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Msg  4165 of 4338  at  9/17/2020 1:28:30 AM  by

JBWIN


Building IP: BMY Patent Application re TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE AND/OR EPX"

United States Patent Application20200291016
Kind CodeA1
Kick; Ellen K. ; et al.September 17, 2020

TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE AND/OR EPX

Abstract

The present invention provides compounds of Formula (I); wherein the substituents are each as defined in the specification, and compositions comprising any of such novel compounds. These compounds are myeloperoxidase (MPO) inhibitors and/or eosinophil peroxidase (EPX) inhibitors, and may be useful for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. ##STR00001##


Inventors:Kick; Ellen K.; (Pennington, NJ) ; Smalheer; Joanne M.; (Yardley, PA) ; Shaw; Scott A.; (Lawrence Township, NJ) ; Vokits; Benjiman P.; (New York City, NY) ; Dilger; Andrew K.; (Ewing, NJ) ; Clark; Charles G.; (Cherry Hill, NJ) ; Valente; Meriah Neissel; (Bedminstar, NJ) ; Jusuf; Sutjano; (Princeton, NJ) ; Wurtz; Nicholas R.; (Pennington, NJ)
Applicant:
NameCityStateCountryType

Bristol-Myers Squibb Company

Princeton

NJ

US
Family ID:1000004866759
Appl. No.:16/083958
Filed:March 16, 2017
PCT Filed:March 16, 2017
PCT NO:PCT/US17/22756
371 Date:September 11, 2018

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62310017Mar 18, 2016

Current U.S. Class:1/1
Current CPC Class:C07D 519/00 20130101; C07D 471/04 20130101
International Class:C07D 471/04 20060101 C07D471/04; C07D 519/00 20060101 C07D519/00

Claims



1. A compound of Formula (I): ##STR00448## wherein R.sup.1 is independently one or more hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, CO.sub.2 (C.sub.1-4 alkyl), CH.sub.2OH, CH.sub.2NH.sub.2, SO.sub.2Me, or SO.sub.2NH.sub.2; n is 0,1, or 2; R.sup.2 is C.sub.1-C.sub.6 alkyl, benzyl, C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, hydroxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy aryl, heteroaryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy, --(CH.sub.2).sub.mNR.sup.3COaryl, --(CH.sub.2).sub.mNR.sup.3C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3 aryl C.sub.1-C.sub.6 alkyl; --(CH.sub.2).sub.mNR.sup.3 heteroaryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.mNR.sup.3 heterocyclyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl aryl, --(CH.sub.2).sub.m NR.sup.3C.sub.9-C.sub.10 bicyclic carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged heterocyclyl, --(CH.sub.2).sub.mNHSO.sub.2 aryl, --(CH.sub.2).sub.2O C.sub.3-C.sub.10 carbocyclyl, --(CH.sub.2).sub.m CO aryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.p heterocyclyl, or --CH.sub.2CO NR.sup.3C.sub.3-C.sub.10 carbocyclyl; any of which is substituted with 0-3 R.sup.4 groups, m is 1, 2, 3, or 4; p is 2 or 3; R.sup.3 is hydrogen, C.sub.1-4 alkyl, 2-(C.sub.1-4 alkoxy)ethyl-, hydroxy C.sub.2-C.sub.4 alkyl, C.sub.1-4 haloalkyl, --CH.sub.2CH(OH)CF.sub.3, --(CH.sub.2) heterocyclyl or --CH.sub.2CONR.sup.xR.sup.y; R.sup.x is hydrogen or C.sub.1-4 alkyl; R.sup.y is hydrogen or C.sub.1-4 alkyl; R.sup.4 is, independently at each occurrence, one or more hydrogen, halogen, hydroxy, amino, cyano, hydroxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, --C.sub.3-6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.6 alkyl-, heterocycle, --COOC.sub.1-C.sub.6 alkyl, or CONR.sup.xR.sup.y; said --C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a, aryl substituted with 0-4 R.sup.a, or a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR.sup.b, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a; R.sup.a is, independently at each occurrence, hydrogen, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl or C.sub.1-4 haloalkoxy; R.sup.b is, independently at each occurrence, hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CO(C.sub.1-4 alkyl), CO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.1-4 alkyl) or --(CH.sub.2).sub.t-phenyl, said --(CH.sub.2).sub.t-phenyl substituted with 0-1 R.sup.d; R.sup.d is hydrogen, C.sub.1-4 alkyl or halogen; t is 1 or 2; and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

