a person suffering from the disease or condition or at risk of the disease or condition.

68. A method of treating, preventing or reducing the risk of one or more diseases or conditions selected from Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke and / or subarachnoid hemorrhage, comprising administering to a human suffering from or at risk of the disease or condition a therapeutically effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof.

69. A method of treating, preventing, or reducing the risk of one or more diseases or conditions selected from chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pulmonary disease, and acute respiratory distress syndrome (ARDS), comprising administering to a human suffering from or at risk of the disease or condition a therapeutically effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof.

70. A method of treating cancer, the method comprising administering to a human suffering from the disease or condition a therapeutically effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof.

71. A compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating or preventing a disease or condition requiring modulation of chloroperoxidase (MPO) activity.

72. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing a disease or disorder with an inflammatory, cardiovascular and / or neural component, and / or a neutrophil-driven disease.

73. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing a disease or disorder having an inflammatory, cardiovascular, respiratory, renal, hepatic and / or neural component, and / or a neutrophil-driven disease.

74. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the preparation of a composition for treating or preventing autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), or the like. BD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular disorders, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2)-induced renal failure, diabetic nephropathy (DKD), endometriosis, end stage renal disease (ESKD), immunoglobulin A vasculitis (Henschoff purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

75. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 53, for use in the preparation of a composition for treating or preventing coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to recurrence of atrial fibrillation / flutter after cardioversion / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), preventing the progression of atherosclerosis and / or promoting regression, COVID-19 (or SARS CoV2)-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal cross-talk, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, drugs that inhibit plaque rupture, improve inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction.

76. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke and / or subarachnoid hemorrhage.

77. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic pulmonary disease, and acute respiratory distress syndrome (ARDS).

78. A compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating cancer.

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