Myeloperoxidase inhibitors

Abstract

This specification relates generally to compounds of formula (I), (Ia) and (Ib), and pharmaceutically acceptable salts thereof, wherein X, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 , and X 1 , X 2 , r, and q have any of the meanings defined herein, along with compositions containing them and their uses in therapy. The compounds are inhibitors of the enzyme MPO and are therefore particularly useful in the treatment or prevention of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable, including diseases with inflammatory, cardiovascular, respiratory, renal, hepatic, and / or neurological components, and neutrophil-driven diseases. [Case 1] JPEG2025528217000291.jpg31128

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Patent Application No. 63 / 398,939, filed August 18, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Myeloperoxidase (MPO) is a heme-containing enzyme primarily expressed in neutrophil granulocytes (neutrophils). MPO is one member of a diverse family of mammalian peroxidase proteins, which also includes eosinophil peroxidase (EPX), lactoperoxidase (LPO), and thyroid peroxidase (TPO). MPO is activated by hydrogen peroxide, the source of which can be NADPH-derived superoxide anion catalyzed by superoxide dismutase (SOD), xanthine oxidase-derived superoxide anion, and hydrogen peroxide formed during purine oxidation. MPO catalyzes the two-electron oxidation of halides (primarily chloride) and pseudohalides (e.g., thiocyanate) to form the germicidal hypohalous acids hypochlorous acid (bleach) and hypothiocyanous acid. These in turn can act on multiple protein, lipid and nucleic acid targets, causing dysfunction and further inflammation. 1 Furthermore, MPO catalyzes the one-electron oxidation of numerous electron-rich substrates through the so-called peroxidation cycle, generating free radicals that are themselves harmful (e.g., urate radicals). 2 ), or by directly oxidizing nitric oxide (NO) or by generating free radicals that oxidize NO, resulting in free radicals that can interfere with NO-driven physiological functions. 1 .

[0003] Numerically, neutrophils are the predominant leukocyte population (50-70% of blood leukocytes in humans) and are a highly dynamic cell population that is part of the first line of defense against stressors, whether microbial or sterile. Within neutrophils, preformed MPO is stored in millimolar concentrations in granules, which fuse with phagosomes containing engulfed microorganisms, leading to MPO activation and microbial killing. 3 Furthermore, MPO can also be released outside the cell, where its oxidative activity can cause damage to adjacent tissues and dysfunction or regulation of biochemical and cellular processes, such as tissue remodeling and fibrosis. This release can occur as a result of either degranulation or NETosis, which releases webs of decondensed DNA coated with intracellular proteins such as MPO, so-called neutrophil extracellular traps (NETs). 4 Furthermore, MPO is also released constitutively. 5 The enzyme is highly cationic and therefore becomes trapped extracellularly in negatively charged structures such as proteoglycans on the extracellular matrix in the vascular wall and interstitium. 6 .

[0004] Given the dominance of neutrophils in inflammatory biology and the abundance of MPO in neutrophils (estimated at 5% of the cell's dry weight), it is not surprising that numerous disease states have been hypothesized to involve the pathological role of myeloperoxidase. Such conditions include not only "traditional" inflammatory diseases such as inflammatory bowel disease and 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 .

[0005] The pathophysiological role of MPO is further supported by human genetic studies and rodent intervention studies. 7 and tissue MPO activity 8A common polymorphism in the MPO promoter regulating coronary microvascular dysfunction 9 , mortality in heart failure 10 , risk of coronary artery disease 11 and its outcomes 12 , risk of developing hepatitis C-related liver fibrosis and cirrhosis 13、14 and the risk of hepatocellular carcinoma and death in alcohol-related cirrhosis 15 In vivo studies in rodents and in vitro studies in humans have reported the efficacy of selective MPO inhibitors for several diseases and / or conditions, including preservation of cardiac function in post-myocardial infarction models. 16 , stabilization of atherosclerotic plaque 17 , pulmonary arterial hypertension 18 , glomerulonephritis 19 and cystic fibrosis 20 Improvement of fatty liver and liver fibrosis 21 22 reduction of vascular dysfunction in conditions of inflammatory vascular dysfunction 23 , normalization of microvascular function 24 , improved relaxation in human cardiomyocytes 25 , and inhibition of neutrophil nephrosis in human neutrophils 26 .

[0006] Although the contribution of MPO to these various disease states may vary depending on the condition, several mechanisms appear to be important in some of these conditions: damage and dysfunction caused by MPO-derived reactive oxygen species, such as hypochlorous acid; 1 In addition, MPO also induces neutrophil activation 27 , and through activation of proteinases that cleave the latent form into active effector proteins, e.g., cytokines. 28 MPO appears to play a regulatory role in inflammation, acting to amplify the inflammatory response. The mechanistic link between MPO and fibrosis is also likely multifactorial, e.g., i) secondary to increased inflammation, ii) through activation of myofibroblasts. 29 and iii) increased collagen secretion itself. 30Finally, active MPO directly (and indirectly) oxidizes NO via the peroxidative cycle, thereby impairing nitric oxide-driven mechanisms such as smooth muscle cell relaxation. 31 This latter mechanism involves MPO being sequestered on proteoglycans, transcytosed by endothelial cells, and spatially deposited in the subendothelial compartment between NO-producing endothelium and NO-receptor smooth muscle. 32 Therefore, the relationship between MPO and microvascular dysfunction and the resulting impaired blood supply to tissues may be of particular importance.

[0007] In summary, there is a medical need and sound rationale for orally active MPO inhibitors for the treatment of chronic inflammatory conditions. To increase the therapeutic index of such agents, it is necessary to obtain MPO inhibitors that are selective for MPO over TPO. The thyroid gland is a key regulator of thermogenesis and metabolic function, and TPO plays a central role through iodination of tyrosine residues to form the thyroid hormones T4 and T3. TPO activation is under the control of thyroid-stimulating hormone, and T4 and T3 are part of a negative feedback mechanism; thus, decreased levels of T3 and T4 upon TPO inhibition result in a compensatory increase in thyroid-stimulating hormone. 33 .

[0008] WO 2003 / 089430, WO 2005 / 037835, WO 2007 / 120097, WO 2007 / 120098 and WO 2007 / 142576 disclose thioxanthine derivatives and their use as MPO inhibitors in therapy.

[0009] WO 2006 / 062465 and WO 2007 / 142577 disclose 2-thioxo-1,2,3,4-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one derivatives that are claimed to be inhibitors of MPO. These compounds are said to be selective for related enzymes such as TPO.

[0010] WO 2009 / 025618 discloses the use of thioxanthine and 2-thioxo-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.

[0011] J. Labeled Compounds and Radiopharmaceuticals, 2012, 55, 393-399, discloses several tritium-labeled thioxanthine derivatives, 13C-labeled thioxanthine derivatives, and 14C-labeled pyrrolo[3,2-d]pyrimidin-4-one compounds, which are described as inactivators of MPO.

[0012] J. Biol. Chem., 2011, 286, 37578-37589 discloses certain thioxanthine derivatives. These compounds are described as inhibiting plasma MPO and reducing protein chlorination in mouse models. These compounds are also claimed to be weak inhibitors of TPO.

[0013] WO 2013 / 068875 discloses thiopyrimidone derivatives that are alleged to be MPO inhibitors.

[0014] WO 2016 / 087338 discloses thioxopyrrolopyrimidone derivatives that are said to be MPO inhibitors.

[0015] Therefore, there is a need for novel therapeutically useful MPO inhibitors, as well as novel MPO inhibitors with improved selectivity for the MPO enzyme over the TPO enzyme and suitable pharmacological properties. DETAILED DESCRIPTION OF THE INVENTION

[0016] This detailed description and its specific examples illustrate embodiments and are for purposes of illustration only. Accordingly, it is not intended to be limiting of the exemplary embodiments set forth herein. Furthermore, it should be understood that various features that are, for clarity, described in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be combined to form subcombinations thereof.

[0017] Listed below are definitions of various terms used in the specification and claims.

[0018] The term "halo" means fluoro, chloro, bromo, and iodo. In one embodiment, halo is fluoro or chloro.

[0019] The term "N-heterocycle" refers to a partially or fully saturated hydrocarbon ring system, ie, non-aromatic, in which at least one of the ring carbon atoms is replaced by nitrogen.

[0020] For the avoidance of doubt, when a group is modified herein by "as defined above," it is to be understood that this group encompasses the broadest definition occurring first, as well as each and every other definition for that group. It is to be understood that any definition, claim, aspect, or embodiment of a variable group of the formula disclosed herein may be combined (where context allows) with any other definition, claim, aspect, or embodiment herein to provide further embodiments of the present invention.

[0021] Certain embodiments disclosed herein provide compounds, compositions and methods for inhibiting myeloperoxidase, and methods for treating diseases or conditions associated with myeloperoxidase.

[0022] compound One embodiment disclosed herein is a compound of formula (I):

[0023] [ka] During the ceremony, 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, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is, if present, independently H, halo, CF, Q or T; However, Y 1 , Y 2 , Y 3 , Y 4 or Y 5 At most one of 1 , Y 2 , Y 3 , Y 4 or Y 5 At least two of Z are CH 1 , Z 2 , Z 3 , Z 4 and Z 5 at most one of Z is halo or CF 1 , Z 2 , Z 3 , Z 4 and Z 5 exactly one of which is Q or T, Q is

[0024] [ka] wherein m is 0, 1, 2, or 3; T is

[0025] [ka] and 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 , N.R. 3 Or O, During the ceremony, R 1 and R 2 is, if present, independently CHF, CHF, or CF; R 3 is, if present, independently H or CH3; The present invention provides a compound, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment, there is provided a compound of any of formula (I):

[0027] In one embodiment, a pharmaceutically acceptable salt of any compound of formula (I) is provided.

[0028] Another embodiment disclosed herein is a compound having the following structure:

[0029] [ka] or any stereoisomer thereof or a 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).

[0030] Yet another embodiment disclosed herein is a compound:

[0031] [ka] or any stereoisomer thereof or a 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).

[0032] Some embodiments disclosed herein include a compound having the following structure:

[0033] [ka] or any stereoisomer thereof or a 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).

[0034] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 2 , Y 3 is, and Y 4 is CH.

[0035] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 2 , Y 3 is, and Y 4 is CH.

[0036] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 is, and Y 4 is CH.

[0037] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 is, and Y 4 is CH.

[0038] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 is, and Y 4 is CH.

[0039] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 is, and Y 4 is CH.

[0040] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 4 is N and Y 1 , Y 2 is, and Y 3 is CH.

[0041] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 4 is N and Y 1 , Y 2 is, and Y 3 is CH.

[0042] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0043] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0044] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0045] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0046] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0047] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0048] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is NR 3 is.

[0049] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is NR 3 is.

[0050] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is NR 3 and R 3 is CH3.

[0051] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is NR 3 and R 3 is CH3.

[0052] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is NR 3 and R 3 is H.

[0053] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is NR 3 and R 3 is H.

[0054] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CH, CF, CHF, CHR, 2 or CFR 2 is.

[0055] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein A is CH, CF, CHF, CHR 2 or CFR 2 is.

[0056] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CH.

[0057] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CH.

[0058] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHF.

[0059] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHF.

[0060] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CF.

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

[0062] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 is.

[0063] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 is.

[0064] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CH2F.

[0065] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CH2F.

[0066] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CHF2.

[0067] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CHF2.

[0068] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CF3.

[0069] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CF3.

[0070] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein s is 0.

[0071] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein s is 0.

[0072] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein s is 1.

[0073] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein s is 1.

[0074] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein s is 2.

[0075] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein s is 2.

[0076] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0077] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0078] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), or Formula (III), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0079] Some embodiments disclosed herein provide a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0080] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 and Z 5 is T or Q.

[0081] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 and Z 5 is T.

[0082] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 and Z 5 is T, and T is

[0083] [ka] In a further embodiment, p is 0.

[0084] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 and 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 still further embodiments, T is

[0085] [ka] In still further embodiments, p is 0.

[0086] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 and Z 5 is T or Q, and Y 1 , Y 2 , Y 3 and Y4 One of them is N.

[0087] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 and Z 5 is T or Q, and Y 1 , Y 2 , Y 3 and Y 4 Two of them are CH and Y 1 , Y 2 , Y 3 and Y 4 One of them is N and the other is Y 1 , Y 2 , Y 3 and Y 4 One of them is CCl.

[0088] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 5 together with the atoms to which they are attached form a 5- or 6-membered N-heterocycle. 2 , Y 3 and Y 4 is CH.

[0089] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z 2 and Z 3 together with the atoms to which they are attached form a 5- or 6-membered N-heterocycle. 1 , Y 4 , and Y 5 is CH.

[0090] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 2is Q. In a further embodiment, m=1.

[0091] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 3 is Q. In a further embodiment, m=1.

[0092] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y 4 is Q. In a further embodiment, m=1.

[0093] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0094] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0095] Some embodiments disclosed herein provide for a compound selected from the following: 1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 3-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, 1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (R)-1-(2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(4-methylpiperazin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-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-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-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-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, 3-(2-(5-fluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-1-((2-(-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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, rac-2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-((2S,4R)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-((2-(piperidin-2-yl)pyridin-3-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(3-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(piperidin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(piperidin-4-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-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-thioxo-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-thioxo-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-Thioxo-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 and pharmaceutically acceptable salts thereof.

[0096] Another embodiment disclosed herein is a compound of formula (Ia):

[0097] [ka] During the ceremony, X 1 =CH or N, each X 2 are independently CH, CF or CCl; r and q are 0, 1 or 2, with the proviso that r+q=2 or 3; The present invention provides a compound, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0098] Another embodiment disclosed herein is a compound of formula (Ib):

[0099] [ka] During the ceremony, X 1 =CH or N, each X 2 are independently CH, CF or CCl; r and q are 0, 1 or 2, with the proviso that r+q=2 or 3; The present invention provides a compound, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0100] Some embodiments disclosed herein provide a compound of Formula (Ia) or Formula (Ib), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each X 2 is CH.

[0101] Some embodiments disclosed herein provide a compound of Formula (Ia) or Formula (Ib), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein r is 1 and q is 1.

[0102] Some embodiments disclosed herein provide a compound of Formula (Ia) or Formula (Ib), or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein r is 1 and q is 2, or r is 2 and q is 1.

[0103] Some embodiments disclosed herein provide a compound of Formula (Ia) or Formula (Ib), or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein r is 0 and q is 2, or r is 2 and q is 0.

[0104] Some embodiments disclosed herein provide a compound of Formula (Ia) or Formula (Ib), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH.

[0105] Some embodiments disclosed herein provide a compound of Formula (Ia) or Formula (Ib), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

[0106] Some embodiments disclosed herein provide for a compound selected from the following: 1-((1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(isoindolin-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(isoindolin-4-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and and pharmaceutically acceptable salts thereof.

[0107] Some embodiments disclosed herein include a compound having the following structure:

[0108] [ka] wherein X, Y 1 , Y 2 , Y 3 , Y 4 , A, R 1 , n, p and s are as defined above for formula (II).

[0109] One embodiment disclosed herein is a compound having the following structure:

[0110] [ka] wherein Y 1 , Y 2 , Y 3 , Y 4, A, R 1 , n, p and s are as defined above for formula (III).

[0111] One embodiment disclosed herein is a compound having the following structure:

[0112] [ka] wherein Y 1 , Y 2 , Y 3 , Y 4 , A, R 1 , n, p and s are as defined above for formula (IV).

[0113] It should be noted that any one of these specific compounds may be dispensed with as a marker for any of the embodiments mentioned herein.

[0114] In some embodiments, provided are processes for the preparation of 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 intermediate compounds used in the preparation thereof.

[0115] Some embodiments disclosed herein provide products obtainable by any of the processes or examples disclosed herein.

[0116] Furthermore, due to the fact that the absolute configuration of the enantiomers of the compounds disclosed herein was determined by spectroscopic testing rather than, for example, X-ray testing, it is understood that the R and S nomenclature would be reversed if the results obtained from the spectroscopic testing were to prove erroneous for any reason.

[0117] Medical and Pharmaceutical Uses The compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), as disclosed herein, and pharmaceutically acceptable salts thereof, are useful because they possess pharmacological activity as inhibitors of the enzyme MPO.

[0118] The compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), as disclosed herein, and pharmaceutically acceptable salts thereof, are indicated for use in the treatment or prevention of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable. In particular, the association of MPO activity with 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.

[0119] The disclosed compounds are indicated for use in the treatment or prevention of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, that respond to the inhibition of MPO. Such diseases or conditions include autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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, fatty liver, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA), and other autoimmune diseases. These include, but are not limited to, pulmonary autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modifications, and type 2 diabetes.

[0120] The disclosed compounds are indicated for use in the treatment or prevention of cardiovascular diseases or conditions in mammals, including humans, that respond to the inhibition of MPO, including, 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.

[0121] The disclosed compounds are also indicated for use in the treatment or prevention of neurological diseases and conditions in mammals, including humans, in which microvascular dysfunction is prominent.

[0122] The disclosed compounds are also indicated for use in the treatment or prevention of neurological diseases and conditions in mammals, including humans, that respond to MPO inhibition. Such diseases and conditions include, but are not limited to, diseases associated 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.

[0123] The disclosed compounds are also indicated for use in the treatment or prevention of neutrophil-driven diseases or conditions in mammals, including humans, including, but not limited to, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).

[0124] The disclosed compounds are indicated for use in the treatment or prevention of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, that respond to the inhibition of MPO. Such diseases or conditions include autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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, fatty liver, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA), and other autoimmune diseases. These include, but are not limited to, autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modifications, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity associated with CKD.

[0125] The disclosed compounds are indicated for use in the treatment or prevention of cardiovascular diseases or conditions in mammals, including humans, that respond to the inhibition of MPO. Such cardiovascular diseases or conditions include 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 / preventing recurrence of atrial fibrillation / flutter after electrical cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arresting the progression and / or causing regression of atheroma, and the treatment of COVID-19 (or SARS-CoV-2). These include, but are not limited to, 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 crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, amelioration of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction.

[0126] The disclosed compounds are also indicated for use in the treatment or prevention of neurological diseases and conditions in mammals, including humans, that respond to MPO inhibition. Such diseases and conditions include, but are not limited to, diseases associated 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.

[0127] The disclosed compounds are indicated for use in the treatment of cancer.

[0128] Prevention is expected to be particularly relevant to the treatment of persons who have previously suffered from or are otherwise considered to be at increased risk of the disease or condition in question. Those at risk of developing a particular disease or condition generally include those who have a family history of the disease or condition, or who have been identified by genetic testing or screening, or who have been identified as being particularly susceptible to developing the disease or condition due to a particular biomarker pattern.

[0129] For the above therapeutic indications, the dosage administered will, of course, vary with the compound used, the mode of administration, and the treatment desired, but in general, satisfactory results are obtained when the compound is administered in a solid dosage of 1 mg to 2000 mg per day.

[0130] The compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), or compounds disclosed herein, and pharmaceutically acceptable derivatives thereof, may be used alone or in the form of a suitable pharmaceutical composition in which the compound or derivative is 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. 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, and at least one pharmaceutically acceptable excipient. Administration may be by, but is not limited to, enteral (including oral, sublingual, or rectal), intranasal, inhalation, intravenous, topical, or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs, MEAulton, Churchill Livingstone, 2002. nd It is described in Ed.2002.

[0131] In some embodiments, there is provided 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, for use in therapy, particularly in the prevention or treatment of one or more conditions or diseases in which inhibition of MPO would be beneficial.

[0132] In some embodiments, there is provided 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, for use in the prevention or treatment of a condition or disease with one or more inflammatory components, in which inhibition of MPO would be beneficial in a mammal, particularly a human.

[0133] In some embodiments, there is provided 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, for use in therapy, particularly in the prevention or treatment of one or more cardiovascular diseases in which inhibition of MPO would be beneficial in mammals, particularly humans.

[0134] In some embodiments, there is provided 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, for use in the prevention or treatment of one or more neurological diseases in which inhibition of MPO would be beneficial in mammals, particularly humans.

[0135] In some embodiments, there is provided 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, for use in therapy, particularly in the prevention or treatment of one or more neutrophil-driven diseases in which inhibition of MPO would be beneficial in mammals, particularly humans.

[0136] In some embodiments, the present invention relates to an inflammatory disease or condition in a mammal, particularly a human, or a disease or condition with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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), and the like.

[0013] Provided is 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, for use in the prevention or treatment of conditions such as pulmonary embolism, pulmonary fibrosis ...

[0137] In some embodiments, there is provided 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, for use in the prevention or treatment of 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, 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.

[0138] In some embodiments, the present invention relates to a cardiovascular disease or condition in a mammal, particularly a human, including, 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, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), or other conditions.

[0013] Provided is 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, for use in the prevention or treatment of conditions such as pulmonary hypertension, pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity.

[0139] In some embodiments, there is provided 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, for use in the prevention or treatment of neurological diseases and conditions, including but not limited to, diseases associated 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, in a mammal, particularly a human.

[0140] In some embodiments, there is provided 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, for use in the prevention or treatment of one or more neutrophil-driven diseases, such as, but not limited to, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS) in a mammal, particularly a human.

[0141] In some embodiments, the present invention relates to an inflammatory disease or condition in a mammal, particularly a human, or a disease or condition with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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), and the like. syndrome), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, 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 dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2)-induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN)

[0023] Provided is 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, for use in the prevention or treatment of CKD, i.e., CKD-associated nephropathy, lupus nephritis, diabetic CKD, hypertensive CKD and / or obesity associated with CKD.

[0142] In some embodiments, the therapeutic agent is used to treat a cardiovascular disease or condition in a mammal, particularly a human, including, 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, 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 / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD). Provided is 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, for use in the prevention or treatment of 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 crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibiting plaque rupture, ameliorating inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction, and the like.

[0143] In some embodiments, there is provided 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, for use in the prevention or treatment of neurological diseases and conditions, including, but not limited to, diseases associated 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, in a mammal, particularly a human.