2. A compound according to claim 1 of Formula (II); ##STR00449## wherein R.sup.1 is hydrogen, halogen, OMe, OCF.sub.3, OCF.sub.2H, methyl, CH.sub.2OH, SO.sub.2NH.sub.2 or CN; R.sup.2 is C.sub.1-C.sub.6 alkyl, benzyl, C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, hydroxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy aryl, heteroaryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy, --(CH.sub.2).sub.mNR.sup.3COaryl, --(CH.sub.2).sub.mNR.sup.3C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3 aryl C.sub.1-C.sub.6 alkyl; --(CH.sub.2).sub.mNR.sup.3 heteroaryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.mNR.sup.3 heterocyclyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl aryl, --(CH.sub.2).sub.m NR.sup.3C.sub.9-C.sub.10 bicyclic carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged heterocyclyl, --(CH.sub.2).sub.mNHSO.sub.2 aryl, --(CH.sub.2).sub.2O C.sub.3-C.sub.10 carbocyclyl, --(CH.sub.2).sub.mCO aryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.pheterocyclyl, or --CH.sub.2CONR.sup.3C.sub.3-C.sub.10 carbocyclyl; any of which is substituted with 0-3 R.sup.4 groups, m is 2 or 3; p is 2 or 3; R.sup.3 is hydrogen, C.sub.1-4 alkyl, 2-(C.sub.1-4 alkoxy)ethyl-, hydroxy C.sub.2-C.sub.4 alkyl, C.sub.1-4 haloalkyl, --(CH.sub.2) heterocyclyl or --CH.sub.2CONR.sup.xR.sup.y; R.sup.x is hydrogen or C.sub.1-4 alkyl; R.sup.y is hydrogen or C.sub.1-4 alkyl; R.sup.4 is, independently at each occurrence, one or more halogen, hydroxy, cyano, hydroxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.6 alkyl, --C.sub.3-6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.6 alkyl-, --COOC.sub.1-C.sub.6 alkyl, or CONR.sup.xR.sup.y; said --C.sub.3-6 cycloalkyl is substituted with 0-3 R.sup.a; said aryl is substituted with 0-4 R.sup.a, or a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR.sup.b, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a; R.sup.a is, independently at each occurrence, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or C.sub.1-4 haloalkoxy; R.sup.b is, independently at each occurrence, hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CO(C.sub.1-4 alkyl), CO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.1-4 alkyl) or --(CH.sub.2).sub.t-phenyl, said --(CH.sub.2).sub.t-phenyl substituted with 0-1 R.sup.d; R.sup.d is F or Cl; and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

3. A compound according to claim 2 of Formula (III); ##STR00450## R.sup.1 is hydrogen, halogen, OMe, OCF.sub.3, OCF.sub.2H, methyl, CH.sub.2OH, SO.sub.2NH.sub.2 or cyano; R.sup.3 is hydrogen, C.sub.1-4 alkyl, 2-(C.sub.1-4 alkoxy)ethyl-, hydroxy ethyl, C.sub.1-4 haloalkyl, --(CH.sub.2) heterocyclyl or --CH.sub.2CONR.sup.xR.sup.y; R.sup.2 is, Me, ethyl, propyl, 2-methylpropyl, 3-phenylpropyl, 2-benzyloxyethyl, 3,3,-diphenylpropyl, 3-cyclohexylethyl, 1-naphthylpropyl, 2-naphthylpropyl, 1-indanylpropyl, 2-(tetrahydro-2H-pyran-4-yl)ethyl, 3-(1,2,3,4-tetrahydroisoquinolin-1-yl)propyl, --(CH.sub.2).sub.2NR.sup.3C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3 aryl C.sub.1-C.sub.6 alkyl; --(CH.sub.2).sub.mNR.sup.3 heteroaryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.mNR.sup.3 heterocyclyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl aryl, --(CH.sub.2).sub.m NR.sup.3C.sub.9-C.sub.10 bicyclic carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged heterocyclyl, ##STR00451## any of which can be substituted with 0-3 R.sup.4 groups; m is 2; R.sup.4 is hydrogen, halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-2 haloalkyl, phenoxy, aryl or benzyl; said --C.sub.3-6 cycloalkyl is substituted with 0-3 R.sup.a; said aryl is substituted with 0-4 R.sup.a, or a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR.sup.b, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a; R.sup.a is, independently at each occurrence, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or C.sub.1-4 haloalkoxy; r is 0 or 1; X is CH.sub.2 or O; and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

4. A compound according to claim 3 wherein R.sup.3 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxyalkyl, C.sub.2-4 hydroxyalkyl, C.sub.1-4 haloalkyl, --CH.sub.2-heterocyclyl or --(CH.sub.2) CONH.sub.2; R.sup.2 is ##STR00452## any of which can be substituted with 0-1 R.sup.4 groups; r is 0 or 1; R.sup.4 is hydrogen, halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-2 haloalkyl, phenoxy, aryl or benzyl; and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

5. A compound selected from the exemplified examples, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

6. A compound according to claim 5 selected from any subset list of compounds, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

7. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.
Description



CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 62/310,017, filed Mar. 18, 2016, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel macrocyclic compounds, which are myeloperoxidase (MPO) inhibitors and/or eosinophil peroxidase (EPX) inhibitors, compositions containing them, and methods of using them, for example, for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

BACKGROUND OF THE INVENTION

[0003] Cardiovascular disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack and stroke, and thereby the principal cause of death in the United States. Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Weber et al., Nature Med, 17(11):1410-1422 (2011)).

[0004] MPO inhibitors have been suggested to reduce the atherosclerotic burden and/or the vulnerability of existing atherosclerotic lesions and thereby decrease the risk of acute myocardial infarction, unstable angina or stroke, and reduce ischemia-reperfusion injury during acute coronary syndrome and ischemic cerebrovascular events. Several lines of data support a role for MPO in atherosclerosis. MPO is expressed in the shoulder regions and necrotic core of human atherosclerotic lesions and active enzyme has been isolated from autopsy specimens of human lesions (Daugherty, A. et al., J. Clin. Invest., 94(1):437-444 (1994)). Moreover, HOCl-modified lipoproteins have been detected in advanced human atherosclerotic lesions (Hazell, L. J. et al., J. Clin. Invest., 97:1535-1544 (1996)). In eroded and ruptured human lesions, as compared to fatty streaks, an increased number of MPO expressing macrophages have been demonstrated, suggesting a particular role for MPO in acute coronary syndromes (Sugiyama, S. et al., Am. J. Pathol. 158(3):879-891 (2001); Tavora, F. R., BMC Cardiovasc. Disord., 9:27 (Jun. 23, 2009)).

[0005] Data accumulated during the last fifteen years indicate that the pro-atherogenic actions of MPO include oxidation of lipoproteins, induction of endothelial dysfunction via consuming nitric oxide and destabilization of atherosclerotic lesions by activation of proteases (Nicholls, S. J. et al., Arterioscler. Thromb. Vasc. Biol., 25(6): 1102-1111 (2005); Nicholls, S. J. et al., JLR, S346-S351 (2009)). Several studies have focused on nitro- and chlorotyrosine modifications of LDL and HDL lipoproteins. Since chlorotyrosine modifications in vivo are generated by hypochlorous acid produced by MPO these modifications are regarded as specific markers of MPO activity (Hazen, S. et al., J. Clin. Invest., 99(9):2075-2081 (1997)).