[0144] In some embodiments, there is provided 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, for use in the prevention or treatment of cancer in a mammal, particularly a human.

[0145] In some embodiments, there is provided 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, for use in the prevention or treatment of coronary artery disease in a mammal, particularly a human.

[0146] In some embodiments, there is provided 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, for use in the prevention or treatment of acute coronary syndrome in a mammal, particularly a human.

[0147] In some embodiments, there is provided 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, for use in the prevention or treatment of heart failure in a mammal, particularly a human.

[0148] In some embodiments, there is provided 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, for use in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.

[0149] In some embodiments, there is provided 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, for use in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.

[0150] In some embodiments, there is provided 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, for use in the prevention or treatment of chronic kidney disease (CKD) in a mammal, particularly a human.

[0151] In some embodiments, there is provided 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, for use in the prevention or treatment of cardiorenal syndrome (CRS) in a mammal, particularly a human.

[0152] In some embodiments, there is provided 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, for use in the prevention or treatment of non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.

[0153] In some embodiments, there is provided 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, for use in the prevention or treatment of arrhythmia in a mammal, particularly a human.

[0154] In some embodiments, there is provided 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, for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.

[0155] In some embodiments, there is provided 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, for use in the prevention or treatment of sickle cell disease in a mammal, particularly a human.

[0156] In some embodiments, there is provided 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, for use in the prevention or treatment of acute kidney injury (AKI) in a mammal, particularly a human.

[0157] In some embodiments, there is provided 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, for use in the prevention or treatment of non-cystic fibrosis bronchiectasis (NCFB) in a mammal, particularly a human.

[0158] In some embodiments, there is provided 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, for use in the prevention or treatment of anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis in a mammal, particularly a human.

[0159] In some embodiments, there is provided 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, for use in the prevention or treatment of Alzheimer's disease in a mammal, particularly a human.

[0160] In some embodiments, there is provided 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, for use in the prevention or treatment of Parkinson's disease in a mammal, particularly a human.

[0161] In some embodiments, there is provided 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, for use in the prevention or treatment of nephritis in a mammal, particularly a human.

[0162] In some embodiments, there is provided 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, for use in the prevention or treatment of inflammatory bowel disease (IBD) in a mammal, particularly a human.

[0163] In some embodiments, there is provided 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, for use in the prevention or treatment of irritable bowel syndrome (IBS) in a mammal, particularly a human.

[0164] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more diseases or conditions in which inhibition of the enzyme MPO is beneficial, comprising administering to a person suffering from or at risk of said 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.

[0165] In some embodiments, methods are provided for treating, preventing, or reducing the risk of a disease or condition with one or more inflammatory components, 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.

[0166] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more cardiovascular diseases or conditions, comprising administering to a person suffering from or at risk of such a 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.

[0167] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more neurological diseases or conditions, comprising administering to a person suffering from or at risk of such a 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.

[0168] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more neutrophil-driven diseases or conditions, comprising administering to a person suffering from or at risk of such diseases or conditions 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.

[0169] In some embodiments, the present invention relates to a disease or condition with one or more inflammatory components, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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), and the like.

[0013] Methods for treating, preventing, or reducing the risk of, rheumatoid arthritis, systemic lupus erythematosus, fatty liver, 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 dysfunction, lipoprotein modifications, or type 2 diabetes are provided, comprising administering to a person suffering from the above-mentioned 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.

[0170] In some embodiments, the present invention relates to one or more cardiovascular diseases or conditions, including, 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, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), and the like.

[0013] Methods for treating, preventing, or reducing the risk of conditions such as pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity are provided, which comprise administering to a person suffering from the above-mentioned 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.

[0171] In some embodiments, the present invention relates to one or more cardiovascular diseases or conditions, including, 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, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), and the like.

[0013] Methods for treating, preventing, or reducing the risk of conditions such as pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and chemotherapy-induced cardiotoxicity are provided, which comprise administering to a person suffering from the above-mentioned diseases or conditions 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.

[0172] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more neurological diseases or conditions, such as, but not limited to, diseases associated 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, comprising administering to a person suffering from 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.

[0173] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more neutrophil-driven diseases or conditions, such as, but not limited to, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), comprising administering to a person suffering from 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.

[0174] In some embodiments, the present invention relates to a disease or condition with one or more inflammatory components, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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), and the like. syndrome), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, 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 dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2)-induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN)

[0013] Methods for treating, preventing, or reducing the risk of, for example, CKD, CKD-associated nephropathy, lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity associated with CKD, are provided, comprising administering to a person suffering from the above-mentioned 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.

[0175] In some embodiments, the present invention relates to one or more cardiovascular diseases or conditions, including, 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, 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 / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD). disease), arrest of atheroma progression and / or initiation of 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)

[0013] Methods for treating, preventing, or reducing the risk of (unspecified fraction) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibiting plaque rupture, ameliorating inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction, and the like, are provided, comprising administering to a person suffering from the above-mentioned 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.

[0176] In some embodiments, methods are provided for treating, preventing, or reducing the risk of one or more neurological diseases or conditions, such as, but not limited to, diseases associated 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, comprising administering to a person suffering from 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.

[0177] In some embodiments, methods of treating cancer are provided, 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.

[0178] In some embodiments, methods are provided for treating, preventing, or reducing the risk of coronary artery disease, comprising administering to a person suffering from or at risk of such a 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.

[0179] In some embodiments, methods are provided for treating, preventing, or reducing the risk of acute coronary syndrome, comprising administering to a person suffering from or at risk of such a 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.

[0180] In some embodiments, methods are provided for treating, preventing, or reducing the risk of heart failure, comprising administering to a person suffering from or at risk of such a 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.

[0181] In some embodiments, methods are provided for treating, preventing, or reducing the risk of heart failure with reduced ejection fraction, comprising administering to a person suffering from or at risk of such a 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.

[0182] In some embodiments, methods are provided for treating, preventing, or reducing the risk of heart failure with preserved ejection fraction, comprising administering to a person suffering from or at risk of such a 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.

[0183] In some embodiments, methods are provided for treating, preventing, or reducing the risk of chronic kidney disease (CKD), comprising administering to a person suffering from or at risk of such a 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.

[0184] In some embodiments, methods are provided for treating, preventing, or reducing the risk of cardiorenal syndrome (CRS), comprising administering to a person suffering from or at risk of such a 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.

[0185] In some embodiments, methods are provided for treating, preventing, or reducing the risk of non-alcoholic steatohepatitis (NASH), comprising administering to a person suffering from or at risk of such a 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.

[0186] In some embodiments, methods are provided for treating, preventing, or reducing the risk of arrhythmia, comprising administering to a person suffering from or at risk of the above-mentioned diseases or conditions 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.

[0187] In some embodiments, methods are provided for treating, preventing, or reducing the risk of chronic obstructive pulmonary disease (COPD), comprising administering to a person suffering from or at risk of such a 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.

[0188] In some embodiments, methods are provided for treating, preventing, or reducing the risk of sickle cell disease, comprising administering to a person suffering from or at risk of such a 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.

[0189] In some embodiments, methods are provided for treating, preventing, or reducing the risk of anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis, comprising administering to a person suffering from or at risk of such a 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.

[0190] In some embodiments, methods are provided for treating, preventing, or reducing the risk of acute kidney injury (AKI), comprising administering to a person suffering from or at risk of such a 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.

[0191] In some embodiments, methods are provided for treating, preventing, or reducing the risk of non-cystic fibrosis bronchiectasis (NCFB), 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.

[0192] In some embodiments, methods are provided for treating, preventing, or reducing the risk of Alzheimer's disease, comprising administering to a person suffering from or at risk of such a 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.

[0193] In some embodiments, methods are provided for treating, preventing, or reducing the risk of Parkinson's disease, comprising administering to a person suffering from or at risk of such a 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.

[0194] In some embodiments, methods are provided for treating, preventing, or reducing the risk of nephritis, comprising administering to a person suffering from or at risk of the above diseases or conditions 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.

[0195] In some embodiments, methods are provided for treating, preventing, or reducing the risk of inflammatory bowel disease (IBD), comprising administering to a person suffering from or at risk of such a 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.

[0196] In some embodiments, methods are provided for treating, preventing, or reducing the risk of irritable bowel syndrome (IBS), comprising administering to a person suffering from or at risk of such a 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.

[0197] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of a disease or condition in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable.

[0198] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of a disease or condition with an inflammatory, cardiovascular and / or neurological component, and / or a neutrophil-driven disease.

[0199] In some embodiments, the present invention is directed to a therapeutic target for 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, fatty liver, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA), and / or anti-neutrophil cytoplasmic autoantibodies (ANCA).

[0013] Provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification and / or type 2 diabetes.

[0200] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in 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), 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, and / or chemotherapy-induced cardiotoxicity.

[0201] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and / or epilepsy.

[0202] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of chronic sinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).

[0203] In some embodiments, the present invention is directed to a therapeutic target for 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, fatty liver, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA), and / or anti-neutrophil cytoplasmic autoantibodies (ANCA). autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2)-induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN)

[0014] Provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of CKD, lupus nephropathy, diabetic CKD, hypertensive CKD and / or obesity associated with CKD.

[0204] In some embodiments, the therapeutic agent is 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), 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 / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arresting the progression and / or causing regression of atheroma, COVID-19 (or SARS-CoV-2)

[0014] Provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of 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 crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibiting plaque rupture, ameliorating inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction.

[0205] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in the treatment or prevention of 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.

[0206] In some embodiments, provided is 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, for use in the manufacture of a medicament for use in the treatment of cancer.

[0207] In some embodiments, a pharmaceutical formulation is provided that includes 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, and a pharmaceutically acceptable diluent, excipient and / or inert carrier.

[0208] In some embodiments, there is provided a pharmaceutical formulation 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 the treatment, particularly the prevention or treatment, of one or more conditions or diseases in which inhibition of MPO would be beneficial.

[0209] In some embodiments, there is provided a pharmaceutical formulation 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 the treatment, particularly the prevention or treatment, of one or more conditions or diseases in which inhibition of MPO would be beneficial.

[0210] In some embodiments, there is provided a pharmaceutical formulation 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 the prevention or treatment of conditions or diseases with one or more inflammatory components in a mammal, particularly a human, in which inhibition of MPO would be beneficial.

[0211] In some embodiments, there is provided a pharmaceutical formulation 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 the treatment, particularly the prevention or treatment, of one or more cardiovascular diseases in a mammal, particularly a human, in which inhibition of MPO would be beneficial.

[0212] In some embodiments, there is provided a pharmaceutical formulation 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 the prevention or treatment of one or more neurological diseases in a mammal, particularly a human, in which inhibition of MPO would be beneficial.

[0213] In some embodiments, there is provided a pharmaceutical formulation 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 the treatment, particularly the prevention or treatment, of one or more neutrophil-driven diseases in a mammal, particularly a human, in which inhibition of MPO would be beneficial.

[0214] In some embodiments, the present invention relates to an inflammatory disease or condition in a mammal, particularly a human, or a disease or condition with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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), and the like.

[0013] Provided are pharmaceutical formulations 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 the prevention or treatment of conditions such as pulmonary embolism, pulmonary fibrosis ...

[0215] In some embodiments, the present invention relates to a cardiovascular disease or condition in a mammal, particularly a human, including, 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, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), or other conditions.

[0013] Provided is a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of conditions such as pulmonary arterial hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm and chemotherapy-induced cardiotoxicity.

[0216] In some embodiments, the present invention relates to a cardiovascular disease or condition in a mammal, particularly a human, including, 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, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), or other conditions.

[0013] Provided is a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of conditions such as pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm and chemotherapy-induced cardiotoxicity.

[0217] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of neurological diseases and conditions, including, but not limited to, diseases associated 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, in a mammal, particularly a human.

[0218] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of one or more neutrophil-driven diseases, such as, but not limited to, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS) in a mammal, particularly a human.

[0219] In some embodiments, the present invention relates to an inflammatory disease or condition in a mammal, particularly a human, or a disease or condition with an inflammatory component, such as, but not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), 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), and the like. syndrome), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, 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 dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2)-induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN)

[0013] Provided is a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of chronic kidney disease (CKD), lupus nephropathy, diabetic CKD, hypertensive CKD and / or obesity associated with CKD, and the like.

[0220] In some embodiments, the therapeutic agent is used to treat a cardiovascular disease or condition in a mammal, particularly a human, including, 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, 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 / preventing recurrence of atrial fibrillation / flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD). disease), arrest of atheroma progression and / or initiation of 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)

[0013] Provided are pharmaceutical formulations 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of (a) (a) (b) (c) (d) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, amelioration of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction, and the like.

[0221] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention or treatment of neurological diseases and conditions, including, but not limited to, diseases associated 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, in a mammal, particularly a human.

[0222] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment of cancer in a mammal, particularly a human.

[0223] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of coronary artery disease in a mammal, particularly a human.

[0224] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of acute coronary syndrome in a mammal, particularly a human.

[0225] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of heart failure in a mammal, particularly a human.

[0226] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.

[0227] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.

[0228] In some embodiments, there is provided a pharmaceutical formulation 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 the prevention or treatment of chronic kidney disease (CKD) in a mammal, particularly a human.

[0229] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of cardiorenal syndrome (CRS) in a mammal, particularly a human.

[0230] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of non-alcoholic steatohepatitis (NASH) in a mammal, particularly a human.

[0231] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of arrhythmia in a mammal, particularly a human.

[0232] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human.

[0233] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of sickle cell disease in a mammal, particularly a human.

[0234] In some embodiments, there is provided a pharmaceutical formulation 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 the prevention or treatment of anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis in a mammal, particularly a human.

[0235] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of Alzheimer's disease in a mammal, particularly a human.

[0236] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of Parkinson's disease in a mammal, particularly a human.

[0237] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of nephritis in a mammal, particularly a human.

[0238] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of inflammatory bowel disease (IBD) in a mammal, particularly a human.

[0239] In some embodiments, there is provided a pharmaceutical formulation 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, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention or treatment of irritable bowel syndrome (IBS) in a mammal, particularly a human.

[0240] In some embodiments, plasma uric acid levels may be used as a stratification tool and pharmacodynamic biomarker for MPO inhibitor treatment with 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.

[0241] In still further embodiments, methods are provided for identifying patients suitable for MPO inhibitor treatment with 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, comprising measuring plasma uric acid levels.

[0242] In some embodiments, predictive biomarkers, i.e., features or variables that reflect the contribution of MPO to disease pathology, may use plasma uric acid levels as a stratification tool and pharmacodynamic biomarker for MPO inhibitor treatment with 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 (uric acid) 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), and biomarkers of nitric oxide production (SDMA, ADMA, Arg, cGMP). Some of these biomarkers can be quantified from blood, plasma, serum, urine, feces, or saliva.

[0243] In still further embodiments, methods are provided that involve measurement of such predictive biomarkers as disclosed herein and identify patients suitable for MPO inhibitor treatment with 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.

[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, exhibits an IC 50 is less than 10 μM.

[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, exhibits an IC 50 is less than 5 μM.

[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, exhibits an IC 50 is less than 1 μM.

[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, exhibits an IC 50 is less than 0.5 μM.

[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, exhibits an IC 50 is less than 0.2 μM.

[0249] 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 a promising pharmacological profile by dissociating desired and undesired effects in vivo.

[0250] These and other embodiments are described in more detail herein below, and further aspects will become apparent to those skilled in the art upon reading the present specification.

[0251] Pharmacological properties The compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), or as disclosed herein, or pharmaceutically acceptable salts thereof, are believed to be useful in the prevention or treatment of a variety of conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable, including, but not limited to, diseases having an inflammatory, cardiovascular and / or neurological component, and neutrophil-driven diseases.

[0252] For the avoidance of doubt, the term "treatment" as used herein includes therapeutic treatment and / or prophylactic treatment.

[0253] When a compound or salt described herein is administered as therapy to treat a disorder, a "therapeutically effective amount" is an amount sufficient to reduce or completely alleviate the symptoms or other deleterious effects of the disorder, cure the disorder, reverse, halt entirely, or slow the progression of the disorder, or reduce the risk of the disorder worsening.

[0254] The compounds described herein are therefore indicated in both the therapeutic and / or prophylactic treatment of these conditions.

[0255] The compounds described herein have the advantage that they may be more effective, less toxic, more selective, more potent, produce fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than compounds known in the prior art.

[0256] Combination therapy 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 administered in conjunction with other compounds used in the treatment of the above conditions.

[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 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 conjunction with one or more additional active ingredients.

[0258] The compounds described herein are useful in treating cardiovascular, metabolic and renal diseases as the following agents: Heart medications, antihypertensive drugs, Diuretics, peripheral vasodilators, Lipid-modifying drugs, antidiabetic drugs, anti-inflammatory drugs, or Anticoagulants can be used in combination with

[0259] Examples of the above include, but are not limited to, digitalis glycosides, antiarrhythmic drugs, 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, cholesterylester transfer protein (CETP) inhibitors, antidiabetic drugs 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).

[0260] When used in combination therapy, it is contemplated that the 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 other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It is also contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately. The specific composition(s) and frequency(ies) of the combination therapy will depend on various factors, including, for example, the route of administration, the condition being treated, the patient's species, any interactions that may occur between the active ingredients when combined in a single composition, any interactions between the active ingredients when administered to an animal patient, and various 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.

[0261] Pharmaceutical Composition Methods for treating a condition in which inhibition of MPO is required are provided, 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.

[0262] 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, are typically administered orally, topically, parenterally, intravenously, intramuscularly, subcutaneously or via other injection methods, buccal, rectal, vaginal, transdermal and / or nasal routes, and / or via inhalation in the form of a pharmaceutical preparation containing the active ingredient or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable dosage form. Depending on the disorder and patient being treated and the route of administration, the composition may be administered in various dosages. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs," MEAulton, Churchill Livingstone, 2002. nd It is described in Ed.2002.

[0263] The optimal dosage and frequency of administration will depend on the particular condition being treated and its severity, the patient species, the age, sex, size and weight, diet, and general health of the particular patient, 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 others skilled in the art.

[0264] 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 or carrier.

[0265] 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% by weight, such as 0.5 to 95% by weight, of the total formulation.

[0266] Some embodiments include a pharmaceutically acceptable salt of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb).

[0267] Some embodiments include pharmaceutically acceptable salts of the compounds disclosed herein.

[0268] Such salts may be advantageous due to one or more of their chemical or physical properties, such as stability at different temperatures and humidities, or desirable solubility in HO, oil, or other solvents. In some cases, salts may be used to aid in the isolation or purification of the compound. In some embodiments (particularly when the salt is intended for administration to an animal, e.g., a human, or when the salt is a reagent for use in making a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable.

[0269] The term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as appropriate for use according to 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 may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0270] When the compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.

[0271] For a review on suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, PH Stahl, PG Vermuth, IUPAC, Wiley-VCH, 2002.

[0272] If the acid co-component is a solid at room temperature and there is no 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 acid co-component, a co-crystal of the co-component with the compound, rather than a salt, may form. 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 encompassed herein.

[0273] It is also 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 a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt of a compound disclosed herein.

[0274] 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 contain bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where bond rotation is restricted about that particular bond, for example, due to the presence of a ring bond or double bond. Stereoisomers may be separated using conventional techniques, for example, chromatography or fractional crystallization, or they may be made by stereoselective synthesis.

[0275] In some embodiments, compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), compounds disclosed herein, and pharmaceutically acceptable salts thereof, encompass any isotopically labeled (or "radiolabeled") derivatives of such compounds. Such derivatives are derivatives of the above compounds in which one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be incorporated include: 2 H (also written as "D" for deuterium) may be mentioned.

[0276] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), and compounds disclosed herein, may be administered in the form of a prodrug or a pharmaceutically acceptable salt thereof, which is broken down in the human or animal body to yield said compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) or (IVb), or a compound disclosed herein.

[0277] Various forms of prodrugs are known in the art, see Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein for examples of prodrug derivatives.

[0278] Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures. [Example]

[0279] The following abbreviations were used:

[0280] [Table 1-1]

[0281] [Table 1-2]

[0282] General conditions (i) The operations were carried out under an atmosphere of an inert gas such as N2 at room temperature (rt), i.e., in the range of 17 to 28°C; (ii) where the reaction is referred to as being degassed or purged, this can be accomplished, for example, by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (e.g., 5-10 minutes), or by repeatedly evacuating the vessel and backfilling it with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g)); (iii) if the reaction refers to the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iv) the progress of the reaction is generally followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMS); (v) When necessary, organic solutions were dried over anhydrous MgSO or NaSO, or dried using an ISOLUTE® Phase Separator, and work-up procedures were carried out using conventional phase separation techniques. For example, when using a drying agent such as MgSO or NaSO to dry the organic layer, it is understood that the organic layer will be filtered before being concentrated. (vi) evaporation was performed either by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (vii) Unless otherwise stated, flash column chromatography was performed on normal-phase silica using either Merck Silica Gel (Art. 9385) or preparatively packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4-330 g), Biotage® Sfar silica HC D cartridges (20 μm, 10-100 g), Interchim puriFlash™ cartridges (25 μm, 4-120 g), Interchim puriFlash™ cartridges (50 μm, 25-330 g), Grace® GraceResolv™ Silica Flash cartridges (4-120 g) or Agela Flash Column Silica-CS cartridges (80-330 g), or on reverse-phase silica, spherical cartridges (20-35 μm, 100 A, 80-330 g) using Agela Technologies C-18. performed manually or automated using the Reveleris® X2 Flash System or similar system; (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either MS and / or UV-triggered fraction collection instruments, using either an isocratic or gradient mobile phase, as described in the Experimental Section; The relevant fractions were collected, combined, and lyophilized or evaporated to give the purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried over Na2SO4 or by using a phase separator and then concentrated under reduced pressure to give the purified compound. (ix) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC equipment, respectively, using either isocratic or gradient runs with mobile phases as described in the Experimental Section; (x) yields, if any, are not necessarily the maximum achievable and, if necessary, reactions were repeated when larger amounts of reaction product were required; (xi) When a particular compound is obtained as an acid addition salt (e.g., a monohydrochloride or dihydrochloride), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the exact stoichiometry of the salt is not generally determined, for example, by elemental analysis data; (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; proton NMR chemical shift values ​​were 300, 400, 500 and 600 MHz, respectively. 1 Measurements were made on a Bruker Avance III 300, 400, 500, and 600 spectrometer operating at H frequencies on the delta scale. Experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as the internal standard. Protons on heteroatoms, such as NH and OH protons, are reported only if detected in the NMR and may therefore be missing. In certain instances, protons may be masked or partially masked by the solvent peak and therefore either missing and not reported, or reported as a multiplet overlapping with the solvent. The following abbreviations (and their derivatives, e.g., dd, doublet of doublets, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. In some cases, the final product structures of the compounds disclosed herein may appear as rotamers in the NMR spectrum, in which case only the peak of the major rotamer is reported. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument, acquiring both positive and negative ion data, generally only ions associated with the parent structure being reported; high-resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar instrument, acquiring either positive or negative ion data, generally only ions associated with the parent structure being reported; (xiii) intermediates were not necessarily completely purified, but their structure and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xiv) Unless otherwise specified, compounds containing asymmetric carbon and / or sulfur atoms were not resolved; (xv) Examples and intermediate compounds are generally named using PerkinElmer's ChemDraw Professional version 20.1.1.125, which generates names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules whenever possible when generating chemical names. Stereoisomers are cited by name and distinguished from one another by stereodescriptors assigned according to the CIP rules.