[0006] ApoA-I isolated from atherosclerotic lesions is modified by reactive chlorine and nitrogen species as well as by reactive carbonyls (Pennathur, S. et al., J. Biol. Chem., 279:42977-42983 (2004); Shao, B. et al., J. Biol. Chem., 279:7856-7866 (2004); Zheng, L. et al., J. Clin. Invest., 114(4):529-541 (2004); Shao, B. et al., JBC in press (2012)). Chlorotyrosine modification of apoA1, the main apolipoprotein of HDL cholesterol, was associated with impaired cholesterol acceptor function (Bergt, C. S. et al., Proc. Natl. Acad. Sci. USA, 101(35):13032-13037 (2004); Zheng, L. et al., J. Clin. Invest., 114(4):529-541 (2004)). Thus, oxidation of apoA-I amino acid residues by the MPO--H.sub.2O.sub.2--Cl.sup.- system is one mechanism for loss of its biological activities.

[0007] The lipid and protein content of LDL are also targets for MPO oxidation and presence of chlorotyrosine in LDL extracted from human atherosclerotic tissues has been shown (Hazen, S. et al., J. Clin. Invest., 2075-2081 (1997)). LDL particles exposed to MPO in vitro become aggregated, leading to facilitated uptake via macrophage scavenger receptors and foam cell formation (Hazell, L. J. et al., Biochem. J., 290 (Pt. 1): 165-172 (1993); Podrez, E. A. et al., J Clin. Invest. 105:1095-1108 (2000)). Thus, MPO appears to play a role in the generation of oxidized LDL, which contributes to atherosclerosis plaque development.

[0008] Further evidence implicating MPO in the pathophysiology of atherosclerosis comes from the study of hMPO transgenic mice crossed with LDL-R KO mice (Castelini L. W. et al., J. Lipid Res., 47:1366-1377 (2006)). These mice expressed MPO in lesions and developed significantly larger aortic lesions than control LDL-R KO mice.

[0009] Many clinical studies have implicated MPO in cardiovascular disease in human patients. Patients with established coronary artery disease have higher plasma and leukocyte MPO levels than healthy controls (Zhang, R. et al., JAMA, 286(17):2136-2142 (2001)). Moreover, in three large prospective studies plasma levels of MPO predicted the risk of future coronary events or revascularization (Baldus, S. et al., Circulation, 108(12):1440-1445 (2003); Brennan, M. et al., N. Engl. J. Med., 349(17):1595-1604 (2003); Kohli, P. et al., Circulation, 122:A13175 (2010)). In two recent large nested case control prospective studies, the EPIC-Norfolk and MONICA-/KORA Augsburg studies, baseline MPO levels in these initially healthy populations turned out to be an excellent predictor of future risk of CAD and CHD respectively, showing that this inflammatory marker precedes the presentation of clinical symptoms of CVD (Meuwese, M. C. et al., J. Am. Coll. Cardiol., 50:159-165 (2007); Karakas et al., J. Int. Med., 271:43-50 (2011)). Interestingly, MPO deficient humans are less affected by cardiovascular disease than controls with normal MPO levels (Kutter, D. et al., Acta Haematol., 104:10-15 (2000)). A polymorphism in the MPO promoter affects expression leading to high and low MPO expressing individuals. In three different studies the high expression genotype has been associated with an increased risk of cardiovascular disease (Nikpoor, B. et al., Am. Heart J., 142(2):336-339 (2001); Makela, R. et al., Lab. Invest. 83(7):919-925 (2003); Asselbergs, F. W. et al., Am. J. Med., 116(6):429-430 (2004)).