[0283] ChemDraw optionally uses stereocenter labels such as "&" and "or" in its drawings to describe the configuration of stereochemical centers present in a structure.

[0284] In general, chemical structures of examples and intermediates containing the label "&" at a stereocenter mean that the configuration of such example or intermediate at that stereocenter is a mixture of both (R) and (S); the label "or" means that the configuration of such example or intermediate is either (S) or (R) at the stereocenter. All unidentified absolute stereocenters "&" and "or" may be present in a single structure.

[0285] In general, the "&" and "or" labels at each stereocenter present in a structure may also include a number. The number may indicate whether the stereocenter varies independently of one another or not. Thus, if two or more stereocenters do not vary independently of one another, i.e., are fixed relative to one another, they have the same number, but if they vary independently of one another, they have different numbers. For example, if a compound has two stereocenters in a ring that are independent of one another, one stereocenter is labeled "or1" (or "&1") and the other is labeled "or2" (or "&2"); if a compound has two stereocenters in a ring that are fixed relative to one another and do not vary independently of one another, both stereocenters are labeled "or1" (or "&1"); if a compound has two stereocenters that are fixed relative to one another and a third stereocenter that varies independently of the former stereocenters, the first two stereocenters are both labeled "or1" (or "&1") and the third stereocenter is labeled "or2" (or "&2").

[0286] It is further noted that, as an artifact of this automatic labeling by ChemDraw, in some instances the two isomers are displayed side by side, with the stereocenter(s) of Isomer 1 labeled "or1" and the stereocenter(s) of Isomer 2 labeled "or2." It is understood that these two compounds are considered to be isomers of each other, as indicated by different properties, e.g., different elution times on chiral HPLC.

[0287] Generally, for chemical structures of examples and intermediates where all stereocenters present are racemic, no label is designated at the stereocenter(s) and the structures are drawn with a straight bond at each stereocenter.

[0288] In general, for example and intermediate structures where all stereocenters are designated as "&", the structures are named with the prefix "rac-". For example and intermediate structures where all stereocenters are designated as "or", the structures are named with the prefix "rel-".

[0289] Generally, 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 with unknown absolute configuration.

[0290] Generally, for examples or intermediates containing two or more stereocenters, the relative stereochemistry is described using the configurational descriptors "S" and "R" for the stereocenters and the prefix "rac-" or "rel-" cited before the name.

[0291] Examples or intermediates named with the prefix "rel-" are single isomers, and the stereocenter(s) in the isomer are designated "R" or "S," although it is understood that the actual stereochemistry of that particular isomer may be the opposite of the label. For example, Example 12a (Isomer 1) is named "rel-(R)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one," but Example 12a may be "(S)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one." For example, Example 18b (Isomer 1) is named "rel-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one," but Example 18b can be "rel-2-thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one."

[0292] Examples or intermediates named with the prefix "rac-" are mixtures of isomers, and the relative stereochemistry of the stereocenters in the isomers is designated by the descriptor "R" or "S," but it is understood that the actual stereochemistry of that particular isomeric mixture also includes the reverse of the descriptor. For example, Example 17b is named "rac-2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one," but Example 17b also includes "2-thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one."

[0293] Preparation of compounds General Scheme In another aspect, there is provided a process for preparing compounds of Formula (I) and Formula (II) or pharmaceutically acceptable salts thereof, the process comprising: a) Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and compounds of formula (I) wherein X is as defined above may be prepared by the addition of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and a compound of formula (V) wherein X is defined as in formula (I) and LG1 is a suitable leaving group such as (C1-C4)alkoxy (such as OEt) or NH2,

[0294] [ka] It can be produced by reaction with a base such as Cs2CO3, NaOH, NH3 or NH4OH. Typically, the reaction is carried out in a suitable organic solvent, such as MeOH or EtOH, at a temperature typically in the range of 20° C. to 80° C. for an extended period of time (e.g., 3 to 24 hours).

[0295] If necessary, the resulting compound of formula (I) may be converted into a pharmaceutically acceptable salt of formula (I), and if desired, the resulting compound of formula (I) may be separated into its individual optical isomers.

[0296] The compound of formula (V) is Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and X is defined as in formula (I) and LG1 is defined above,

[0297] [ka] It can be prepared by reacting with benzoyl isothiocyanate (1-3 equivalents). Typically, the reaction is carried out in an inert organic solvent such as DCM or MeCN at room temperature for 1-24 hours. Optionally, the reaction may be carried out in the presence of an organic base such as DIPEA.

[0298] The compound of formula (VI) above is represented by Y 1 , Y 2 , Y 3 , Y 4 and Y 5 can be prepared by reacting a compound of formula (VII), wherein X and LG1 are defined as in formula (I), with a compound of formula (VIII), wherein X and LG1 are defined as above.

[0299] [ka]

[0300] The conditions are such that reductive alkylation of a compound of formula (VIII) results in the formation of an N-C bond between the nitrogen atom of the compound of formula (VIII) and the carbon atom of the aldehyde group of a compound of formula (VII). The reaction conditions are conventional reductive alkylation conditions. Typically, the amine compound as a hydrochloride salt is treated with DIPEA or TEA and HOAc in an organic solvent such as EtOH, MeOH, DCM, or DCE in the presence of an aldehyde compound of formula (VII). After stirring the mixture for a period of time, e.g., at room temperature, a reducing agent such as NaBHCN, NaBH, or NaBH(OAc) is added, and the resulting mixture is stirred, typically at a temperature ranging from 20°C to 80°C, until the reaction is complete, e.g., for 1 to 20 hours, to give a compound of formula (VI). (See, e.g., J. Org. Chem 1996, 61, 3849.)

[0301] Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Certain compounds of formula (VII), wherein is defined as formula (I), can be prepared from compounds of formula (IX), (X), (XI) and (XII) according to the methods shown in Scheme TA1 and the description below, and by methods analogous to those described in the Examples.

[0302] [ka]

[0303] Method a1: Compound of formula (IX) can be reacted with pyridine x SO3 (e.g., 2 equivalents) in DMSO in the presence of TEA (e.g., 3.5 equivalents) at room temperature until the reaction is complete (1 to 17 hours) to give compound of formula (VII) (Parikh-Doering conditions, J. Am. Chem. Soc. 1967, 89, 5505).

[0304] Method a2: Compounds of formula (IX) can be reacted with pyridinium chlorochromate (PCC) (e.g., 1.5 equivalents) in an inert organic solvent such as DCM at room temperature for a long period of time (e.g., 1-2 hours) to give compounds of formula (VII). (Synthesis, 1982, 245)

[0305] Method a3: Compounds of formula (IX) can be reacted with DMP (e.g., 1.1 to 2 equivalents) in an inert organic solvent, such as DCM, at temperatures typically ranging from 0°C to 30°C for an extended period of time (e.g., 1 hour) to give compounds of formula (VII). (J. Am. Chem. Soc. 1991, 113, 7277)

[0306] Method a4: Compounds of formula (IX) can be reacted with excess activated MnO2 (e.g., 5-7 equivalents) in an inert organic solvent such as DCM at room temperature for an extended period of time (e.g., 48 hours) to give compounds of formula (VII) (Synthesis, 1976, 65).

[0307] Method b1: Compounds of formula (VII) can be obtained by treating compounds of formula (X) with synthesis gas (H2 / CO, 1 / 1) in the presence of a catalyst (which may be, for example, a mixture of diacetoxypalladium, 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 (6-21 hours). (Angew. Chem. Int. ed. 2006, 45, 154).

[0308] Method b2: Compounds of formula (X) can be treated with a strong base such as butyllithium in an inert solvent such as THF, followed by treatment of the resulting mixture with DMF to give compounds of formula (VII). The reaction can be carried out at low temperatures, such as -78°C to -60°C.

[0309] Method c1: Compounds of formula (XI) can be treated with nitric acid (4-8 equivalents) in an inert organic solvent such as DCM to give compounds of formula (VII). The reaction is usually carried out at room temperature for extended periods of time (24-72 hours).

[0310] Method d1: A compound of formula (XII), wherein PG 1 and P.G. 2 are protecting groups which may or may not be joined to form a ring (e.g., -CH-CH- or -CH-CH-CH-), which may be the same as each other, for example, methyl or ethyl, with an acid such as TsOH (e.g., 0.1 to 0.2 equivalents) in a water / acetone mixture, typically at a temperature in the range of 25°C to 60°C for an extended period of time (typically overnight), to provide a compound according to formula (VII).

[0311] Method d2:PG 1 and P.G. 2 Compounds according to formula (VII) can be obtained by treating a compound of formula (XII), wherein X is as defined above, with excess aqueous HCl in MeCN, typically at a temperature in the range of 25° C. to 90° C. for an extended period of time (typically overnight).

[0312] Compounds of formula (VIII), wherein X and LG1 are as defined above, are commercially available, known in the art, or can be prepared by conventional methods known to those skilled in the art.

[0313] Compounds of formula (IX), (X), (XI) and (XII) are either commercially available, known in the art or can be prepared by methods analogous to those described in the Examples and description below, or by conventional methods known to those skilled in the art.

[0314] Y 1 , Y 2 , Y 3 , Y 4 , X, A, R 1Compounds of formula (II) wherein n, p and s are as defined above in formula (II) can be prepared by Y 1 , Y 2 , Y 3 , Y 4 , X, A, R 1 , n, p and s are defined as above and LG1 is defined as above, by reacting a compound of formula (XIII)

[0315] [ka] with a base such as Cs2CO3, NaOH, NH3 or NH4OH. The reaction is typically carried out in a suitable organic solvent, such as MeOH or EtOH, at a temperature typically in the range of 20°C to 80°C for an extended period of time (3 to 24 hours). If necessary, the resulting compound of formula (II) may be converted to a pharmaceutically acceptable salt of formula (II), and, if desired, the resulting compound of formula (II) may be separated into its individual optical isomers.

[0316] The compound of formula (XIII) is Y 1 , Y 2 , Y 3 , Y 4 , X, A, R 1 a compound of formula (XIV), wherein n, p and s are as defined above in formula (II) and LG1 is as defined above,

[0317] [ka] It can be prepared by reacting with benzoyl isothiocyanate (1-3 equivalents). Typically, the reaction is carried out in an inert organic solvent such as DCM or MeCN at room temperature for 1-24 hours. Optionally, the reaction may be carried out in the presence of an organic base such as DIPEA.

[0318] The compound of formula (XIV) above is Y 1 , Y 2 , Y 3 , Y 4 , A, R 1A compound of formula (XV), wherein n, p and s are defined as in formula (I), can be prepared by reacting a compound of formula (VIII), wherein X and LG1 are defined as above.

[0319] [ka]

[0320] The conditions are such that reductive alkylation of a compound of formula (VIII) results in the formation of an N-C bond between the nitrogen atom of the compound of formula (VIII) and the carbon atom of the aldehyde group of a compound of formula (XV). The reaction conditions are conventional reductive alkylation conditions. Typically, the amine compound as a hydrochloride salt is treated with DIPEA or TEA and HOAc in an organic solvent such as EtOH, MeOH, DCM, or DCE in the presence of an aldehyde compound of formula (XV). After stirring the mixture for a period of time, e.g., at room temperature, a reducing agent such as NaBHCN, NaBH, or NaBH(OAc) is added, and the resulting mixture is stirred, typically at a temperature ranging from 20°C to 80°C, until the reaction is complete, e.g., for 1 to 20 hours, to give a compound of formula (XIV). (See, e.g., J. Org. Chem 1996, 61, 3849.)

[0321] Compounds of formula (VIII), wherein X and LG1 are as defined above, are commercially available, known in the art, or can be prepared by conventional methods known to those skilled in the art.

[0322] Y 1 , Y 2 , Y 3 , Y 4 , A, R 1 Certain compounds of formula (XV), where n, p and s are defined as in formula (I), can be prepared from compounds of formula (XVI), (XVII), (XVIII) and (XIX) according to the methods shown in Scheme TA2 and in the description below, and by methods analogous to those described in the Examples.

[0323] [ka]

[0324] Method a1: Compound of formula (XVI) can be reacted with pyridine x SO3 (e.g., 2 equivalents) in DMSO in the presence of TEA (e.g., 3.5 equivalents) at room temperature until the reaction is complete (1 to 17 hours) to give compound of formula (XV) (Parikh-Doering conditions, J. Am. Chem. Soc. 1967, 89, 5505).

[0325] Method a2: Compounds of formula (XVI) can be reacted with pyridinium chlorochromate (PCC) (e.g., 1.5 equivalents) in an inert organic solvent such as DCM at room temperature for a long period of time (e.g., 1-2 hours) to give compounds of formula (XV). (Synthesis, 1982, 245)

[0326] Method a3: Compounds of formula (XVI) can be reacted with DMP (e.g., 1.1 to 2 equivalents) in an inert organic solvent, such as DCM, typically at temperatures ranging from 0°C to 30°C for an extended period of time (e.g., 1 hour) to give compounds of formula (XV). (J. Am. Chem. Soc. 1991, 113, 7277)

[0327] Method a4: Compounds of formula (XVI) can be reacted with excess activated MnO2 (e.g., 5-7 equivalents) in an inert organic solvent such as DCM at room temperature for an extended period of time (e.g., 48 hours) to give compounds of formula (XV) (Synthesis, 1976, 65).

[0328] Method b1: Compounds of formula (XV) can be obtained by treating compounds of formula (XVII) with synthesis gas (H2 / CO, 1 / 1) in the presence of a catalyst (which may be, for example, a mixture of diacetoxypalladium, 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).

[0329] Method b2: Compounds of formula (XVII) can be treated with a strong base such as butyllithium in an inert solvent such as THF, and then the resulting mixture can be treated with DMF to give compounds of formula (XV). The reaction can be carried out at low temperatures, such as -78°C to -60°C.

[0330] Method c1: Compounds of formula (XVIII) can be treated with nitric acid (4-8 equivalents) in an inert organic solvent such as DCM to give compounds of formula (XV). The reaction is usually carried out at room temperature for extended periods of time (24-72 hours).

[0331] Method d1:PG 1 and P.G. 2 Compounds of formula (XIX), wherein X is defined as above, can be treated with an acid such as TsOH (e.g., 0.1-0.2 equivalents) in a water / acetone mixture at a temperature typically in the range of 25°C to 60°C for an extended period of time (typically overnight) to provide compounds according to formula (XV).

[0332] Method d2:PG 1 and P.G. 2 Compounds according to formula (XV) can be obtained by treating a compound of formula (XIX), wherein X is defined as above, with excess aqueous HCl in MeCN, typically at a temperature in the range of 25° C. to 90° C. for an extended period of time (typically overnight).

[0333] Compounds of formula (VIII), wherein X and LG1 are as defined above, are commercially available, known in the art, or can be prepared by conventional methods known to those skilled in the art.

[0334] Compounds of formula (XVI), (XVII), (XVIII) and (XIX) are either commercially available, known in the art or can be prepared by methods analogous to those described in the examples and description below, or by conventional methods known to those skilled in the art.

[0335] According to the method shown in Scheme TA3, Y 1 , Y 2 , Y 3 , Y 4 , A, R 1 , n, p and s are defined as in formula (I), and FG 1 is CH2OH, Br, CH2-OMe or CH(OPG 1 )(OPG 2 ) and PG 1 and P.G. 2 Certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) can be prepared, wherein

[0336] [ka]

[0337] Process 1: Y 1 , Y 2 , Y 3 , Y 4 and FG 1 Compounds of formula (XX), wherein Y is as defined above, can be treated with a strong base, such as butyllithium, in an inert organic solvent, such as THF, to give Y 1 , Y 2 , Y 3 , Y 4 and FG 1is as defined above and M is Li, the compound according to formula (XXI) can be obtained. The reaction can be carried out at low temperature, for example -78°C, under an inert atmosphere, for example under nitrogen.

[0338] Process 2:Y 1 , Y 2 , Y 3 , Y 4 and FG 1 Compounds of formula (XX), wherein Y is as defined above, can be treated with iPrMgCl×LiCl (Turbo Grignard) in an inert organic solvent such as THF to give Y 1 , Y 2 , Y 3 , Y 4 and FG 1 A compound according to formula (XXI) can be obtained, in which M is Mg and R is as defined above. The reaction can be carried out under an inert atmosphere, e.g., nitrogen, at a temperature ranging from -40°C to room temperature, depending on the substrate used (Chem. Eur. J. 2019, 25, 2695).

[0339] Process 3:Y 1 , Y 2 , Y 3 , Y 4 and FG 1 is as defined above and M is Mg or Li, with a compound of formula (XXII) in an inert organic solvent, such as THF, to give Y 1 , Y 2 , Y 3 , Y 4 , A, R 1 , n, p and s are defined as in formula (I), and FG 1 A compound according to formula (XXIII) can be obtained, wherein is defined as above. The reaction can be carried out under an inert atmosphere, for example under nitrogen, at a temperature ranging from -78°C to room temperature depending on the substrate used.

[0340] Step 4: Compound of formula (XXIII) is treated with a strong acid such as TFA or HCl to give Y 1 , Y 2 , Y3 , Y 4 , A, R 1 , n, p and s are defined as in formula (I), and FG 1 Compounds according to formula (XXIV) (enamine) and / or formula (XXV) (imine), wherein is defined as above, can be obtained. The reaction is carried out in an inert organic solvent, such as DCM or MeOH, at a temperature in the range of 20° C. to 100° C. Following the procedure described in step 5, compounds of formula (XXIV) and formula (XXV) can be isolated before reduction, or, for compound (XXV), can be reduced in situ.

[0341] Step 5: Y is obtained by any of the methods described in i) to iii) below. 1 , Y 2 , Y 3 , Y 4 , A, R 1 , n, p and s are defined as in formula (I), and FG 1 Specific compounds according to formulae (XVI), (XVII), (XVIII) and (XIX) can be obtained, where i) treating a compound of formula (XXV) as defined above with a reducing agent such as, for example, NaBH4, NaBH(OAc)3 or NaBH3CN, the reaction being carried out in an inert organic solvent such as, for example, MeOH, DCM or THF at room temperature, or 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 an extended period of time. The reaction is carried out in an inert organic solvent such as HOAc, MeOH, EtOAc or a mixture of HOAc / MeOH, optionally in the presence of an organic base such as DIPEA, or iii) The reaction may be carried out by reacting a compound of formula (XXIV) as defined above with LiBHEt3 in an inert organic solvent such as THF at a temperature between about 0°C and about room temperature.

[0342] According to the method shown in Scheme TA4, Y 1 , Y 2 , Y 3 , Y4 and n is as defined in formula (I), FG 1 Certain compounds of (XVI), (XVII), (XVIII) and (XIX) can be prepared where is defined as above, s is 0, p is 0 and A is CH2.

[0343] [ka]

[0344] Step 1: A compound of formula (XXVI) is reacted with a Grignard reagent CH2=CH-(CH2) in an inert solvent such as THF or DCM, optionally in the presence of CeCl3. x -MgBr (where x is 0, 1 or 2) at about -78°C, and optionally separating the resulting intermediate into its diastereomers by conventional methods, such as silica gel chromatography, to give Y 1 , Y 2 , Y 3 , Y 4 and FG 1 Compounds according to formula (XXVII) can be obtained, in which x is 0, 1 or 2, as defined above. (Chem.Rev.2010,110,3600)

[0345] Step 2: Compounds of formula (XXVII) as defined above can be reacted with allyl bromide in an inert organic solvent, such as THF, in the presence of a strong base, such as LiHMDS or NaH, at about room temperature to 60° C. to give Y 1 , Y 2 , Y 3 , Y 4 and FG 1 Compounds according to formula (XXVIII), wherein: is as defined above and x is 0, 1 or 2, can be obtained.

[0346] Step 3: Y is obtained by reacting a compound of formula (XXVIII) as defined above with a metathesis catalyst, such as a second generation Grubbs catalyst. 1 , Y 2 , Y 3 , Y4 and FG 1 is as defined above and x is 0, 1 or 2, to give compounds according to formula (XXIX). The reaction is carried out in an inert organic solvent, such as DCM, at about room temperature to 40°C for an extended 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).

[0347] Step 4: Compounds of formula (XXIX) as defined in formula (I) are reduced with a metal catalyst, such as Pd / C, under a hydrogen atmosphere at room temperature for a long period of time to give Y 1 , Y 2 , Y 3 , Y 4 and n is defined as in formula (I), and FG 1 Certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) can be obtained, wherein is defined as above, s is 0, p is 0 and A is CH. The reaction is carried out in an inert organic solvent, such as, for example, MeOH, THF or EtOAc.

[0348] According to the method shown in Scheme TA5, Y 1 , Y 2 , Y 3 and Y 4 is CH, C-halo or C-CF, n is 1, p is 0 or 1, s is 0, and A is CH or CH-R 2 and R 1 and R 2 is as defined in formula (I), and FG 2 is CH2OH, CHOMe or CH(OPG 1 )(OPG 2 ) in which PG 1 and P.G. 2 Certain compounds of formula (XVI), (XVIII) and (XIX) can be prepared, wherein:

[0349] [ka]

[0350] Step 1: Y 1 , Y 2 , Y 3 and Y 4 is CH, C-halo or C-CF3, p is 0 or 1, and R 1 is as defined in formula (I), and FG 2 is CH2OH, CHOMe or CH(OPG 1 )(OPG 2 ) in which PG 1 and P.G. 2 Compounds of formula (XXX), where X is defined as above, can be treated with a metal catalyst, such as PtO, under a hydrogen atmosphere (1-5 bar) for an extended period of time at about room temperature to give compounds of formula (XVI), (XVIII), or (XIX), as defined in Scheme TA5. The reaction can be carried out under acidic conditions, for example in HOAc, or in mixtures of HCl / MeOH or HCl / EtOH.

[0351] According to the method shown in Scheme TA6, Y 1 , Y 2 , Y 3 and Y 4 is defined as in formula (I), n is 0, 1 or 2, p is 0 or 1, s is 0, and A is CH or CH—R 2 and R 1 and R 2 is defined as in formula (I), and FG 2 Certain compounds of formula (XVI), (XVIII) and (XIX) can be prepared, wherein:

[0352] [ka]

[0353] Step 1: p is 0 or 1, and R 1 is defined as in formula (I), by reacting a compound of formula (XXXI) with Y 1 , Y 2 , Y3 and Y 4 is defined as in formula (I), and FG 2 with a compound of formula (XXXII) as defined above to form Y 1 , Y 2 , Y 3 and Y 4 is defined as in formula (I), p is 0 or 1, and R 1 is defined as in formula (I), and FG 2 Compounds according to formula (XXXIII), wherein R is defined as above, can be obtained. The reaction is carried out under a nitrogen atmosphere in an inert organic solvent, such as THF, at a lower temperature, for example, about −78° C., until the reaction is complete. Compounds of formula (XXXII) can be prepared from the corresponding bromide according to the procedure described in Scheme TA3 (Step 1). Compounds of formula (XXXI) can be prepared by reacting the corresponding pyridine compound with benzyl bromide using conditions known to those skilled in the art.

[0354] Step 2: Y is 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 at room temperature for an extended period of time. 1 , Y 2 , Y 3 and Y 4 is defined as in formula (I), n is 0, 1 or 2, p is 0 or 1, s is 0, and A is CH or CH—R 2 and R 1 and R 2 is defined as in formula (I), and FG 2 It is possible to obtain specific compounds of formula (XVI), (XVIII) and (XIX), wherein X is defined as above. The reaction is carried out in an inert organic solvent, such as MeOH, for example.

[0355] Step 3: p is 0 or 1, n is 0, 1 or 2, and R 1 is as defined in formula (I), 1 , Y 2 , Y 3 and Y 4is defined as in formula (I), and FG 2 is defined as above, to give a compound of formula (XXXI) 1 , Y 2 , Y 3 and Y 4 is defined as in formula (I), p is 0 or 1, n is 0, 1 or 2, and R 1 is as defined in formula (I), and FG 2 Compounds according to formula (XXXVI), wherein R is defined as above, can be obtained. The reaction is carried out in a mixture of an organic solvent, such as dioxane, and water in the presence of a pallidum catalyst, such as CataCXium A-Pd-G3, and a base, such as K2CO3 or Cs2CO3, at slightly elevated temperatures, for example 60°C to 100°C, over an extended reaction time. Compounds of formula (XXXV) can then be prepared, for example, according to the procedure described in J. Org. Chem 2005, 70, 7324.

[0356] Step 4: Y is obtained by reducing a compound of formula (XXXVI) as defined above with a metal catalyst such as Pd / C or Pd(OH) / C under a hydrogen atmosphere at room temperature for an extended period of time. 1 , Y 2 , Y 3 and Y 4 is defined as in formula (I), n is 0, 1 or 2, p is 0 or 1, s is 0, and A is CH or CH—R 2 and R 1 and R 2 is defined as in formula (I), and FG 2 Certain compounds of formula (XVI), (XVIII) and (XIX), wherein: is defined as above. The reaction can be carried out in an inert organic solvent, such as MeOH, optionally in the presence of an acid, such as HOAc.

[0357] According to the method shown in Scheme TA7, Y 1 , Y 2 , Y 3 and Y 4 is defined as in formula (I), n is 1, p is 0, s is 0, A is O, and FG1 Certain compounds of formula (XVI), (XVII), (XVIII) and (XIX) can be prepared, wherein:

[0358] [ka]

[0359] Process 1: Y 1 , Y 2 , Y 3 and Y 4 is as defined in formula (I), and FG 1 A compound of formula (XXXVII), wherein R is 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 (2-3 equivalents), such as TEA, at a temperature ranging from 0° C. to 40° C. (Angew. Chem. Int. Ed. Engl. 2008, 47, 3784).

[0360] According to the method shown in Scheme TA8, Y 3 and Y 4 is defined as in formula (I), and Y 1 , Y 2 or Y 5 one of which is CQ, where Q and m are as defined in formula (I), and FG 1 Certain compounds of formula (IX), (X), (XI) and (XII) can be prepared, wherein:

[0361] [ka]

[0362] Step 1: m is defined as above, and LG 3 and L.G. 4 are suitable leaving groups, which may be the same or different, such as Cl, Br, I, OMs or OTs, with a compound of formula (XL) as defined above to give Y 3and Y 4 is defined as in formula (I), and Y 1 , Y 2 or Y 5 is CQ, and Q and m are as defined in formula (I), to give a compound of formula (XLI). 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 in the range of 0°C to 40°C.

[0363] Step 2: Hydrolysis of a compound of formula (XLI) as defined above to give Y 3 and Y 4 is defined as in formula (I), and Y 1 , Y 2 or Y 5 is CQ, and Q and m are as defined in formula (I), to give a compound of formula (XLII). The reaction is carried out in an organic solvent, such as n-butyl alcohol, 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.

[0364] Step 3: Curtius rearrangement of the compound of formula (XLII) to give Y 3 and Y 4 is defined as in formula (I), and Y 1 , Y 2 or Y 5 one of which is CQ, where Q and m are as defined in formula (I), and FG 1 Certain compounds of formulas (IX), (X), (XI), and (XII) can be prepared, where X is as defined above. The reaction can be carried out by treating with DPPA in an inert organic solvent, such as THF, toluene, MeCN, or acetone, in the presence of an alcohol, such as tert-BuOH or BnOH, and an organic base, such as TEA or DIPEA, at a temperature ranging from about 20°C to 120°C. This can be followed by deprotection of the amine (e.g., Boc or Cbz) using standard conditions. (ChemMedChem. 2018, 13, 2351).

[0365] According to the method shown in Scheme TA9, Y 1 , Y 2 , Y 3 and Y 4 is CH, C-halo or C-CF3, and Y 5 is CT, T is as defined in formula (I), n is 1, p is 0 or 1, s is 0, and A is CH2 or CH-R 2 and R 1 and R 2 is as defined in formula (I), and FG 2 Certain compounds of formula (IX), (XI) and (XII) can be prepared, wherein:

[0366] [ka]

[0367] Process 1: Y 1 , Y 2 , Y 3 and Y 4 is CH, C-halo or C-CF3, p is 0 or 1, and R 1 is as defined in formula (I), and FG 2 A compound of formula (XLIII), wherein is as defined above, is treated with a metal catalyst such as PtO2 under an atmosphere of hydrogen (1-5 bar) at about room temperature for an extended reaction time. The reaction can be carried out under acidic conditions, for example in HOAc or in a mixture of HCl / MeOH or HCl / EtOH.

[0368] It will also be understood that in some of the reactions mentioned herein, it may be necessary / desirable to protect any sensitive groups in the compounds. Where protection is necessary or desirable, suitable methods for protection are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (see, for illustration, "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 4th Edition, by TW Greene and PGM Wutz, Wiley-Interscience (2007)). Thus, if a reactant contains a group such as amino, aldehyde, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0369] Suitable protecting groups for hydroxy 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 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.

[0370] Protective groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical arts. Those skilled in the art will understand how to deprotect compounds containing 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, by T.W. Greene and P.G.M. Wutz, Wiley-Interscience (2007)).

[0371] Those skilled in the art will recognize that certain compounds of formulas (V) through (XLIII) above are sometimes referred to as "protected derivatives."

[0372] Those skilled in the art will recognize that the individual process steps described above may be performed in a different order and / or individual reactions may be performed at different stages in the overall pathway (i.e., substituents may be added to intermediates and / or chemical transformations may be performed other than those described above in connection with a particular reaction) to obtain the compounds disclosed herein in an alternative, and in some cases more convenient, manner, which may obviate or require the need for protecting groups.

[0373] Those skilled in the art will understand that chiral isomers of the compounds herein may be resolved at any stage of the synthetic 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 may also be introduced by asymmetric synthesis. All stereoisomers are included within the scope of this disclosure.

[0374] Those skilled in the art will appreciate that fluorinating agents such as, for example, DAST, XtalFluor-E, XtalFluor-M, or Deoxo-Fluor can be used to convert -C=O, -CHO, or C-OH groups to -CF, -CFH, or CF, respectively. (J. Org. Chem. 2010, 75, 3401).

[0375] Those skilled in the art will appreciate that the starting materials for any of the above processes are, in some cases, commercially available.

[0376] Those skilled in the art will appreciate that for some of the starting materials mentioned above, the processes may be found in general common knowledge.

[0377] It will also be understood that some of the compounds described in the above processes may exhibit the phenomenon of tautomerism, and that the above processes include any tautomeric forms.

[0378] In another aspect, an intermediate disclosed herein is provided. In another aspect, an intermediate, or a salt thereof, 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.

[0379] Intermediates Intermediate 1 tert-Butyl 2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0380] [ka]

[0381] Step A. (2-(pyridin-2-yl)phenyl)methanol

[0382] [ka] Benzo[c][1,2]oxaborol-1(3H-ol) (50.4 g, 375.96 mmol) and 2M Na2CO3(aq) (216 mL, 410.14 mmol) was 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 (confirmed by LC-MS). The reaction was cooled to room temperature, and the organic layer was separated and washed with water (600 mL). The product was extracted into HCl(aq) (1 M, 300 mL). The pH of the aqueous phase was adjusted to 10 with NaOH(aq) (3.8 M), and the product was back-extracted into EtOAc. The organic layer 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.

[0383] Step B. (2-(piperidin-2-yl)phenyl)methanol

[0384] [ka] A solution of (2-(pyridin-2-yl)phenyl)methanol (168 g, 907 mmol) in AcOH (1200 mL) was degassed with N2 (g) for 30 min, then platinum(IV) oxide (4.48 g, 18.14 mmol) was added, and the slurry was transferred to a 3 L hydrogenation reactor and hydrogenated at 5 bar until reduction was complete. The reaction mixture was filtered, and most of the AcOH was evaporated. When the residue weighed approximately 380 g, water (1 L) was added, and the aqueous phase was washed twice with DCM (1 L and 300 mL). The combined DCM phases were washed with water (200 mL), and the combined acidic aqueous phases were made alkaline to pH 12-13 with 50% NaOH (aq) to give a precipitate. The solid was filtered off, washed with water (3 × 500 mL), and dried in vacuo at 45 °C for 90 h to give the title compound (148 g, 87%) as a solid. 1H NMR(400MHz,DMSO)δ 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)

[0385] Step C. tert-Butyl 2-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate

[0386] [ka] BocO (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 mixture was washed with water (2 x 100 mL), dried (passed 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 0-25% 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.

[0387] Step D. tert-Butyl 2-(2-formylphenyl)piperidine-1-carboxylate

[0388] [ka] Sulfur trioxide pyridine complex (7.37 g, 46.33 mmol) dissolved in DMSO (21 mL) was added dropwise to a cold (approximately 14 °C, internal temperature never exceeding 25 °C) 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). The resulting mixture was stirred at room temperature for 2 h. MTBE (250 mL) and saturated aqueous NaHCO (150 mL) were added, and the organic phase was separated and washed with water (2 × 100 mL). The organic phase was dried (Na SO ), filtered, and evaporated to give the crude title compound (6.60 g, 98%) as an amber oil. MS (ESI): m / z [M+H] + 290.

[0389] Step E. tert-Butyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)piperidine-1-carboxylate

[0390] [ka] NaBHCN (1.564 g, 24.88 mmol) was added in five portions to a mixture of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (4.35 g, 22.81 mmol), DIPEA (3.97 mL, 22.81 mmol), tert-butyl 2-(2-formylphenyl)piperidine-1-carboxylate (6.0 g, 20.7 mmol), AcOH (2.39 mL, 41.5 mmol), and EtOH (99.5%) (60 mL) (exothermic), resulting in a brownish mixture. The reaction was stirred overnight at room temperature, quenched with water, and evaporated. The crude product was dissolved in a mixture of DCM and saturated NaHCO (aq). The DCM phase was dried through a phase separator and evaporated to give the crude product (12.07 g) as an amber oil. MS(ESI):m / z[M+H] + 428.

[0391] Step F. tert-Butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)piperidine-1-carboxylate

[0392] [ka] 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.

[0393] Step G. tert-Butyl 2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate. 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 N(g) atmosphere for 3 h. The solvent was removed in vacuo and the residue was dissolved in water (150 mL). The pH was adjusted to approximately 6 with AcOH and extracted with EtOAc (3 x 150 mL). Solid particles formed and were filtered off to give the crude title compound (3.63 g). The organic layer was dried (MgSO) and evaporated in vacuo to give a further (10.21 g) of the crude title compound as a yellow oil. MS (ESI): m / z [M+H] + 441.

[0394] Intermediate 2 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0395] [ka]

[0396] Step A. tert-Butyl 2-(5-chloro-2-(hydroxymethyl)phenyl)piperidine-1-carboxylate

[0397] [ka] 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 BocO (4.82 mL, 20.98 mmol) in DCM (100 mL) was stirred at room temperature for 5 h. The mixture was washed with water (2 x 200 mL), dried over MgSO, and evaporated. The crude product was purified by flash chromatography using 100% EtOAc as the mobile phase to give the title compound (5.61 g, 90%). MS (ESI): m / z [M+H] + 326.

[0398] Step B. tert-Butyl 2-(5-chloro-2-formylphenyl)piperidine-1-carboxylate

[0399] [ka] 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 EtO (100 mL), resulting in 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 the title compound (3.64 g, 67%). MS (ESI): m / z [M+H] + 324.

[0400] Step C. tert-Butyl 2-(5-chloro-2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)piperidine-1-carboxylate

[0401] [ka] To a solution of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (648 mg, 3.40 mmol), DIPEA (0.592 mL, 3.40 mmol), tert-butyl 2-(5-chloro-2-formylphenyl)piperidine-1-carboxylate (1.0 g, 3.09 mmol), and AcOH (0.357 mL, 6.18 mmol) in anhydrous EtOH (100 mL) was added NaCNBH (233 mg, 3.71 mmol). The reaction was stirred at room temperature for 3 h, quenched with water, and evaporated. The crude product was purified by preparative HPLC on a Kromasil C column (10 μm, 250 × 20 mm i.d.) using a gradient of 30–95% MeCN in a HO / MeCN / FA (95 / 5 / 0.2) buffer system as the mobile phase to give the title compound (771 mg, 58%). 1H NMR(400MHz,CDCl3)δ1.22-1.4(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) ,4.16-4.57(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).

[0402] Step D. tert-Butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)-5-chlorophenyl)piperidine-1-carboxylate

[0403] [ka] 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 the crude product as an orange viscous material (426 mg, 100%), which was used without purification. MS (ESI): m / z [M+H] + 626.

[0404] Step E. tert-Butyl 2-(5-chloro-2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0405] [ka] 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) was added Cs2CO3 (1.605 g, 4.93 mmol) and the reaction was stirred at 50 °C under an atmosphere of N2(g) for 3 h. The solvent was removed in vacuo and the residue was dissolved in water (25 mL), the pH adjusted to ∼6 with AcOH, and then extracted with EtOAc (3 × 50 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The crude product was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 50 mm i.d.) using a gradient of 20-70% MeCN in a HO / MeCN / FA (95 / 5 / 0.2) buffer system as the mobile phase to give the title compound as a yellow / white solid (1.0 g, 85%), which was used in the next step without purification. MS (ESI): m / z [M+H] + 475.

[0406] Step F. 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one tert-Butyl 2-(5-chloro-2-((4-oxo-2-thioxo-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 h. The solvent was evaporated and the crude product was dissolved in EtOAc, washed with water, filtered through a phase separator, and evaporated to give the title compound as a white solid in quantitative yield. MS (ESI): m / z [M+H] + 375.

[0407] Intermediate 3 tert-Butyl 2-(5-chloro-2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)pyrrolidine-1-carboxylate

[0408] [ka]

[0409] Step A. tert-Butyl 2-(5-chloro-2-(hydroxymethyl)phenyl)pyrrolidine-1-carboxylate

[0410] [ka] 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 Registry Number 1391024-08-0) (4.62 g, 21.82 mmol) and BocO (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 by passing 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.

[0411] Step B. tert-Butyl 2-(5-chloro-2-formylphenyl)pyrrolidine-1-carboxylate

[0412] [ka] Sulfur trioxide pyridine complex (611 mg, 3.84 mmol) was added portionwise 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 h. The mixture was diluted with MTBE (100 mL), washed with saturated NaHCO3 (aq) (40 mL) and water (40 mL), and dried (MgSO4). Filtration and evaporation of the solvent gave the title compound (559 mg, 94%). MS (ESI): m / z [M+H] + 310.

[0413] Step C. Ethyl 3-((2-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-chlorobenzyl)amino)-1H-pyrrole-2-carboxylate

[0414] [ka] A mixture of tert-butyl 2-(5-chloro-2-formylphenyl)pyrrolidine-1-carboxylate (0.552 g, 1.78 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (0.375 g, 1.97 mmol), and TEA (0.296 mL, 2.14 mmol) was stirred in MeOH (15 mL) for 30 min. AcOH (0.204 mL, 3.56 mmol) was added, followed by NaCNBH (0.112 g, 1.78 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in DCM (70 mL), washed with water (30 mL), and dried by passing through a phase separator. 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 mm i.d.) using a gradient of 30-70% MeCN in a HO / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase to give the title compound (380 mg, 48%). MS (ESI): m / z [M+H] + 448.

[0415] Step D. Ethyl 3-(3-benzoyl-1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-chlorobenzyl)thioureido)-1H-pyrrole-2-carboxylate

[0416] [ka] 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 h. Evaporation of the solvent gave the crude product (499 mg, 100%), which was used in the next step without purification. MS (ESI): m / z [M+H] + 611.

[0417] Step E. tert-Butyl 2-(5-chloro-2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)pyrrolidine-1-carboxylate 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 h. The solvent was evaporated, and water (80 mL) was added to the residue. The pH was adjusted to 6 with AcOH and extracted with EtOAc (4 x 50 mL). The organic phase was separated and dried (MgSO4). Evaporation of the solvent gave the crude product (3.7 g), which was slurried in DMSO / water. The precipitate was filtered off and washed with water and a small amount of MeOH to give the title compound (3.2 g, 100%). MS (ESI): m / z [M+H] + 461.

[0418] Intermediate 4 tert-Butyl 3-(5-chloro-2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)morpholine-4-carboxylate

[0419] [ka]

[0420] Step A. 1-((allyloxy)methyl)-2-bromo-4-chlorobenzene

[0421] [ka] To a solution of (2-bromo-4-chlorophenyl)methanol (CAS Registry Number 143888-84-0) (5 g, 22.6 mmol) and 3-bromoprop-1-ene (2.05 mL, 23.7 mmol) in toluene (50 mL) / THF (50 mL) was added NaH (0.542 g, 22.6 mmol) in portions, 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 (aq) (100 mL) and brine (100 mL). The organic phase was dried (MgSO4) and evaporated to give the crude product (5.60 g), 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 the title compound (4.36 g, 74%). 1 H 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).

[0422] Step B. (2-((allyloxy)methyl)-5-chlorophenyl)magnesium chloride

[0423] [ka] iPrMgCl×LiCl (1.3 M, 18.99 mL, 24.69 mmol) was added to a cold (0 °C) solution of 1-(allyloxymethyl)-2-bromo-4-chlorobenzene (5.87 g, 22.44 mmol) in THF (50 mL) under a N2(g) atmosphere. The reaction mixture was allowed to reach room temperature over 5 h and then stirred at room temperature for 16 h. The solution was stored at -20 °C under a N2(g) atmosphere before use.

[0424] Step C. tert-Butyl 3-oxomorpholine-4-carboxylate

[0425] [ka] BocO (11.87 g, 54.40 mmol) dissolved in anhydrous THF (30 mL) was added to a solution of morpholin-3-one (CAS reg. no. 109-11-5) (5 g, 49.45 mmol) and DMAP (6.65 g, 54.40 mmol) in anhydrous THF (60 mL), and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed by evaporation, and the crude product was dissolved in EtOAc and washed with NaHCO (aq) and water. The organic phase was dried (MgSO), and the solvent was removed by evaporation to give the crude product, which was purified by flash chromatography using a gradient of 10–80% EtOAc in heptane as the mobile phase to give the title compound as a white solid (8.37 g, 84%). 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).