[0010] MPO inhibitors are expected to preserve heart function and reduce heart failure burden in patients. In MPO null mice, preservation of left ventricular (LV) function has been observed in both a coronary artery ligation model (Askari, A. T. et al., J. Exp. Med., 197:615-624 (2003)) and an ischemia reperfusion model (Vasilyev, N. et al., Circulation, 112:2812-2820 (2005)), suggesting that MPO may provide a mechanistic link between inflammation, oxidant stress, and impaired cardiac remodeling. High circulating levels of MPO have also been linked to chronic heart failure in patients. Systemic MPO was increased in patients with established chronic systolic HF and correlated with diastolic dysfunction independent of age and plasma B-type natriuretic peptide (Tang, W. H. et al., Am. J. Cardiol., 98:796-799 (2006)). Studies also showed that systemic MPO in subjects with myocardial infarction (MI) (Mocatta, T. J. et al., J. Am. Coll. Cardiol., 49:1993-2000 (2007)) or chronic systolic HF (Tang, W. H. et al., J. Am. Coll. Cardiol., 49:2364-2370 (2007)) may predict long-term adverse clinical events.

[0011] Inhibitors of MPO or EPX may be used to treat other neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, and stroke as well as other inflammatory diseases or conditions like asthma, COPD, cystic fibrosis, inflammatory bowel disease, chronic kidney disease, renal glomerular damage and rheumatoid arthritis.

[0012] In these chronic inflammatory diseases, a role of MPO in the development of tissue injury has been suggested. In lesional tissues of patients with Alzheimer's disease, MPO protein was detected along with elevated levels of chlorotyrosine (Green, P. S. et al., J Neurochem., 90:724-733 (2004)). In an animal model of Parkinson's disease, increased levels of chlorotyrosine and HOCl-modified proteins in brain tissues have been reported (Choi, D. K. et al., J. Neuroscience, 25(28):6394-6600 (2005)). In asthmatic patients the level of bromotyrosine, a molecular fingerprint of eosinophil-catalyzed oxidation was associated with symptom severity (Wedes, S. H. et al., J. Pediatr., 248-255 (2011)). Upon allergen challenge, a model that elicits primarily a strong eosinophilic response, lung segments of asthmatic subjects exhibit a >10 fold increase in bronchioalveolar lavage 3-bromotyrosine an indicator of eosinophil activity vs. a 3-fold increase in 3-chlorotyrosine characteristic of MPO activity (Wu, W. et al., JCI, 105:1455-1463 (2000)). The presence of HOCl-modified protein was also detected in patients with membranous glomerulonephritis (Grone et al., Lab. Invest., 82:5-14 (2002)). High MPO circulating levels have been implicated in the development of cardiovascular and chronic kidney disease in patients on hemodialysis (Honda, H. et al., Clin. J. Am. Soc., Nephrol., 142-151 (2009). In addition MPO activity and 3-chlorotyrosine levels were also increased during hemodyalisis in patients with end-stage renal disease (Delporte, C et al., Talanta, 99:603-609 (2012)). Similarly, there is accumulation of neutrophils and eosinophils in conjunction with MPO and EPX seen in intestinal mucosa of patients with inflammatory bowel disease (Kruidenier, L. et al., J. Pathol., 201:17-27 (2003); Carlson, M. et al., Am. J. Gastrol., 94(7):1876-1883 (1999)) and in synovial fluids of rheumatoid arthritis patients (Edwards, S. W. et al., Biochem. J., 250:81-85 (1988); Nucombe, H. L. et al., Ann. Rheum. Dis., 50:237-242 (1991)).

[0013] Thus, there is considerable evidence that MPO and/or EPX derived oxidants contribute to tissue injury in chronic inflammatory disorders. MPO and/or EPX inhibitors are anticipated to reduce the levels of oxidants and tissue injury associated with the progression of these diseases.

SUMMARY OF THE INVENTION

[0014] The present disclosure provides novel triazolopyridine compounds, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as MPO inhibitors and/or EPX inhibitors.