[0426] Step D. tert-Butyl (2-(2-(2-((allyloxy)methyl)-5-chlorophenyl)-2-oxoethoxy)ethyl)carbamate

[0427] [ka] (2-((allyloxy)methyl)-5-chlorophenyl)magnesium chloride (41.3 mL, 12.35 mmol) was cooled to -30 °C and transferred via cannula to a solution of tert-butyl 3-oxomorpholine-4-carboxylate (2.58 g, 12.84 mmol) in THF (30 mL), also at -30 °C. The reaction mixture was allowed to reach room temperature overnight, diluted with DCM (200 mL), and washed with saturated NH4Cl(aq) (80 mL) and brine (80 mL). The organic phase was dried over 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 the title compound (3.70 g, 78%) as a yellow oil. MS (ESI): m / z [M+H] + 384.

[0428] Step E. 3-(2-((allyloxy)methyl)-5-chlorophenyl)morpholine

[0429] [ka] 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) was added dropwise acetyl chloride (20.1 mL, 282 mmol). After stirring at 0 °C for 10 min, the reaction was allowed to reach room temperature and stirred for 2 h. Additional acetyl chloride (11.1 g, 140 mmol) was added and the reaction was stirred until LCMS showed complete formation of the imine in situ. NaBH3CN (8.86 g, 141 mmol) was added and the reaction was stirred for 30 min. The reaction was quenched with water, the pH was adjusted to 8 with saturated NaHCO3 (aq), and the reaction mixture was extracted with DCM. The organic phase was dried using a phase separator and concentrated to give the title compound as a yellow oil (3.58 g, 95%). MS (ESI): m / z [M+H] + 268.

[0430] Step F. tert-Butyl 3-(2-((allyloxy)methyl)-5-chlorophenyl)morpholine-4-carboxylate

[0431] [ka] BocO (3.81 g, 17.44 mmol) followed by TEA (4.62 mL, 33.29 mmol) were added to a solution of 3-(2-((allyloxy)methyl)-5-chlorophenyl)morpholine (4.245 g, 15.85 mmol) in DCM (100 mL), and the reaction was stirred at room temperature overnight. DCM (50 mL) was added, and the organic phase was washed with brine (20 mL) and dried on a phase separator. Evaporation of the solvent gave the crude product, which was purified by flash chromatography using a gradient of 0 to 40% EtOAc in heptane as the mobile phase to give the title compound (2.70 g, 46%) 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).

[0432] Step G. tert-Butyl 3-(5-chloro-2-(hydroxymethyl)phenyl)morpholine-4-carboxylate

[0433] [ka] A mixture of tert-butyl 3-(2-(allyloxymethyl)-5-chlorophenyl)morpholine-4-carboxylate (1.226 g, 3.33 mmol), PdCl (0.812 g, 4.58 mmol), and NaOAc (0.902 g, 11.00 mmol) in AcOH (20 mL) / water (80 μL) was heated at 50 °C for 3 h. The reaction was diluted with DCM (150 mL) and washed with saturated NaHCO (aq) (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 C column (10 μm, 250 × 50 mm i.d.) using a gradient of 20–60% MeCN in a HO / MeCN / NH (95 / 5 / 0.2) buffer system as the mobile phase to give the title compound (816 mg, 75%). MS(ESI):m / z[MH] + 326

[0434] Step H. tert-Butyl 3-(5-chloro-2-formylphenyl)morpholine-4-carboxylate

[0435] [ka] 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 h. The reaction mixture was diluted with MTBE (100 mL), washed with saturated NaHCO3 (aq) (40 mL), water (40 mL), and dried (MgSO4). Evaporation of the solvent gave the title compound (770 mg, 95%). MS (ESI): m / z [M+H] + 326.

[0436] Step I. tert-Butyl 3-(5-chloro-2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)morpholine-4-carboxylate

[0437] [ka] tert-Butyl 3-(5-chloro-2-formylphenyl)morpholine-4-carboxylate (770 mg, 2.36 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (451 mg, 2.36 mmol) were dissolved in MeOH (15 mL) and TEA (0.393 mL, 2.84 mmol), and the mixture was stirred at room temperature for 10 min. AcOH (0.271 mL, 4.73 mmol) was added, and the mixture was stirred at room temperature for an additional 10 min. NaBHCN (149 mg, 2.36 mmol) was added, and the mixture was stirred at room temperature for 4 h. The solvent was evaporated, and the residue was diluted with DCM (100 mL), washed with water (40 mL), and dried on a 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 mm i.d.) using a gradient of 35 to 75% MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) buffer as the mobile phase to give the title compound (600 mg, 55%). MS (ESI): m / z [M+H] + 464.

[0438] Step J. tert-Butyl 3-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)-5-chlorophenyl)morpholine-4-carboxylate

[0439] [ka] 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.

[0440] Step K. tert-Butyl 3-(5-chloro-2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)morpholine-4-carboxylate 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) was added Cs2CO3 (834 mg, 2.56 mmol) and the mixture was heated at 65 °C for 6 h. 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 x 50 mL). The organic phase was dried (MgSO4) and evaporated to give the crude title compound (836 mg). MS (ESI): m / z [M+H] + 477.

[0441] Intermediate 5 tert-Butyl 3-(5-chloro-2-((6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)phenyl)morpholine-4-carboxylate

[0442] [ka]

[0443] Step A. tert-Butyl 3-(2-(((5-carbamoyl-1H(imidazol-4-yl)amino)methyl)-5-chlorophenyl)morpholine-4-carboxylate

[0444] [ka] 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 Registry Number 21299-72-9) (118 mg, 0.94 mmol) in EtOH (10 mL) was added AcOH (0.054 mL, 0.94 mmol) and the reaction was heated at 70 °C for 16 h. The solvent was evaporated and the residue was dissolved in MeOH (20 mL) and cooled on an ice bath. NaBHCN (35.4 mg, 0.94 mmol) was added and the reaction was stirred at 0 °C for 2 h and at room temperature for 16 h. Additional EtOH (20 mL) was added, followed by NaBHCN (15 mg, 0.40 mmol), and stirring was continued at room temperature for 3 h. 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 mm i.d.) using a gradient of 15–60% MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) buffer as the mobile phase to give the title compound (343 mg, 84%). MS (ESI): m / z [M+H] + 436.

[0445] Step B. tert-Butyl 3-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)-5-chlorophenyl)morpholine-4-carboxylate

[0446] [ka] 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) was added benzoyl isothiocyanate (0.337 mL, 2.51 mmol) and the reaction was stirred at room temperature for 18 hours. Evaporation of the solvent gave the crude product, which was used in the next step without purification. MS (ESI): m / z [M+H] + 599.

[0447] Step C. tert-Butyl 3-(5-chloro-2-((6-oxo-2-thioxo-1,2,6,7-tetrahydro-3 H -purin-3-yl)methyl)phenyl)morpholine-4-carboxylate 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 h. 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 mm i.d.) using a gradient of 5–50% MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) buffer as the mobile phase to give the title compound (566 mg, 57%). MS (ESI): m / z [M+H] + 478.

[0448] Intermediate 6 tert-Butyl 2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)azepane-1-carboxylate

[0449] [ka]

[0450] Step A. (2-((allyloxy)methyl)phenyl)magnesium chloride

[0451] [ka] iPrMgCl×LiCl (1.3 M, 130 mL, 169.5 mmol) was added to a cold (0 °C) solution of 1-(allyloxymethyl)-2-bromobenzene (CAS Registry Number 1447109-22-9) (35 g, 154.1 mmol) in THF (100 mL). The reaction mixture was allowed to reach room temperature over 5 h and then stirred at room temperature for 16 h. This reagent was used directly in the next step.

[0452] Step B. tert-Butyl (6-(2-((allyloxy)methyl)phenyl)-6-oxohexyl)carbamate

[0453] [ka] (2-((allyloxy)methyl)phenyl)magnesium chloride (25 g, 145.77 mmol) (from the above reaction mixture) was cooled to -5 °C and added via cannula to a solution of tert-butyl 2-oxoazepane-1-carboxylate (CAS registration number 106412-36-6) (40.4 g, 189.51 mmol) in THF (100 mL) at -5 °C, ensuring that the temperature did not exceed -3 °C. The reaction mixture was allowed to reach room temperature over 6 h and then stirred at room temperature for 16 h. The reaction was quenched by the addition of NHCl (aq) (20 mL). EtOAc (200 mL) was added and the phases were separated. The organic phase was dried (MgSO) and the solvent 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 the title compound (16 g, 30%). MS (ESI): m / z [M+H] + 362.

[0454] Step C. 2-(2-((allyloxy)methyl)phenyl)azepane

[0455] [ka] To a solution of tert-butyl 6-(2-(allyloxymethyl)phenyl)-6-oxohexylcarbamate (1 g, 2.77 mmol) in DCM (10 mL) was added TFA (2.131 mL, 27.66 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was removed by evaporation and coevaporated with toluene (3 × 50 mL). The residue was dissolved in MeOH (10 mL), and NaBH3CN (0.191 g, 3.04 mmol) was added. The mixture was stirred at room temperature for 20 h. DIPEA (0.580 mL, 3.32 mmol) was added, and the mixture was stirred for an additional 20 h. Only the intermediate imine was observed by LCMS. H2SO4 (0.147 mL, 2.77 mmol) was added dropwise, resulting in effervescence and the reaction being complete in 30 min. 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 the title compound as a colorless oil (0.52 g, 77%). MS (ESI): m / z [M+H] + 246.

[0456] Step D. tert-Butyl 2-(2-((allyloxy)methyl)phenyl)azepane-1-carboxylate

[0457] [ka] BocO (1.06 g, 4.84 mmol) was added 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) at 0 °C, and the mixture was allowed to reach room temperature over 30 min. The reaction mixture was concentrated, and the crude product was purified by flash chromatography using a gradient of 10-70% EtOAc in heptane as the mobile phase to give the title compound (0.96 g, 63%). MS (ESI): m / z [M+H] + 346.

[0458] Step E. tert-Butyl 2-(2-(hydroxymethyl)phenyl)azepane-1-carboxylate

[0459] [ka] 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 were added PdCl (2.66 g, 15.02 mmol) and NaOAc (2.71 g, 33.05 mmol). The mixture was stirred at 50 °C for 2 h. DCM (130 mL) was added and the organic phase was washed with saturated NaHCO (aq) (3 × 30 mL). The organic phase was dried (MgSO) 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 the title compound (2.26 g, 74%). MS (ESI): m / z [M+H] + 306.

[0460] Step F. tert-Butyl 2-(2-formylphenyl)azepane-1-carboxylate

[0461] [ka] To a solution of tert-butyl 2-(2-(hydroxymethyl)phenyl)azepane-1-carboxylate (2.186 g, 7.16 mmol) in DMSO (4.4 mL) was added DIPEA (4.38 mL, 25.05 mmol), followed by the dropwise addition (5 min) of sulfur trioxide pyridine complex (2.278 g, 14.32 mmol) dissolved in DMSO (6.7 mL). The mixture was stirred at room temperature for 2 h. MTBE (100 mL) was added and the organic phase was washed with saturated NaHCO3 (aq) (40 mL) and water (40 mL). The organic phase was dried (MgSO4) and evaporated to give the crude title compound (82.6 g).

[0462] Step G. tert-Butyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)azepane-1-carboxylate

[0463] [ka] A mixture of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (1.960 g, 10.28 mmol), DIPEA (1.79 mL, 10.3 mmol), and AcOH (1.09 mL, 18.85 mmol) in 99.5% EtOH (20 mL) was added to tert-butyl 2-(2-formylphenyl)azepane-1-carboxylate (2.6 g, 8.57 mmol) to give a brownish solution. After stirring the solution for 15 minutes, NaBHCN (0.727 g, 11.57 mmol) was added over 5 minutes. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL) and MTBE (100 mL) was added. The layers were separated, and the organic phase was dried (MgSO) and evaporated. The crude product was purified by flash chromatography using a gradient of 10-80% EtOAc in heptane as the mobile phase to give the title compound (2.58 g, 68%). MS (ESI): m / z [M+H] + 441.

[0464] Step H. tert-Butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)azepane-1-carboxylate

[0465] [ka] 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) was added benzoyl isothiocyanate (0.947 mL, 7.05 mmol) and the reaction was stirred at room temperature for 4 hours. The solvent was removed in vacuo to give the crude product (3.5 g, 99%), which was used in the next step without purification. MS (ESI): m / z [M+H] + 605.

[0466] Step I. tert-Butyl 2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)azepane-1-carboxylate Cs2CO3 (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 a N2(g) atmosphere for 3 h. The mixture was concentrated in vacuo, and the crude product was purified by flash chromatography using a gradient of 10-80% EtOAc in heptane to give the title compound (1.70 g, 65%). MS (ESI): m / z [M+H] + 455.

[0467] Intermediate 7 tert-Butyl (R)-2-(5-chloro-2-((6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)phenyl)azepane-1-carboxylate

[0468] [ka]

[0469] Step A. (S,E)-N-(2-bromo-5-chlorobenzylidene)-2-methylpropane-2-sulfinamide

[0470] [ka] To a solution of 2-bromo-5-chlorobenzaldehyde (10 g, 45.57 mmol) in DCM (300 mL) was added S-2-methylpropane-2-sulfinamide (5.63 g, 46.48 mmol), followed by 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 the title compound as a yellow oil (14.77 g, 100%). MS (ESI): m / z [M+H] + 322.

[0471] Step B. (S)—N-(1-(2-bromo-5-chlorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide

[0472] [ka] Flask 1: Cerium(III) chloride (99 mg, 0.40 mmol) was added to a round-bottom flask and then dried with a heat gun under vacuum. 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.

[0473] Flask 2: (S,E)-N-(2-bromo-5-chlorobenzylidene)-2-methylpropane-2-sulfinamide (100 mg, 0.29 mmol) was dissolved in THF (1 mL) and cooled to -78 °C. The solution in flask 1 was added in one portion. The resulting mixture was stirred at -78 °C for 2 minutes. The reaction was quenched with saturated NH4Cl (aq) in an ice bath and extracted with EtOAc. The solvent was evaporated and the residue was co-evaporated with DCM to give the title compound (110 mg, 94%) as a colorless oil (mixture of diastereomers). MS (ESI): m / z [M+H] + 378.

[0474] Step C. (S)-N-Allyl-N-(1-(2-bromo-5-chlorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide

[0475] [ka] 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) was added allyl bromide (6.85 mL, 79.21 mmol), followed by 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 NH4Cl (aq). The mixture was extracted with DCM and evaporated. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as the mobile phase to give the title compound (4.0 g, 60%) as a yellow oil (mixture of diastereomers). MS (ESI): m / z [M+H] + 418.

[0476] Step D. (R)-2-(2-bromo-5-chlorophenyl)-1-((S)-tert-butylsulfinyl)-2,3,4,7-tetrahydro-1H-azepine

[0477] [ka] Grubbs' second generation catalyst (0.231 g, 0.27 mmol, CAS Registry Number 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) under a N2(g) atmosphere. The reaction mixture was refluxed for 6 h and the solvent was evaporated to leave the crude title compound as a slightly brownish oil (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 (1.47 g, 42%) as an oil. MS (ESI): m / z [M+H] + 390.

[0478] Step E. (R)-2-(2-bromo-5-chlorophenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride

[0479] [ka] 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) was added a 4 M solution of HCl in dioxane (8.83 mL, 35.32 mmol), and the resulting mixture was stirred at room temperature for 1 hour. Evaporation of the volatiles afforded the crude title compound as a slightly brownish solid (1.26 g). MS (ESI): m / z [M+H] + 286.

[0480] Step F. tert-Butyl (R)-2-(2-bromo-5-chlorophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate

[0481] [ka] 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) dissolved in DCM (25 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with brine, and passed through a phase separator to dryness. 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. Because unreacted BocO coeluted on the column, the product mixture was redissolved in DCM (20 mL), and then DEA (5 mL) was added. The mixture was stirred at room temperature for 3 h. The solvent was evaporated and the crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in heptane as the mobile phase to give the title compound (1.31 g, 96%).

[0482] Step G. tert-Butyl (R)-2-(5-chloro-2-formylphenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate

[0483] [ka] tert-Butyl (R)-2-(2-bromo-5-chlorophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (100 mg, 0.26 mmol), Pd(OAc) (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 vessel and placed in an autoclave. The autoclave was purged with CO (g) several times and then charged with synthesis gas (CO:H, 1:1, 5 bar). The autoclave was heated in an oil bath at 100 °C for 18 h. The solvent was evaporated, and the crude product was purified by flash chromatography using a gradient of 0–25% EtOAc in heptane as the mobile phase to give the title compound (80 mg, 92%). MS(ESI):m / z[M+H] + 236.

[0484] Step H. tert-Butyl (R)-2-(5-chloro-2-formylphenyl)azepane-1-carboxylate

[0485] [ka] To a solution of tert-butyl (R-2-(5-chloro-2-formylphenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (390 mg, 1.16 mmol) in MeOH (10 mL) was added Pd / C (16.31 mg, 0.12 mmol) and the resulting mixture was hydrogenated at 1 bar for 2 h. 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 the crude title compound as a viscous yellow oil (400 mg). MS (ESI): m / z [M+H] + 238.

[0486] Step I. tert-Butyl (R)-2-(2-(((5-carbamoyl-1H-imidazol-4-yl)amino)methyl)-5-chlorophenyl)azepane-1-carboxylate

[0487] [ka] AcOH (0.068 mL, 1.18 mmol) was added to a solution of tert-butyl (R)-2-(5-chloro-2-formylphenyl)azepane-1-carboxylate (400 mg, 1.18 mmol) and 4-amino-1H-imidazole-5-carboxamide (194 mg, 1.54 mmol) in EtOH (10 mL), and the reaction was heated at 40° C. for 16 h. The reaction mixture was diluted with EtOH (10 mL), NaBHCN (134 mg, 3.55 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (4 mL) and concentrated. The residue was diluted with DCM (100 mL) and washed with brine (20 mL). The crude product was purified by preparative HPLC on an XBridge C18 column (10 μm, 250 × 50 mm i.d.) using a gradient of 10-70% MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) as the buffer system to give the title compound (63 mg, 12%). MS (ESI): m / z [M+H] + 448.

[0488] Step J. tert-Butyl (R)-2-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)-5-chlorophenyl)azepane-1-carboxylate

[0489] [ka] tert-Butyl (R-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 h and the solvent was evaporated to give the title compound in quantitative yield. MS (ESI): m / z [M+H] + 611.

[0490] Step K. tert-Butyl (R)-2-(5-chloro-2-((6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)phenyl)azepane-1-carboxylate tert-Butyl (R-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 NaOH (aq) (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 then the solvent was evaporated. The crude product was purified by preparative HPLC on a Kromasil C column (10 μm 250 × 20 mm i.d.) using a gradient of 10–60% MeCN in HO / MeCN / FA (95 / 5 / 0.2) buffer as the mobile phase to give the title compound (34 mg, 50%). MS (ESI): m / z [M+H] + 488.

[0491] Intermediate 8 tert-Butyl (R)-3-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)morpholine-4-carboxylate

[0492] [ka]

[0493] Step A. (S,E)-N-(2-bromobenzylidene)-4-methylbenzenesulfinamide

[0494] [ka] To a solution of 2-bromobenzaldehyde (2.37 g, 12.81 mmol) in anhydrous DCM (150 mL) was added Ti(OEt) (13.3 mL, 64.0 mmol), followed by (S-4-methylbenzenesulfinamide (2.03 g, 13.1 mmol), and the reaction was refluxed for 4 h. The reaction was quenched with saturated NH Cl (aq) (300 mL) and stirred for 10 min. The reaction mixture was extracted with DCM and dried through a phase separator. The solvent was evaporated and EtOAc and heptane were added to give a white solid, which was filtered off and dried to give the title compound (3.29 g, 80%). MS (ESI): m / z [M+H] + 322.

[0495] Step B. (S)—N-((R)-(2-bromophenyl)(1,3-dithian-2-yl)methyl)-4-methylbenzenesulfinamide

[0496] [ka] n-BuLi (2.5 M) (3.50 mL, 8.76 mmol) was slowly added to a solution of 1,3-dithiane (1.13 g, 9.37 mmol) in anhydrous THF (33 mL) at −20° C. After 1.5 h, the resulting solution was cooled to −78° C. and added via syringe to a solution of (S,E)-N-(2-bromobenzylidene)-4-methylbenzenesulfinamide (2.019 g, 6.27 mmol) in anhydrous THF (39 mL) at 78° C. The reaction was stirred for 20 min and quenched at −78° C. by the addition of saturated NH4Cl (aq). 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 gradient of 0–45% EtOAc in heptane as the mobile phase to give the title compound (2.011 g, 72.5%) as a white solid. MS(ESI):m / z[M+H] + 442.

[0497] Step C. (R)-N-(1-(2-bromophenyl)-2-hydroxyethyl)-4-methylbenzenesulfonamide

[0498] [ka] A solution of (S)—N—((R)-(2-bromophenyl)(1,3-dithian-2-yl)methyl)-4-methylbenzenesulfinamide (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 (aq) (70 mL) at −20° C., and the reaction was stirred at −20° C. for 12 minutes and then at room temperature for 10 minutes. The reaction was quenched with NaSO (18 mL) and heptane / DCM (1 / 1, 18 mL). The organic phase was separated and washed with NaHCO (aq) (25 mL), water (25 mL), and brine (25 mL), then dried over 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. NaBH (1.39 g, 36.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by the addition of saturated NH Cl (aq) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over a phase separator, and concentrated under reduced pressure to give the title compound (1.867 g, 68%). MS (ESI): m / z [M+H] + 370.

[0499] Step D. (R)-3-(2-bromophenyl)-4-tosylmorpholine

[0500] [ka] 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) at 0 °C under a N2 (g) atmosphere. After 10 min, a solution of diphenyl(vinyl)sulfonium trifluoromethanesulfonate (2.193 g, 6.05 mmol, CAS Registry Number 247129-29-88) in DCM (45 mL) was added dropwise, and the reaction was stirred at 0 °C for 3 h and then at room temperature overnight. The reaction was then quenched with saturated NH4Cl (aq), 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 gradient of 0-35% EtOAc in heptane as the mobile phase to give the title compound (0.676 g, 33.8%). MS (ESI): m / z [M+H] + 396.

[0501] Step E. (R)-3-(2-bromophenyl)morpholine hydrobromide

[0502] [ka] A solution of (R)-3-(2-bromophenyl)-4-tosylmorpholine (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 EtO (13 mL), giving a precipitate. The precipitate was filtered, washed with EtO, and dried under vacuum to give the title compound as a white solid (0.452 g, 82%). MS (ESI): m / z [M+H] + 242.

[0503] Step F. tert-Butyl (R)-3-(2-bromophenyl)morpholine-4-carboxylate

[0504] [ka] BocO (0.336 g, 1.54 mmol) followed by TEA (0.601 mL, 4.34 mmol) were added to a solution of (R)-3-(2-bromophenyl)morpholine hydrobromide (0.452 g, 1.40 mmol) in DCM (12 mL), and the reaction was stirred at room temperature overnight. DCM was added, and the organic phase was washed with brine, dried over a phase separator, and evaporated. The crude product was purified by flash chromatography using a gradient of 0 to 30% EtOAc in heptane to give the title compound (0.470 g, 98%) as a white 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).

[0505] Step G. tert-Butyl (R)-3-(2-formylphenyl)morpholine-4-carboxylate

[0506] [ka] tert-Butyl (R)-3-(2-bromophenyl)morpholine-4-carboxylate (0.441 g, 1.29 mmol), Pd(OAc) (0.014 g, 0.06 mmol), CataCXium A (0.069 g, 0.19 mmol), and TMEDA (0.145 mL, 0.97 mmol) were dissolved in toluene (2.5 mL) and sealed in an autoclave. The autoclave was charged with synthesis gas (CO:H, 1:1, 5 bar) and heated in an oil bath at 100 °C for 6 h. The reaction was concentrated, and the crude product was purified by flash chromatography using a gradient of 0–35% EtOAc in heptane as the mobile phase to give the title compound (0.235 g, 62.6%) as a yellow oil. MS (ESI): m / z [M-Boc+H] + 192.

[0507] Step H. tert-Butyl (R)-3-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)morpholine-4-carboxylate

[0508] [ka] tert-Butyl (R)-3-(2-formylphenyl)morpholine-4-carboxylate (0.220 g, 0.76 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (0.144 g, 0.76 mmol) were dissolved in MeOH (5.5 mL) and TEA (0.126 mL, 0.91 mmol), and the mixture was stirred at room temperature for 10 min. AcOH (0.086 mL, 1.51 mmol) was added, and the mixture was stirred at room temperature for 10 min. NaBH3CN (0.040 mL, 0.76 mmol) was added, and the mixture was stirred at room temperature for 4 h. The solvent was evaporated, and the residue was dissolved in DCM, washed with water, and dried on a phase separator. The solvent was evaporated, and the crude product was purified by flash chromatography using a gradient of 0–20% EtOAc in DCM as the mobile phase to give the title compound (0.124 g, 38%). MS(ESI): m / z [M-Boc+H] + 430.

[0509] Step I. tert-Butyl (R)-3-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)morpholine-4-carboxylate

[0510] [ka] Benzoyl isothiocyanate (0.039 mL, 0.29 mmol) was added to a solution of tert-butyl (R)-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. Evaporation of the solvent gave the title compound in estimated quantitative yield. MS (ESI): m / z [M-Boc+H] + 593.

[0511] Step J. tert-Butyl (R)-3-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)morpholine-4-carboxylate Cs2CO3 (0.188 g, 0.58 mmol) was added to a solution of tert-butyl (R)-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 h. The solvent was evaporated and the residue was diluted with water (10 mL), acidified to pH 4 with AcOH and extracted with EtOAc (3 x 10 mL). The organic phase was dried (MgSO4), filtered and evaporated to give the crude title compound (0.169 g). MS (ESI): m / z [M+H] + 443.

[0512] Intermediate 9 Benzyl 4-methyl-2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate

[0513] [ka]

[0514] Step A. tert-Butyl 3-(2-bromophenyl)piperazine-1-carboxylate

[0515] [ka] A mixture of 2-(2-bromophenyl)piperazine (CAS reg. no. 910444-36-9) (4.172 g, 17.30 mmol), BocO (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 h and then partitioned between water and DCM. The organic layer was washed with water, dried on a phase separator, and evaporated in vacuo. The crude product was purified by flash chromatography using a gradient system of DCM / MeOH / NHOH (99 / 1 / 0.2 to 9 / 1 / 0.2) to afford the title compound as a yellow oil in quantitative yield. MS (ESI): m / z [M+H] + 341.

[0516] Step B. 1-Benzyl 4-(tert-butyl) 2-(2-bromophenyl)piperazine-1,4-dicarboxylate

[0517] [ka] A mixture of tert-butyl 3-(2-bromophenyl)piperazine-1-carboxylate (2.457 g, 7.2 mmol), benzyl carbonochloridate (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 h. After cooling, the reaction mixture was diluted with EtOAc (200 mL) and washed with saturated NaHCO (aq) (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 the title compound (2.84 g, 83%) as an oil.

[0518] Step C. 1-Benzyl 4-(tert-butyl)2-(2-formylphenyl)piperazine-1,4-dicarboxylate

[0519] [ka] 1-Benzyl 4-(tert-butyl) 2-(2-bromophenyl)piperazine-1,4-dicarboxylate (2.69 g, 5.66 mmol), Pd(OAc) (0.064 g, 0.28 mmol), CataCXium A (0.304 g, 0.85 mmol), and TMEDA (0.64 mL, 4.24 mmol) were dissolved in toluene (11 mL) and sealed in an autoclave. The autoclave was charged with synthesis gas (CO:H, 1:1, 5 bar) and heated in an oil bath at 100 °C for 18 h. 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 the title compound (1.46 g, 61%). MS (ESI): m / z [M+H] + 425.

[0520] Step D. 1-Benzyl 4-(tert-butyl) 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)piperazine-1,4-dicarboxylate

[0521] [ka] 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, and NaBH (0.287 g, 7.58 mmol) was added in small portions, and the reaction was stirred at room temperature for 3.5 hours. Additional NaBH (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 0-18% EtOAc in DCM as the mobile phase to give the title compound (0.85 g, 44%). MS (ESI): m / z [M+H] + 563.

[0522] Step E. 1-Benzyl 4-(tert-butyl) 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)piperazine-1,4-dicarboxylate

[0523] [ka] 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) was added benzoyl isothiocyanate (0.204 mL, 1.52 mmol) and the reaction was stirred at room temperature for 4 hours. Evaporation of the solvent gave the crude product in estimated quantitative yield. MS (ESI): m / z [M+H] + 726

[0524] Step F. 1-Benzyl 4-(tert-butyl) 2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1,4-dicarboxylate

[0525] [ka] 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) was added Cs2CO3 (0.99 g, 3.03 mmol) and the mixture was heated at 65 °C for 3.5 h. 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 times) and the combined organic layers were dried (MgSO4). Evaporation of the solvent gave the title compound (0.75 g, 86%). MS (ESI): m / z [M+H] + 574.

[0526] Step G. Benzyl 2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate 2,2,2-trifluoroacetate

[0527] [ka] TFA (3.3 mL) was added to a solution of 1-benzyl 4-(tert-butyl) 2-(2-((4-oxo-2-thioxo-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. Evaporation of the solvent gave the title compound (0.77 g, 10%). MS (ESI): m / z [M+H] + 476.

[0528] Step H. Benzyl 4-methyl-2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate To a solution of benzyl 2-(2-((4-oxo-2-thioxo-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) was added formaldehyde (33 wt% in HO) (0.668 mL, 6.53 mmol) followed by NaBH(OAc) (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 NaHCO (aq) and brine. The organic phase was filtered through a phase separator and the solvent evaporated to give the title compound as a solid (0.590 g, 92%). MS (ESI): m / z [M+H] + 490.

[0529] Intermediate 10 2-Thioxo-1-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0530] [ka]

[0531] Step A. 2-(2-(methoxymethyl)phenyl)-4-(trifluoromethyl)pyridine

[0532] [ka] 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)Cl×CHCl (1.32 g, 1.44 mmol) were added, and the resulting solution was stirred at 100 °C for 16 h. 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 the title compound (13 g, 75%) as a light brown liquid. MS (ESI): m / z [M+H] + 268.

[0533] Step B. 2-(2-(methoxymethyl)phenyl)-4-(trifluoromethyl)piperidine

[0534] [ka] 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 under N2(g) atmosphere, followed by 12 M HCl (2.88 mL) and PtO2 (230 mg, 1.01 mmol). The mixture was evacuated and recharged with H2(g) (x3), then hydrogenated at 1 bar and room temperature for 3 h. The reaction was filtered and concentrated in vacuo. The residue was diluted with water (40 mL) and the pH was adjusted to 10 with saturated Na2CO3 (aq). The resulting aqueous solution was extracted with DCM (2 x 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 the title compound as a light yellow solid (1.2 g, 51%). MS (ESI): m / z [M+H] + 274.

[0535] Step C. 2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine

[0536] [ka] 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 h 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 (NaSO), and concentrated in vacuo. The crude product was purified by flash chromatography using heptane / EtOAc (6 / 1) as the mobile phase to give the title compound as a light yellow solid (2.95 g, 94%). MS (ESI): m / z [M+H] + 274.

[0537] Step D. 2-(2-(bromomethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine

[0538] [ka] 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 min, and 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 give the title compound as a light brown oil (250 mg, 80%). MS (ESI): m / z [M+H] + 476.

[0539] Step E. (2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)phenyl)methanol

[0540] [ka] KOH (710 mg, 12.6 mmol) was added to a solution of 2-(2-(bromomethyl)phenyl)-1-tosyl-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 h 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 (NaSO), and concentrated in vacuo. The residue was purified by flash chromatography using 5% EtOAc in heptane as the mobile phase to give the title compound as a light yellow solid (1.8 g, 69%). MS (ESI): m / z [M+H] + 414.

[0541] Step F. 2-(1-Tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde

[0542] [ka] 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 0-20° C. for 2 h. 1 M NaOH (aq) 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 (NaSO), and concentrated in vacuo. The crude product was purified by flash chromatography using 14% EtOAc in heptane as the mobile phase to give the title compound (1.75 g, 98%) as a red oil. MS (ESI): m / z [M+H] + 412.

[0543] Step G. Ethyl 3-((2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-pyrrole-2-carboxylate

[0544] [ka] To a solution of 2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde (1.75 g, 4.25 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (970 mg, 6.29 mmol) in DCE (40 mL) was added AcOH (225 mg, 3.76 mmol) and NaBH(OAc) (2.71 g, 12.79 mmol). The resulting solution was stirred at room temperature for 16 h and then quenched by the addition of saturated NaHCO (aq) (20 mL). The resulting aqueous solution was diluted with DCM (40 mL) and water (30 mL), and the organic layer was washed with water (40 mL) and brine (40 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by flash chromatography using 17% EtOAc in heptane as the mobile phase to give the title compound as a white solid (2.0 g, 86%). MS (ESI): m / z [M+H] + 550.

[0545] Step H. Ethyl 3-(3-benzoyl-1-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)thioureido)-1H-pyrrole-2-carboxylate

[0546] [ka] 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 give the crude title compound as a yellow solid (2.1 g). MS (ESI): m / z [M+H]+ 713.

[0547] Step I. 2-Thioxo-1-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one To a solution of ethyl 3-[[(2-[1-[(4-methylbenzene)sulfonyl]-4-(trifluoromethyl)piperidin-2-yl]phenyl)methyl][(phenylformamido)methanethioyl]amino]-1H-pyrrole-2-carboxylate (1.94 g, 2.72 mmol) in MeOH (50 mL) was added CsCO (1.72 g, 5.28 mmol, 1.94 equiv.), and the reaction was stirred at 50 °C for 4 h and then concentrated in vacuo. The residue was dissolved in water (80 mL) and AcOH (737 mg). The pH value of the solution was adjusted to 6 with 3 M HCl (aq.), and 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 the mobile phase to give the title compound as a light yellow solid (1.35 g, 88%). MS (ESI): m / z [M+H] + 563.

[0548] Intermediate 11 tert-Butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0549] [ka]

[0550] Step A. tert-Butyl 2-oxo-5-(trifluoromethyl)piperidine-1-carboxylate

[0551] [ka] DMAP (1.61 g, 13.2 mmol) and BocO (3.13 g, 14.36 mmol) were added to a solution of 5-(trifluoromethyl)piperidin-2-one (CAS Registry Number 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 (NaSO), and concentrated in vacuo to give the title compound (3.18 g, 99%). 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).

[0552] Step B. (2-Bromophenyl)magnesium chloride

[0553] [ka] In an oven-dried flask under a N2(g) atmosphere, a solution of 1,2-dibromobenzene (1.204 mL, 10 mmol) in THF (10 mL) was cooled to -40 °C. iPrMgClxLiCl (1.3 M, 7.69 mL, 10.00 mmol) was added dropwise over 2 min. The mixture was stirred at -40 °C for 10 min, and then the reaction was allowed to reach 0 °C over 2 h. The reaction mixture was used directly in the next step.

[0554] Step C. tert-Butyl (5-(2-bromophenyl)-5-oxo-2-(trifluoromethyl)pentyl)carbamate

[0555] [ka] To a solution of tert-butyl 2-oxo-5-(trifluoromethyl)piperidine-1-carboxylate (891 mg, 3.33 mmol) in anhydrous THF (15 mL) in an oven-dried flask under a N atmosphere, (2-bromophenyl)magnesium chloride (18.9 mL, 10.00 mmol) was added dropwise via syringe at 40 °C. The mixture was allowed to slowly reach room temperature and stirred for 15 h. Saturated NH4Cl (aq) (30 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (30 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (2.3 g). MS (ESI): m / z [M+H] + 324.

[0556] Step D. 2-(2-Bromophenyl)-5-(trifluoromethyl)piperidine

[0557] [ka] To tert-butyl (5-(2-bromophenyl)-5-oxo-2-(trifluoromethyl)pentyl)carbamate (1.41 g, 3.33 mmol) was added HCl (1.25 M in MeOH) (25 mL, 31.25 mmol), and the mixture was stirred at room temperature for 1.5 h, at 65 °C for 1 h, and at 40 °C for 16 h. The mixture was concentrated in vacuo, and the residue was dissolved in MeOH (20 mL). NaBHCN (0.42 g, 6.67 mmol) was added, and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added, and the mixture was concentrated in vacuo. DCM (25 mL) was added to the residue, and the organic layer was washed with saturated NaHCO (aq) (20 mL) using a phase separator. The aqueous layer was extracted with DCM (3 × 25 mL), and the combined organic layers were concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 40-100% EtOAc in heptane as the mobile phase to give the title compound (0.245 g, 24%). MS (ESI): m / z [M+H] + 308.

[0558] Step E. tert-Butyl 2-(2-bromophenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0559] [ka] DIPEA (0.17 mL, 0.95 mmol) and BocO (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 h. 1 M KHSO (aq) (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 the title compound (330 mg, 102%), which was used without further purification.

[0560] Step F. tert-Butyl 2-(2-formylphenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0561] [ka] tert-Butyl 2-(2-bromophenyl)-5-(trifluoromethyl)piperidine-1-carboxylate (330 mg, 0.81 mmol), Pd(OAc) (9.07 mg, 0.04 mmol), CataCXium A (43.5 mg, 0.12 mmol), and TMEDA (0.091 mL, 0.61 mmol) were dissolved in toluene (1.5 mL) and sealed in an autoclave. The autoclave was charged with synthesis gas (CO:H, 1:1, 5 bar). The mixture was stirred in an oil bath at 100 °C for 17 h and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10–50% EtOAc in heptane as the mobile phase to give the title compound (127 mg, 44%). 1 H NMR(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(1 H,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).

[0562] Step G. tert-Butyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0563] [ka] DIPEA (0.068 mL, 0.39 mmol), AcOH (0.041 mL, 0.71 mmol), and tert-butyl 2-(2-formylphenyl)-5-(trifluoromethyl)piperidine-1-carboxylate (127 mg, 0.36 mmol) were added to a solution of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (74.5 mg, 0.39 mmol) in EtOH (10 mL), and the mixture was stirred at 40 °C for 15 h. NaBHCN (67.0 mg, 1.07 mmol) was added in one portion, and the mixture was stirred at room temperature for 4.5 h. Additional NaBHCN (0.037 mL, 0.71 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Water (10 mL) was added, and the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (10 mL), and the resulting mixture was washed with brine (5 mL) 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 internal diameter) using a gradient of 40 to 85% MeCN in a HO / MeCN / AcOH (95 / 5 / 0.2) buffer system as the mobile phase to give the title compound (110 mg, 62%). MS (ESI): m / z [M+H] + 308.

[0564] Step H. tert-Butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)-5-(trifluoromethyl)piperidine-1-carboxylate

[0565] [ka] Bensoyl isothiocyante (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.

[0566] Step I. tert-Butyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)-5-(trifluoromethyl)piperidine-1-carboxylate 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)thioureido)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 h 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. 1 M HCl was added to the aqueous phase until a pH of 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 the title compound (175 mg). MS (ESI): m / z [M+H] + 509.

[0567] Intermediate 12 1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0568] [ka]

[0569] Step A. Benzyl 4,4-difluoro-2-(2-(methoxymethyl)phenyl)piperidine-1-carboxylate

[0570] [ka] 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 h, and the reaction was quenched with NH4Cl(aq) (10 mL). The resulting 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 as the mobile phase to afford the title compound (800 mg, 42%) as a light yellow oil. MS (ESI): m / z [M+H] + 376.

[0571] Step B. Benzyl 4,4-difluoro-2-(2-formylphenyl)piperidine-1-carboxylate

[0572] [ka] 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 as the mobile phase to afford the title compound (138 mg, 48%) as a brown oil. MS (ESI): m / z [M+H] + 360.

[0573] Step C. Benzyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate

[0574] [ka] 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) was added TEA (2.5 g, 24.7 mmol) and NaBH(OAc) (3.2 g, 15.1 mmol). The resulting solution was stirred at room temperature for 48 h, and the reaction was quenched by the addition of water (20 mL). The resulting aqueous solution was extracted with DCM (3 × 30 mL), washed with brine (2 × 20 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0–20% EtOAc in petroleum ether as the mobile phase to give the title compound (1.9 g, 76%) as a brown oil. MS (ESI): m / z [M+H] + 498.

[0575] Step D. Benzyl 2-(2-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate

[0576] [ka] 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 h and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in petroleum ether as the mobile phase to give the title compound (1.8 g, 68%) as a brown oil. MS (ESI): m / z [M+H] + 661.

[0577] Step E. Benzyl 4,4-difluoro-2-(2-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0578] [ka] 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 h and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in DCM as the mobile phase to give the title compound as a white solid (1.2 g, 86%). MS (ESI): m / z [M+Na] + 533.

[0579] Step F. 1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one Benzyl 4,4-difluoro-2-(2-((4-oxo-2-thioxo-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) / PhOH (460 mg, 4.90 mmol), and the resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The crude product was purified by preparative HPLC on an XBridge C18 OBD column (5 μm, 150 × 19 mm i.d.) using a gradient of 0 to 100% MeCN in HO / NH3 (100 / 0.03) to give the title compound as a white solid (190 mg, 52%).

[0580] Intermediate 13 2-Thioxo-3-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one

[0581] [ka]

[0582] Step A. 4-((2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-imidazole-5-carboxamide

[0583] [ka] 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. NaBH (680 mg, 18.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of 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 (NaSO), and 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 the title compound as a white solid (3.6 g, 77%). MS (ESI): m / z [M+Na] + 522.

[0584] Step B. 4-(3-benzoyl-1-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)thioureido)-1H-imidazole-5-carboxamide

[0585] [ka] 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 the crude title compound as a yellow solid (1.8 g). MS (ESI): m / z [M+Na] + 685.

[0586] Step C. 2-Thioxo-3-(2-(1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one 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 h and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in DCM as the mobile phase to give the title compound as a light yellow solid (400 mg, 88%). MS (ESI): m / z [M+Na] + 564.

[0587] Intermediate 14 2-Thioxo-3-(2-((2R,4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one

[0588] [ka]

[0589] Step A. 2-((2R,4S)-1-Tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde

[0590] [ka] 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 0-20 °C overnight. The resulting solution was washed with water (2 × 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 as the mobile phase to give the title compound as a yellow solid (1.36 g, 83%). MS (ESI): m / z [M+Na]+ 412.

[0591] Step B. 4-((2-((2R,4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)amino)-1H-imidazole-5-carboxamide

[0592] [ka] 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. NaBH (460 mg, 12.16 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction 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 (NaSO), and 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 the title compound as a white solid (2.5 g, 79%). MS (ESI): m / z [M+Na] + 522.

[0593] Step C. 4-(3-benzoyl-1-(2-((2R,4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)thioureido)-1H-imidazole-5-carboxamide

[0594] [ka] 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), and the resulting solution was stirred at room temperature for 4 hours and concentrated in vacuo to give the crude title compound as a yellow solid (3.3 g, crude). MS (ESI): m / z [M+Na] + 685.

[0595] Step D. 2-Thioxo-3-(2-((2R,4S)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one 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% NH3 (aq) / EtOH (2 / 1, 30 mL) was stirred at 50° C. overnight and then concentrated under vacuum. The crude product was purified by flash chromatography using DCM / MeOH (15 / 1) as the mobile phase to give the title compound as a light yellow solid (1.8 g, 72%). MS (ESI): m / z [M+Na] + 564.

[0596] Intermediate 15 (2R,4S)-2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine

[0597] [ka] Obtained by chiral separation in step C of Intermediate 10. [α] D = -87 (c = 1 g / 100 mL, MeCN).

[0598] Intermediate 16 2-Thioxo-3-(2-((2S,4R)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one

[0599] [ka] Prepared as described for Intermediate 14 using Intermediate 17 (2S,4R)-2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine as starting material. MS (ESI): m / z [M+Na] + 564.

[0600] Intermediate 17 (2S,4R)-2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine.