[0015] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0016] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0017] The compounds of the invention may be used in the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX.

[0018] The compounds of the invention may be used in therapy.

[0019] The compounds of the invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX.

[0020] Examples of diseases or disorders associated with the activity of MPO and/or EPX include, but are not limited to, atherosclerosis, coronary artery disease, acute coronary syndrome, dyslipidemias and the sequelae thereof, heart failure, lung diseases including asthma, COPD and cystic fibrosis, and neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, and stroke, as well as chronic inflammatory diseases such as inflammatory bowel disease, renal glomerular damage and rheumatoid arthritis.

[0021] The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).

[0022] Other features and advantages of the invention will be apparent from the following detailed description and claims.

I. Compounds of the Invention

[0023] In a first aspect, the present invention provides a compound of Formula (I):

##STR00002##

wherein

[0024] R.sup.1 is independently one or more hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, CN, CO.sub.2 (C.sub.1-4 alkyl), CH.sub.2OH, CH.sub.2NH.sub.2, SO.sub.2Me, or SO.sub.2NH.sub.2;

[0025] n is 0, 1, or 2;

[0026] R.sup.2 is C.sub.1-C.sub.6 alkyl, benzyl, C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, hydroxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy aryl, heteroaryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy, --(CH.sub.2).sub.mNR.sup.3COaryl, --(CH.sub.2).sub.mNR.sup.3C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3 aryl C.sub.1-C.sub.6 alkyl; --(CH.sub.2).sub.mNR.sup.3 heteroaryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.mNR.sup.3 heterocyclyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl aryl, --(CH.sub.2).sub.m NR.sup.3C.sub.9-C.sub.10 bicyclic carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged heterocyclyl, --(CH.sub.2).sub.mNHSO.sub.2 aryl, --(CH.sub.2).sub.20C.sub.3-C.sub.10 carbocyclyl, --(CH.sub.2).sub.m CO aryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.pheterocyclyl, or --CH.sub.2CO NR.sup.3C.sub.3-C.sub.10 carbocyclyl; any of which is substituted with 0-3 R.sup.4 groups,

[0027] m is 1, 2, 3, or 4;

[0028] p is 2 or 3;

[0029] R.sup.3 is hydrogen, C.sub.1-4 alkyl, 2-(C.sub.1-4 alkoxy)ethyl-, hydroxy C.sub.2-C.sub.4 alkyl, C.sub.1-4 haloalkyl, --CH.sub.2CH(OH)CF.sub.3, --(CH.sub.2) heterocyclyl or --CH.sub.2CONR.sup.xR.sup.y;

[0030] R.sup.x is hydrogen or C.sub.1-4 alkyl;

[0031] R.sup.y is hydrogen or C.sub.1-4 alkyl;

[0032] R.sup.4 is, independently at each occurrence, one or more hydrogen, halogen, hydroxy, amino, cyano, hydroxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, --C.sub.3-6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.6 alkyl-, heterocycle, --COOC.sub.1-C.sub.6 alkyl, or CONR.sup.xR.sup.y;

[0033] said --C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a, aryl substituted with 0-4 R.sup.a,

[0034] or a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR.sup.b, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a;

[0035] R.sup.a is, independently at each occurrence, hydrogen, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl or C.sub.1-4 haloalkoxy;

[0036] R.sup.b is, independently at each occurrence, hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CO(C.sub.1-4 alkyl), CO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.1-4 alkyl) or --(CH.sub.2).sub.t-phenyl, said --(CH.sub.2).sub.t-phenyl substituted with 0-1 R.sup.d;

[0037] R.sup.d is hydrogen, C.sub.1-4 alkyl or halogen;

[0038] t is 1 or 2;

[0039] and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

[0040] In a second aspect, the invention provides, within the scope of the first aspect, a compound of Formula (II);