[0601] [ka] Obtained by chiral separation in step C of Intermediate 10. [α] D =+78(c=1g / 100mL, MeCN).

[0602] Intermediate 18 Benzyl 4,4-difluoro-2-(2-((6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)phenyl)piperidine-1-carboxylate

[0603] [ka]

[0604] Step A. Benzyl 2-(2-(((5-carbamoyl-1H-imidazol-4-yl)amino)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate

[0605] [ka] 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 h. NaBH (100 mg, 2.64 mmol) was added, and the resulting solution was stirred at 20 °C for an additional 4 h. The reaction was then quenched by the addition of 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 as the mobile phase to give the title compound (790 mg, 66%) as a white solid. MS (ESI): m / z [M+Na] + 470

[0606] Step B. Benzyl 2-(2-((3-benzoyl-1-(5-carbamoyl-1H-imidazol-4-yl)thioureido)methyl)phenyl)-4,4-difluoropiperidine-1-carboxylate

[0607] [ka] 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 h. The solid that formed was collected by filtration, washed with MeCN (3×1 mL), and dried to give the title compound as a light yellow solid (230 mg, 57%). MS (ESI): m / z [M+Na] + 633.

[0608] Step C. Benzyl 4,4-difluoro-2-(2-((6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)phenyl)piperidine-1-carboxylate 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) was added 28% NH3 (aq) (2 mL) dropwise. The resulting solution was stirred at 50° C. for 24 h and then concentrated in vacuo. The residue was purified by preparative TLC using DCM / MeOH (20 / 1) as the mobile phase to give the title compound as an off-white solid (80 mg, 98%). MS (ESI): m / z [M+Na] + 512.

[0609] Intermediate 19 3-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one

[0610] [ka]

[0611] Step A. Methyl 3-(2-bromophenyl)-3-oxopropanoate

[0612] [ka] 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 h, cooled to room temperature, and diluted with water (700 mL). The pH was adjusted to 4 with 12 M 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 (NaSO) and concentrated in vacuo to give the crude title compound as a red liquid (120 g, 93%), which was used without further purification. MS (ESI): m / z [M+H] + 257.

[0613] Step B. Methyl 2-(2-bromobenzoyl)pent-4-enoate

[0614] [ka] 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 h. 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 h and then concentrated in vacuo. The residue was diluted with water (600 mL), and the pH was adjusted to 7 with 2 M HCl (aq.). The resulting aqueous solution was extracted with DCM (3 × 100 mL), dried (NaSO), and concentrated in vacuo to give the crude title compound as a light brown liquid (78 g, 97%). MS (ESI): m / z [M+H] + 297.

[0615] Step C. 1-(2-bromophenyl)pent-4-en-1-one

[0616] [ka] 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 to reflux for 2.5 h and then cooled to room temperature. The pH of the solution was adjusted to 6 with 4 M HCl (aq). 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 (NaSO), and concentrated in vacuo. The crude product was purified by flash chromatography using 0–5% EtOAc in petroleum ether to afford the title compound as a yellow liquid (36 g, 60%, yield over three steps). MS (ESI): m / z [M+H] +239.

[0617] Step D. 1-(2-bromophenyl)-N-(4-methoxybenzyl)pent-4-en-1-amine

[0618] [ka] 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) was added TiCl (23 g, 121 mmol) dropwise under a N atmosphere at -78 °C. The mixture was stirred at -78 °C to 20 °C for 5 h. A solution of NaBHCN (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 h, and the reaction was quenched with saturated KCO (aq) (80 mL). The resulting solution was extracted with EtO (2 x 400 mL), and the combined organic layers were washed with water (2 x 400 mL) and brine (400 mL), dried (NaSO), 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 the title compound as a light yellow oil (27.7 g, 66%). MS (ESI): m / z [M+H] + 360.

[0619] Step E. 2-(2-Bromophenyl)-5-iodo-1-(4-methoxybenzyl)piperidine

[0620] [ka] 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 the reaction was quenched with water (100 mL). The resulting organic layer was separated and washed with water (100 mL), brine (100 mL), then dried (NaSO) and concentrated in vacuo to give the crude title compound as a black oil (40 g). MS (ESI): m / z [M+H] + 486.

[0621] Step F. 6-(2-bromophenyl)-1-(4-methoxybenzyl)piperidin-3-ol

[0622] [ka] AgOAc (82.2 g, 492 mmol) was added portionwise to a solution of 2-(2-bromophenyl)-5-iodo-1-(4-methoxybenzyl)piperidine (40 g, 82 mmol) in toluene (400 mL), and the mixture was stirred at 25 °C for 1.5 h. The resulting solid was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH (400 mL), KCO (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 the addition of saturated NHCl (aq) (50 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were washed with water (2 × 300 mL) and brine (300 mL), then dried (NaSO) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in petroleum ether as the mobile phase to give the title compound as a light yellow oil (9.62 g, 32%, 2 steps). MS (ESI): m / z [M+H] + 376.

[0623] Step G. 2-(2-Bromophenyl)-5-fluoro-1-(4-methoxybenzyl)piperidine

[0624] [ka] 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 h, and the reaction was quenched with water (4 mL). The resulting aqueous solution was diluted with DCM (50 mL), and the organic layer was washed with saturated NaHCO (aq) (50 mL) and brine (50 mL), then dried (Na SO ) 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 the title compound (2.45 g, 81%) as a light yellow solid. MS (ESI): m / z [M+H] + 378.

[0625] Step H. 2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzaldehyde

[0626] [ka] A solution of n-BuLi (2.5 M in hexanes) (2.34 mL, 5.84 mmol) was added to a solution of 2-(2-bromophenyl)-5-fluoro-1-(4-methoxybenzyl)piperidine (2.21 g, 5.84 mmol) in THF (40 mL) under a N2(g) atmosphere at -78 °C. The mixture was stirred at -78 °C for 45 min, and DMF (1.28 g, 3.00 equiv.) was added dropwise at -78 °C. The resulting solution was stirred at -70 °C to -60 °C for 1 h, and the reaction was quenched with water (2 mL). The resulting aqueous solution was extracted with DCM (3 × 100 mL), and the combined organic layers were washed with water (2 × 40 mL) and brine (40 mL), then 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 give the title compound as a light yellow solid (1.6 g, 84%). MS (ESI): m / z [M+H] + 328.

[0627] Step I. 4-((2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)amino)-1H-imidazole-5-carboxamide

[0628] [ka] 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 NaBH (181 mg, 4.89 mmol) was added in small portions. The resulting solution was stirred at room temperature for 1 hour, and the reaction was quenched by the dropwise addition of water (10 mL) at 0 °C. The resulting solid was collected by filtration and dried under vacuum to give the title compound as an off-white solid (2.0 g, 94%). MS (ESI): m / z [M+H] + 438.

[0629] Step J. 4-(3-benzoyl-1-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)thioureido)-1H-imidazole-5-carboxamide

[0630] [ka] 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 0-5% MeOH in DCM as the mobile phase to give the title compound as a light yellow solid (2.24 g, 82%). MS (ESI): m / z [M+H] + 601.

[0631] Step K. 3-(2-(5-fluoro-1-(4-methoxybenzyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one 4M NaOH(aq) (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 h, then the reaction was quenched with AcOH (2.0 mL). The resulting mixture was concentrated in vacuo, diluted with DCM (150 mL), washed with brine (2 × 70 mL), then dried (NaSO) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0–5% MeOH in DCM as the mobile phase to afford the title compound as an off-white solid (1.2 g, 75%). MS (ESI): m / z [M+H] + 480.

[0632] Intermediate 20 tert-Butyl 2-(3-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0633] [ka]

[0634] Step A. 2-Bromo-3-(1,3-dioxolan-2-yl)pyridine

[0635] [ka] TsOH (1.852 g, 10.75 mmol) was added to 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 h. The solvent was removed under reduced pressure, and the residue was poured into saturated NaHCO (aq) (300 mL). The mixture was extracted with EtOAc (3 × 150 mL), and the combined organic layers were dried (Na SO ), filtered, and evaporated to give the title compound as a yellow liquid (11.00 g, 89%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 230.

[0636] Step B. tert-Butyl (5-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate

[0637] [ka] n-BuLi (2.5 M in hexanes) (12.2 mL, 30.4 mmol) was added dropwise to a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (6.36 g, 27.6 mmol) in THF (180 mL) under a N2(g) atmosphere at −78 °C, and the mixture was stirred at −78 °C for 0.5 h. A solution of tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (CAS Registry Number 911634-72-5) (7.45 g, 27.9 mmol) in THF (20 mL) was added dropwise, maintaining the temperature below −78 °C. The solution was allowed to reach room temperature and stirred for an additional 2 h. The reaction was quenched by the addition of saturated NH4Cl(aq) (2 mL), and the resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (300 mL) and washed with water (2 x 200 mL) and brine (2 x 300 mL), then dried (NaSO) and evaporated to dryness. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in petroleum ether as the mobile phase to give the title compound as a yellow solid (6.87 g, 59%). MS (ESI): m / z [M+H] + 419.

[0638] Step C. tert-Butyl 3'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate

[0639] [ka] TFA (4.64 g, 40.7 mmol) was added to a solution of tert-butyl (5-(3-(1,3-dioxolan-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 h. The mixture was washed with saturated NaHCO3 (aq) (3 x 300 mL) and brine (2 x 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 as the mobile phase to give the title compound (3.17 g, 58%) as a yellow solid. MS (ESI): m / z [M+H] + 401.

[0640] Step D. tert-Butyl 2-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0641] [ka] In a flask containing Pd / C (10% Pd w / w, 650 mg) under a N2(g) atmosphere, a solution of TEA (2.40 g, 23.7 mmol) and tert-butyl 3'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate (3.17 g, 7.92 mmol) in EtOAc (50 mL) was added. The flask was evacuated, filled with H2(g) three times, and hydrogenated at 1 bar for 36 h at room temperature. The catalyst was filtered off, 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 as the mobile phase to give the title compound (2.53 g, 79%) as a white solid. MS (ESI): m / z [M+H] + 403.

[0642] Step E. tert-Butyl 2-(3-formylpyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0643] [ka] A solution of tert-butyl 2-(3-(1,3-dioxolan-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 h. The solvent was removed under vacuum. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in petroleum ether as the mobile phase to give the title compound (1.00 g, 70%) as a white solid. MS (ESI): m / z [M+H] + 259.

[0644] Step F. tert-Butyl 2-(3-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0645] [ka] To a 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) in DCE (10 mL) was added AcOH (215 mg, 3.58 mmol) and NaBH(OAc) (2.28 g, 10.75 mmol). The resulting solution was stirred at room temperature for 2 h, and the reaction was quenched by the addition of water (20 mL). The organic layer was separated and washed with brine (2 × 20 mL), then dried (NaSO) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0–10% MeOH in DCM as the mobile phase to afford the title compound (0.9 g, 79%) as an off-white solid. MS(ESI):m / z[M+H] +497.

[0646] Step G. tert-Butyl 2-(3-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0647] [ka] 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 h and then concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in petroleum ether as the mobile phase to give the title compound as a light yellow solid (2.05 g, 84%). MS (ESI): m / z [M+H] + 660.

[0648] Step H. tert-Butyl 2-(3-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate A suspension of tert-butyl 2-(3-((3-benzoyl-1-(2-(ethoxycarbonyl)-1H-pyrrol-3-yl)thioureido)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 h 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 under vacuum to give the title compound as a yellow solid (1.2 g, 76%). MS (ESI): m / z [M+H] + 510.

[0649] Intermediate 21 rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0650] [ka]

[0651] Step A. tert-Butyl 4-(difluoromethyl)piperidine-1-carboxylate

[0652] [ka] DAST (11.3 g, 49.5 mmol) was added dropwise to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g, 23.4 mmol) in DCM at 0° C. over 15 min. The resulting solution was stirred at 0° C. for an additional 15 min, and the reaction was quenched by the addition of NaHCO (aq) (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 (NaSO) 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 afford the title compound (3.6 g, 65%) as an off-white solid. MS (ESI): m / z [M+H] + 180.

[0653] Step B. tert-Butyl 4-(difluoromethyl)-2-oxopiperidine-1-carboxylate

[0654] [ka] To a solution of tert-butyl 4-(difluoromethyl)piperidine-1-carboxylate (3.6 g, 15.30 mmol) in EtOAc (63 mL) was added RuO (890 mg, 5.24 mmol), followed by the addition of a solution of NaIO (9.84 g, 46.0 mmol) in water (36 mL) in several portions at 0 °C. The resulting solution was stirred at 25 °C for 15 h. The solid was filtered off. The filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), then dried (NaSO) 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 the title compound as a white solid (2.5 g, 66%). MS (ESI): m / z [M+H] + 194

[0655] Step C. tert-Butyl (3-(difluoromethyl)-5-(2-(methoxymethyl)phenyl)-5-oxopentyl)carbamate

[0656] [ka] To a solution of 1-bromo-2-(methoxymethyl)benzene (800 mg, 4.00 mmol) in THF (15 mL), n-BuLi (2.2 M, 2 mL, 4.4 mmol) was added dropwise at −78°C under a N2(g) atmosphere, and the mixture was stirred at −78°C for 30 minutes. To the reaction mixture, a solution of tert-butyl 4-(difluoromethyl)-2-oxopiperidine-1-carboxylate (1.0 g, 4.01 mmol) in THF (5 mL) was added dropwise at −100°C, and the resulting solution was stirred at −78°C for 2 hours. The reaction was quenched by the addition of NH4Cl(aq) (15 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL), and the organic layers were combined and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in DCM as the mobile phase to give the title compound as a light yellow oil (1.0 g, 67%). MS (ESI): m / z [M+H] + 372.

[0657] Step D. 4-(Difluoromethyl)-6-(2-(methoxymethyl)phenyl)-1,2,3,4-tetrahydropyridine

[0658] [ka] 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) was added TFA (4.0 mL). The resulting solution was stirred in a microwave reactor at 100 °C for 30 min and concentrated in vacuo. The residue was diluted with DCM (50 mL) and washed with saturated Na2CO3 (aq) (2 x 70 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow oil (2.0 g, 70%). MS (ESI): m / z [M+H] + 254.

[0659] Step E. 4-(Difluoromethyl)-6-(2-(methoxymethyl)phenyl)-1-tosyl-1,2,3,4-tetrahydropyridine

[0660] [ka] 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) was added TsCl (2.24 g, 26.4 mmol) in small portions at 0 °C. The resulting solution was stirred at 20 °C for 20 h and then diluted with DCM (80 mL). The resulting mixture was washed with water (2 × 50 mL) and brine (60 mL), then dried (Na SO ) 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 the title compound (2.0 g, 63%) as a light yellow solid. MS (ESI): m / z [M+H] + 408.

[0661] Step F. 4-(Difluoromethyl)-2-(2-(methoxymethyl)phenyl)-1-tosylpiperidine

[0662] [ka] 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 refilled with N2(g) twice, then evacuated and refilled with H2(g) twice, and then stirred under an H2(g) atmosphere at 30 °C for 2 days. The solids were 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 the title compound (1.1 g, 55%) as a light yellow oil. MS (ESI): m / z [M+H] +410.

[0663] Step G. 2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzaldehyde

[0664] [ka] To a solution of 4-(difluoromethyl)-2-(2-(methoxymethyl)phenyl)-1-tosylpiperidine (1.1 g, 2.70 mmol) in DCM (20 mL) was added HNO (1.0 mL, 22.30 mmol) dropwise at 0 °C. The resulting solution was stirred at room temperature for 15 h and then diluted with DCM (60 mL). The resulting mixture was washed with water (2 × 40 mL) and brine (40 mL), then dried (NaSO) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0 to 15% EtOAc in petroleum ether as the mobile phase to afford the title compound (770 mg, 72%) as a light yellow solid.

[0665] Step H. Ethyl 3-((2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzyl)amino)-1H-pyrrole-2-carboxylate

[0666] [ka] A solution of 2-(4-(difluoromethyl)-1-tosylpiperidin-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) (1.25 g, 5.90 mmol) in DCE (30 mL) was stirred at 20 °C for 15 h and then diluted with DCM (30 mL). The resulting mixture was washed with water (2 × 30 mL) and brine (30 mL), then dried (NaSO) and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc / petroleum ether (1 / 2) as the mobile phase to give the title compound (867 mg, 83%) as a light yellow solid. MS (ESI): m / z [M+H] + 532.

[0667] Step I. Ethyl 3-(3-benzoyl-1-(2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzyl)thioureido)-1H-pyrrole-2-carboxylate

[0668] [ka] 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) was added benzoyl isothiocyanate (346 mg, 2.12 mmol), and the resulting solution was stirred at room temperature for 15 hours, then concentrated in vacuo to give the crude title compound as a light yellow solid (1.2 g). MS (ESI): m / z [M+H] + 695.

[0669] Step J. 1-(2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0670] [ka] To a solution of ethyl 3-(3-benzoyl-1-(2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzyl)thioureido)-1H-pyrrole-2-carboxylate (1.2 g, 1.73 mmol) in MeOH (30 mL) was added CsCO (1.12 g, 3.45 mmol), and the resulting solution was stirred at 50 °C for 5 h 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 2 M HCl. The resulting mixture was extracted with DCM (2 × 30 mL), and the combined organic layers were dried over (NaSO) and concentrated in vacuo to give the title compound as a light yellow solid (680 mg, 72%). MS (ESI): m / z [M+H] + 545.

[0671] Step K. rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one To a solution of 1-(2-(4-(difluoromethyl)-1-tosylpiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (650 mg, 1.19 mmol) in HBr-AcOH (15 mL) was added phenol (225 mg, 2.39 mmol), and the resulting solution was stirred at 25 °C for 4 hours and then concentrated under vacuum. The crude product was purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 150 × 19 mm i.d.) using a gradient of 10 to 85% MeCN in a HO / NH3 (95 / 5 / 0.03) buffer system as the mobile phase to give the title compound (320 mg, 69%) as a light yellow solid. MS (ESI): m / z [M+H] + 391.

[0672] Intermediate 22 tert-Butyl 2-(3-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyridin-2-yl)piperidine-1-carboxylate

[0673] [ka]

[0674] Step A. tert-Butyl 3'-(1,3-dioxolan-2-yl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate

[0675] [ka] 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) / water (6 mL) was added to 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) was added at room temperature, and the resulting suspension was stirred at 80 °C under N2(g) atmosphere for 15 h. The reaction mixture was dried (Na2SO4), filtered, and evaporated. The crude product was purified by flash chromatography using a gradient of 5-25% EtOAc in petroleum ether as the mobile phase to give the title compound as a yellow solid (1.0 g, 69%). MS (ESI): m / z [M+H] + 333.

[0676] Step B. tert-Butyl 2-(3-(1,3-dioxolan-2-yl)-1,2-dihydropyridin-2-yl)piperidine-1-carboxylate

[0677] [ka] Pd(OH)2 / C (10% Pd, 1014 mg, 0.72 mmol) was added to tert-butyl 3'-(1,3-dioxolan-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 evacuated and refilled with H2(g) five times. The resulting suspension was stirred under an atmosphere of H2(g) at 25 °C for 16 h. 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 pale yellow viscous material, which was used directly in the next step without further purification. MS (ESI): m / z [M+H], respectively. + 337 and 335.

[0678] Step C. tert-Butyl 2-(3-(1,3-dioxolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate

[0679] [ka] To a mixture of the product obtained in step B (700 mg, 2.08 mmol) in chloroform (20 mL) was added MnO2 (3.62 g, 41.6 mmol) at room temperature, and the resulting suspension was stirred at 80 °C for 16 h. 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 give a yellow viscous material. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:5) to give the title compound (240 mg, 34%) as a pale yellow viscous material. MS (ESI): m / z [M+H] + 335.

[0680] Step D. tert-Butyl 2-(3-formylpyridin-2-yl)piperidine-1-carboxylate

[0681] [ka] pTsOH×HO (25.03 mg, 0.13 mmol) was added to tert-butyl 2-(3-(1,3-dioxolan-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 h. The reaction mixture was poured into brine (100 mL) and extracted with EtOAc (3×50 mL), and the organic layer was dried (NaSO), filtered, and evaporated to give a yellow viscous material. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (135 mg, 71%) as a pale yellow viscous material. MS (ESI): m / z [M+H] + 335.

[0682] Step E. tert-Butyl 2-(3-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-2-yl)piperidine-1-carboxylate

[0683] [ka] AcOH (2.0 mL, 34.9 mmol) was added to tert-butyl 2-(3-formylpyridin-2-yl)piperidine-1-carboxylate (600 mg, 2.07 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (473 mg, 2.48 mmol) in MeOH (25 mL) at room temperature, and the resulting solution was stirred at 60° C. for 2 hours. NaBH (260 mg, 4.13 mmol) was added to the reaction mixture at room temperature, and the resulting solution was stirred at 60° C. for 5 hours. The reaction mixture was poured into saturated NaHCO (aq) (125 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give a yellow viscous material. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:3) to give the title compound (100 mg, 11%) as a pale yellow viscous material. MS(ESI): m / z [M+H]+ 429.

[0684] Step F. tert-Butyl 2-(3-((4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl)pyridin-2-yl)piperidine-1-carboxylate Benzoyl isothiocyanate (76 mg, 0.47 mmol) was added to 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 h. The solvent was removed under reduced pressure and the residue was dissolved in MeOH (10 mL). CsCO (152 mg, 0.47 mmol) was added and the resulting solution was stirred at 50 °C for 15 h. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (EtOAc:petroleum ether = 1:2) to give the title compound as a pale yellow oil (90 mg, 87%), which solidified upon standing. MS (ESI): m / z [M+H] + 442.

[0685] Intermediate 23 (9H-Fluoren-9-yl)methyl 2-(2-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0686] [ka]

[0687] Step A. 3-Bromo-2-(1,3-dioxolan-2-yl)pyridine

[0688] [ka] pTsOH (1.85 g, 10.8 mmol) was added to 3-bromopicolinaldehyde (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 h. The solvent was removed under reduced pressure, and the residue was poured into saturated NaHCO (aq) (300 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were dried (Na SO ), filtered, and evaporated to give the title compound as a yellow liquid (9.50 g, 77%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 230 / 232.

[0689] Step B. tert-Butyl (5-(2-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate

[0690] [ka] n-BuLi (2.5 M in hexane, 3.6 mL, 9.0 mmol) was added to 3-bromo-2-(1,3-dioxolan-2-yl)pyridine (1.894 g, 8.23 ​​mmol) in THF (10 mL) at −78° C. The resulting solution was stirred at −78° C. for 15 minutes under a N2(g) atmosphere. To this stirred solution was added dropwise a solution of tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (CAS Registry Number 911634-72-5) (2.0 g, 7.48 mmol) in THF (10 mL) under a N2(g) atmosphere at −78° C. The resulting solution was then stirred at −78° C. for 1 hour. The reaction mixture was poured into brine (200 mL) and extracted with EtOAc (3 x 100 mL), and the combined organic layers were dried (Na2SO4), filtered, and evaporated to give a yellow viscous material. The crude product was purified by flash chromatography using a gradient of 10-30% EtOAc in petroleum ether as the mobile phase to give the title compound (2.2 g, 70%) as a pale yellow viscous material. MS (ESI): m / z [M+H] + 419.

[0691] Step C. 2'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine

[0692] [ka] To 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) was added TFA (0.81 mL, 10.5 mmol) at room temperature, and the resulting solution was stirred for 20 h. 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 (NaSO), filtered, and evaporated to give the title compound as a yellow viscous material (1.5 g, 95%). MS (ESI): m / z [M+H] + 301.

[0693] Step D. 2-(1,3-dioxolan-2-yl)-3-(4-(trifluoromethyl)piperidin-2-yl)pyridine

[0694] [ka] To 2'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine (1.30 g, 4.33 mmol) in MeOH (20 mL) / AcOH (2.0 mL) was added Pd(OH)2 / C (0.81 g, 0.87 mmol) at room temperature. The reaction mixture was evacuated and refilled with H2(g) five times. The resulting suspension was stirred under an H2(g) atmosphere at room temperature for 8 hours. The reaction mixture was filtered through Celite, and the solvent was removed under reduced pressure to give the title compound (1.0 g, 76%) as a yellow viscous material. MS (ESI): m / z [M+H] + 303.

[0695] Step E. (9H-Fluoren-9-yl)methyl 2-(2-(1,3-dioxolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0696] [ka] To 2-(1,3-dioxolan-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) was added Fmoc-Cl (1.03 g, 3.97 mmol) at room temperature, and the resulting solution was stirred for 15 h. The reaction mixture was poured into brine (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give a yellow viscous material. The crude product was purified by flash chromatography using a gradient of 5–50% EtOAc in petroleum ether as the mobile phase to give the title compound (1.05 g, 60%) as a white solid. MS (ESI): m / z [M+H] + 525.

[0697] Step F. (9H-Fluoren-9-yl)methyl 2-(2-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0698] [ka] 6M HCl (aq) (50 mL, 300 mmol) was added to (9H-fluoren-9-yl)methyl 2-(2-(1,3-dioxolan-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 saturated NaHCO (aq, 250 mL) and extracted with EtOAc (3 × 125 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give the title compound as a brown viscous material (0.7 g, 73%). MS (ESI): m / z [M+H] + 481.

[0699] 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 To (9H-fluoren-9-yl)methyl 2-(2-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (700 mg, 1.46 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (270 mg, 1.75 mmol) in MeOH (20 mL) / AcOH (4.00 mL) was added NaBH (137 mg, 2.19 mmol) at room temperature, and the resulting solution was stirred at 60 °C for 3 h. The reaction mixture was poured into saturated NaHCO (aq) (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give a yellow viscous material. The crude product was purified by flash chromatography using a gradient of 5-30% EtOAc in petroleum ether as the mobile phase to give the title compound (660 mg, 73%) as a pale yellow viscous material that solidified upon standing. MS (ESI): m / z [M+H] + 481.

[0700] Intermediate 24 (9H-Fluoren-9-yl)methyl 2-(4-(((2-(ethoxycarbonyl)-1H-pyrrol-3-yl)amino)methyl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0701] [ka]

[0702] Step A. 3-Bromo-4-(1,3-dioxolan-2-yl)pyridine

[0703] [ka] pTsOH (1.85 g, 10.8 mmol) was added to 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 h. The solvent was removed under reduced pressure, and the residue was poured into saturated NaHCO (aq) (300 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give the title compound as a yellow liquid (10.0 g, 81%). MS (ESI): m / z [M+H] + 230 / 232.

[0704] Step B. tert-Butyl (5-(4-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate

[0705] [ka] To 3-bromo-4-(1,3-dioxolan-2-yl)pyridine (4.95 g, 21.52 mmol) in THF (30 mL) was added n-BuLi (2.5 M in hexanes, 9.0 mL, 22.5 mmol) at −78° C. The resulting solution was stirred at −78° C. for 15 minutes under a N2(g) atmosphere. To this stirred solution was added dropwise a solution of tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (5.0 g, 18.71 mmol) in THF (30 mL) under a N2(g) atmosphere at −78° C. 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 viscous material. The crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in petroleum ether as the mobile phase to give the title compound as a pale yellow viscous material (4.60 g, 59%). MS (ESI): m / z [M+H] + 419.

[0706] Step C. 4'-(1,3-dioxolan-2-yl)-4-(trifluoromethyl)-1,4,5,6-tetrahydro-2,3'-bipyridine

[0707] [ka] To tert-butyl (5-(4-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-oxo-3-(trifluoromethyl)pentyl)carbamate (4.6 g, 10.99 mmol) in DCM (60 mL) was added TFA (14.4 mL, 186.9 mmol) at room temperature and stirred at 20° C. for 15 h. The solvent was removed under reduced pressure. The residue was poured into saturated NaHCO (aq) (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (NaSO), filtered and evaporated to give the title compound as a brown solid (3.20 g, 97%). MS (ESI): m / z [M+H] + 301.

[0708] Step D. 4-(1,3-dioxolan-2-yl)-3-(4-(trifluoromethyl)piperidin-2-yl)pyridine

[0709] [ka] To 4'-(1,3-dioxolan-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 was added lithium triethylborohydride (1 M in THF) (22 mL, 22 mmol). The resulting solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was poured into saturated NaHCO3 (aq) (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give the title compound as a yellow viscous material (2.0 g, 90%). MS (ESI): m / z [M+H] + 303.

[0710] Step E. (9H-Fluoren-9-yl)methyl 2-(4-(1,3-dioxolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0711] [ka] To 4-(1,3-dioxolan-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) was added Fmoc-Cl (2.05 g, 7.94 mmol), and the resulting solution was stirred at room temperature for 15 h. The reaction mixture was poured into brine (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give a yellow viscous material. The crude product was purified by flash chromatography using a gradient of 5–50% EtOAc in petroleum ether as the mobile phase to give the title compound (1.15 g, 33%) as a white solid. MS (ESI): m / z [M+H] + 525.

[0712] Step F. (9H-Fluoren-9-yl)methyl 2-(4-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0713] [ka] To (9H-fluoren-9-yl)methyl 2-(4-(1,3-dioxolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (1.1 g, 2.10 mmol) in MeCN (30 mL) was added HCl (6 M, aq) (15 mL, 90.0 mmol) and the resulting solution was stirred at 90° C. for 15 h. The reaction mixture was poured into saturated NaHCO (250 mL) and extracted with EtOAc (3×125 mL). The combined organic layers were dried (Na SO ), filtered and evaporated to give the title compound as a brown viscous material (0.95 g, 94%). MS (ESI): m / z [M+H] + 481.

[0714] 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 To (9H-fluoren-9-yl)methyl 2-(4-formylpyridin-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (900 mg, 1.87 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (347 mg, 2.25 mmol) in MeOH (20 mL) / AcOH (4.00 mL) was added NaBH (177 mg, 2.81 mmol) at room temperature, and the resulting solution was stirred at 60 °C for 3 h. The reaction mixture was poured into saturated NaHCO (aq) (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give a yellow viscous material. The crude product was purified by preparative TLC (EtOAc:petroleum ether, 1:2) to give the title compound (550 mg, 47.5%) as a pale yellow oil that solidified upon standing. MS(ESI):m / z[M+H] + 619.

[0715] Intermediate 25 rac-(2R,4R)-2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine

[0716] [ka] The isomeric mixture obtained from Intermediate 10 Step B was chromatographed on a ChiralPak-AD-H column (5 μm, 250×20 mm id) using hexane / IPA 95 / 5 as the mobile phase to give the title compound.

[0717] Intermediate 26 rac-2-((2R,4R)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde

[0718] [ka] Intermediate 25 The title compound was prepared from rac-(2R,4R)-2-(2-(methoxymethyl)phenyl)-1-tosyl-4-(trifluoromethyl)piperidine in essentially the same manner as described for Intermediate 21, Step G.

[0719] Intermediate 27 rac-2-Thioxo-1-(2-((2R,4R)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0720] [ka] Intermediate 26: The title compound was prepared from rac-2-((2R,4R)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde in essentially the same manner as described for Intermediate 10. MS (ESI): m / z [M+H] + 619.

[0721] Intermediate 28 rac-2-Thioxo-3-(2-((2R,4R)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one

[0722] [ka] The title compound was prepared from rac-2-((2R,4R)-1-tosyl-4-(trifluoromethyl)piperidin-2-yl)benzaldehyde intermediate 26 and 4-amino-1H-imidazole-5-carboxamide in essentially the same manner as described for intermediate 27. MS (ESI): m / z [M+H] + 564.

[0723] Intermediate 29 1-(Isoquinolin-8-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0724] [ka]

[0725] Step A. Ethyl 3-((isoquinolin-8-ylmethyl)amino)-1H-pyrrole-2-carboxylate

[0726] [ka] Ethyl 3-amino-1H-pyrrole-2-carboxylate (0.364 g, 1.91 mmol) was suspended in EtOH (12 mL) and DIPEA (0.315 mL, 1.91 mmol) and stirred for 10 min. AcOH (0.219 mL, 3.82 mmol) and NaBHCN (0.360 g, 5.73 mmol) were added, and the reaction mixture was stirred for 5 min. A solution of isoquinoline-8-carbaldehyde (0.300 g, 1.91 mmol) in EtOH (15 mL) was added dropwise over 15 min, and the reaction was stirred overnight and then poured into 1 M aqueous HCl (100 mL). The acidic aqueous phase was washed with EtO (3 × 30 mL), and the aqueous layer was then made basic with NaOH and extracted with EtO (3 × 50 mL). The combined organic layers were washed with water (30 mL), dried (Na2SO4), filtered and evaporated to give the title compound as a brown viscous mass. MS (ESI): m / z [M+H] + 295.

[0727] Step B. Ethyl 3-(3-benzoyl-1-(isoquinolin-8-ylmethyl)thioureido)-1H-pyrrole-2-carboxylate

[0728] [ka] Benzoyl isothiocyanate (0.191 mL, 1.42 mmol) was added dropwise to a solution of ethyl 3-((isoquinolin-8-ylmethyl)amino)-1H-pyrrole-2-carboxylate (0.420 g, 1.42 mmol) and DIPEA (0.235 mL, 1.42 mmol) in DCM (20 mL) and the reaction was stirred overnight. The reaction was filtered and the filtrate was evaporated to give the title compound (0.5 g, 77%).

[0729] Step C. 1-(Isoquinolin-8-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one To a solution of ethyl 3-(3-benzoyl-1-(isoquinolin-8-ylmethyl)thioureido)-1H-pyrrole-2-carboxylate (0.500 g, 1.09 mmol) in MeOH (20 mL) was added NaOH (0.218 g, 5.45 mmol), and the reaction was gently refluxed for 6 hours, then allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. After shaking and settling, the mixture was filtered, and the collected solid was washed with a small amount of EtOAc, collected, and dried to give the title compound (105 mg, 31%). MS (ESI): m / z [M+H] + 309.

[0730] Intermediate 30 tert-Butyl (1-(4-((4-ox...

Claims

1. A compound of formula (I): 【Chemical 1】 During the ceremony, 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, Z １ , Z ２ , Z ３ , Z ４ and Z ５ is, if present, independently H, halo, CF ３ , Q or T; However, Y １ , Y ２ , Y ３ , Y ４ Or Y ５ At most one of １ , Y ２ , Y ３ , Y ４ Or Y ５ At least two of Z are CH; １ , Z ２ , Z ３ , Z ４ and Z ５ at most one of ３ and Z １ , Z ２ , Z ３ , Z ４ and Z ５ is Q or T, Q is 【Chemistry 2】 wherein m is 0, 1, 2, or 3; T is 【Chemistry 3】 and p is 0 or 1; s is 0, 1 or 2; n is 0, 1 or 2; A is CH ２ , C.F. ２ , CHF, CHR ２ , C.F.R. ２ , N.R. ３ Or O, During the ceremony, R １ and R ２ is, if present, independently CH ２ F, CHF ２ Or CF ３ and R ３ is, if present, independently H or CH ３ That is, The compound, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

2. The following structure: 【Chemistry 4】 10. The compound of claim 1, having the formula:

3. The following structure: 【Chemistry 5】 10. The compound of claim 1, having the formula:

4. The following structure: 【Chemistry 6】 10. The compound of claim 1, having the formula:

5. Y １ is N and Y ２ , Y ３ But, Y ４ 5. The compound of claim 1, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

6. Y ２ is N and Y １ , Y ３ But, Y ４ 5. The compound of claim 1, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

7. Y ３ is N and Y １ , Y ２ But, Y ４ 5. The compound of claim 1, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

8. Y ４ is N and Y １ , Y ２ But, Y ３ 8. The compound of any one of claims 1 to 7, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

9. 9. The compound according to any one of claims 1 to 8, wherein n is 0, or any stereoisomer or pharmaceutically acceptable salt thereof.

10. 9. The compound according to any one of claims 1 to 8, wherein n is 1, or any stereoisomer or pharmaceutically acceptable salt thereof.

11. 9. The compound according to any one of claims 1 to 8, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 2.

12. A is NR ３ 12. The compound according to any one of claims 1 to 11, wherein:

13. R ３ is CH ３ 13. The compound of claim 12, wherein:

14. R ３ is H, or any stereoisomer or pharmaceutically acceptable salt thereof.

15. A is CH ２ , C.F. ２ , CHF, CHR ２ or CFR ２ 12. The compound according to any one of claims 1 to 11, wherein:

16. A is CH ２ 16. The compound of claim 15, wherein:

17. 16. The compound of claim 15, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein A is CHF.

18. A is CF ２ 16. The compound of claim 15, wherein:

19. A is CHR ２ 16. The compound of claim 15, wherein:

20. R ２ is CH ２ 20. The compound of claim 19, wherein R is C, or any stereoisomer or pharmaceutically acceptable salt thereof.

21. R ２ is CHF ２ 20. The compound of claim 19, wherein:

22. R ２ is CF ３ 20. The compound of claim 19, wherein:

23. 23. The compound of any one of claims 1 to 22, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein s is 0.

24. 23. The compound of any one of claims 1 to 22, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein s is 1.

25. 23. The compound of any one of claims 1 to 22, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein s is 2.

26. 26. The compound of any one of claims 1 to 25, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.

27. 26. The compound of any one of claims 1 to 25, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 1.

28. Y ５ CZ ５ and Z ５ is T or Q, or any stereoisomer or pharmaceutically acceptable salt thereof.

29. Z ５ is T, or any stereoisomer or pharmaceutically acceptable salt thereof.

30. T, 【Chemistry 7】 30. The compound of claim 29, wherein:

31. 31. The compound of claim 30, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.

32. Y １ , Y ２ , Y ３ and Y ４ 32. The compound of any one of claims 28 to 31, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein is CH.

33. Y １ , Y ２ , Y ３ and Y ４ or any stereoisomer or pharmaceutically acceptable salt thereof.

34. Y １ , Y ２ , Y ３ and Y ４ Two of the groups are CH, and Y １ , Y ２ , Y ３ and Y ４ One of them is N and the other is Y. １ , Y ２ , Y ３ and Y ４ or any stereoisomer or pharmaceutically acceptable salt thereof.

35. Y ２ is Q, or any stereoisomer or pharmaceutically acceptable salt thereof.

36. Y ３ is Q, or any stereoisomer or pharmaceutically acceptable salt thereof.

37. Y ４ is Q, or any stereoisomer or pharmaceutically acceptable salt thereof.

38. 38. The compound of claim 35, 36 or 37, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein m=1.

39. 39. The compound of any one of claims 28 to 38, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein X is CH.

40. 39. The compound of any one of claims 28 to 38, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein X is N.

41. 1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 3-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, 1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (R)-1-(2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(4-methylpiperazin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-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-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(4,4-difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-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-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, 3-(2-(5-fluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-1-((2-(-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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, rac-2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-((2R,4S)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-((2S,4R)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-((2-(piperidin-2-yl)pyridin-3-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(3-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(piperidin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (R)-1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(piperidin-4-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-thioxo-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-thioxo-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-thioxo-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-thioxo-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 10. The compound of claim 1 selected from pharmaceutically acceptable salts thereof.

42. The following structure: 【Chemistry 8】 10. The compound of claim 1, having the formula:

43. The following structure: 【Chemistry 9】 10. The compound of claim 1, having the formula:

44. The following structure: 【Chemistry 10】 10. The compound of claim 1, having the formula:

45. A compound of formula (Ia): 【Chemistry 11】 During the ceremony, X １ =CH or N, Each X ２ are independently CH, CF, or CCl; r and q are 0, 1 or 2, provided that r+q=2 or 3; The compound, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

46. A compound of formula (Ib): 【Chemistry 12】 During the ceremony, X １ =CH or N, Each X ２ are independently CH, CF, or CCl; r and q are 0, 1 or 2, provided that r+q=2 or 3; The compound, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

47. Each X ２ 47. The compound of claim 45 or 46, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein is CH.

48. 48. The compound of any one of claims 45 to 47, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein r is 1 and q is 1.

49. 48. The compound of any one of claims 45 to 47, wherein r is 1 and q is 2, or r is 2 and q is 1, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

50. 48. The compound of any one of claims 45 to 47, wherein r is 0 and q is 2, or r is 2 and q is 0, or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

51. X １ 51. The compound of any one of claims 45 to 50, or any stereoisomer or pharmaceutically acceptable salt thereof, wherein is CH.

52. X １ is N, or any stereoisomer or pharmaceutically acceptable salt thereof.

53. 1-((1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(isoindolin-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(isoindolin-4-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and 47. The compound of claim 46 selected from pharmaceutically acceptable salts thereof.

54. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 44, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

55. 54. A pharmaceutical composition comprising a compound of formula (Ia) or (Ib) according to any one of claims 45 to 53, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

56. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable.

57. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases or conditions with an inflammatory, cardiovascular and / or neurological component, and / or neutrophil-driven diseases.

58. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition with an inflammatory, cardiovascular, respiratory, renal, hepatic and / or neurological component, and / or a neutrophil-driven disease.

59. 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) steatohepatitis), 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, fatty liver, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA) 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of COVID-19 (or SARS-CoV-2)-induced renal failure, diabetic kidney disease (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 associated with CKD.

60. 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, prolongation of time to recurrence of atrial fibrillation / flutter after electrical cardioversion / prevention of recurrence, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arrest of progression and / or inducing regression of atheroma, COVID-19 (or SARS) 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of 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 crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, amelioration of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction.

61. 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of 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. 54. The compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of chronic sinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).

63. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

64. 54. A method of treating, preventing, or reducing the risk of one or more diseases or conditions in which inhibition of the enzyme MPO is beneficial, said method comprising administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

65. 54. A method of treating, preventing or reducing the risk of one or more of a disease or condition with an inflammatory, cardiovascular, respiratory, renal, hepatic and / or neurological component, and / or a neutrophil-driven disease, comprising administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

66. 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) steatohepatitis), 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, fatty liver, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA) autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2)-induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN) 54. A method of treating, preventing, or reducing the risk of one or more diseases or conditions selected from: urinary tract infection (URI), urinary tract infection (UCI), urinary tract infection (UR ...

67. 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, prolongation of time to recurrence of atrial fibrillation / flutter after electrical cardioversion / prevention of recurrence, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arrest of progression and / or inducing regression of atheroma, COVID-19 (or SARS) 54. A method of treating, preventing, or reducing the risk of one or more diseases or conditions selected from 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 crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, amelioration of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction, and / or non-ST-segment elevation myocardial infarction, comprising administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof.

68. 54. 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 person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

69. 54. A method of treating, preventing, or reducing the risk of one or more diseases or conditions selected from chronic sinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS), comprising administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

70. 54. A method of treating cancer, comprising administering to a person suffering from said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

71. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of a disease or condition in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable.

72. 54. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 53 for use in the manufacture of a medicament for use in the treatment or prevention of diseases or conditions with an inflammatory, cardiovascular and / or neurological component and / or neutrophil-driven diseases.

73. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of diseases or conditions with an inflammatory, cardiovascular, respiratory, renal, hepatic and / or neurological component, and / or neutrophil-driven diseases.

74. 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) steatohepatitis), 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, fatty liver, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic autoantibodies (ANCA) 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of COVID-19 (or SARS-CoV-2)-induced renal failure, diabetic kidney disease (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 associated with CKD.

75. 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, prolongation of time to recurrence of atrial fibrillation / flutter after electrical cardioversion / prevention of recurrence, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), arrest of progression and / or inducing regression of atheroma, COVID-19 (or SARS) 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of 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 crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, amelioration of inflammation associated with plaque rupture, secondary myocardial infarction, ST-segment elevation myocardial infarction and / or non-ST-segment elevation myocardial infarction.

76. 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of 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. 54. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 53, for use in the manufacture of a medicament for use in the treatment or prevention of chronic sinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).

78. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of cancer.

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