##STR00003##

wherein

[0041] R.sup.1 is hydrogen, halogen, OMe, OCF.sub.3, OCF.sub.2H, methyl, CH.sub.2OH, SO.sub.2NH.sub.2 or CN; R.sup.2 is C.sub.1-C.sub.6 alkyl, benzyl, C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, hydroxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy aryl, heteroaryl C.sub.1-C.sub.6 alkyl-, --(CH.sub.2).sub.2C.sub.1-C.sub.6 alkoxy, --(CH.sub.2).sub.mNR.sup.3COaryl, --(CH.sub.2).sub.mNR.sup.3C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3 aryl C.sub.1-C.sub.6 alkyl; --(CH.sub.2).sub.mNR.sup.3 heteroaryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.mNR.sup.3 heterocyclyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl aryl, --(CH.sub.2).sub.m NR.sup.3C.sub.9-C.sub.10 bicyclic carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged heterocyclyl, --(CH.sub.2).sub.mNHSO.sub.2 aryl, --(CH.sub.2).sub.20C.sub.3-C.sub.10 carbocyclyl, --(CH.sub.2).sub.mCO aryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.pheterocyclyl, or --CH.sub.2CONR.sup.3C.sub.3-C.sub.10 carbocyclyl; any of which is substituted with 0-3 R.sup.4 groups,

[0042] m is 2 or 3;

[0043] p is 2 or 3;

[0044] R.sup.3 is hydrogen, C.sub.1-4 alkyl, 2-(C.sub.1-4 alkoxy)ethyl-, hydroxy C.sub.2-C.sub.4 alkyl, C.sub.1-4 haloalkyl, --(CH.sub.2) heterocyclyl or --CH.sub.2CONR.sup.xR.sup.y;

[0045] R.sup.x is hydrogen or C.sub.1-4 alkyl;

[0046] R.sup.y is hydrogen or C.sub.1-4 alkyl;

[0047] R.sup.4 is, independently at each occurrence, one or more halogen, hydroxy, cyano, hydroxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.6 alkyl, --C.sub.3-6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.6 alkyl-, --COOC.sub.1-C.sub.6 alkyl, or CONR.sup.xR.sup.y;

[0048] said --C.sub.3-6 cycloalkyl is substituted with 0-3 R.sup.a; said aryl is substituted with 0-4 R.sup.a,

[0049] or a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR.sup.b, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a;

[0050] R.sup.a is, independently at each occurrence, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or C.sub.1-4 haloalkoxy;

[0051] R.sup.b is, independently at each occurrence, hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CO(C.sub.1-4 alkyl), CO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.1-4 alkyl) or --(CH.sub.2).sub.t-phenyl, said --(CH.sub.2).sub.t-phenyl substituted with 0-1 R.sup.d;

[0052] R.sup.d is F or Cl;

[0053] and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

[0054] In a third aspect, the present invention includes a compound of Formula (III);

##STR00004##

wherein

[0055] R.sup.1 is hydrogen, halogen, OMe, OCF.sub.3, OCF.sub.2H, methyl, CH.sub.2OH, SO.sub.2NH.sub.2 or cyano;

[0056] R.sup.3 is hydrogen, C.sub.1-4 alkyl, 2-(C.sub.1-4 alkoxy)ethyl-, hydroxy ethyl, C.sub.1-4 haloalkyl, --(CH.sub.2) heterocyclyl or --CH.sub.2CONR.sup.xR.sup.y;

[0057] R.sup.2 is, Me, ethyl, propyl, 2-methylpropyl, 3-phenylpropyl, 2-benzyloxyethyl, 3,3,-diphenylpropyl, 3-cyclohexylethyl, 1-naphthylpropyl, 2-naphthylpropyl, 1-indanylpropyl, 2-(tetrahydro-2H-pyran-4-yl)ethyl, 3-(1,2,3,4-tetrahydroisoquinolin-1-yl)propyl, --(CH.sub.2).sub.2NR.sup.3C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3 aryl C.sub.1-C.sub.6 alkyl; --(CH.sub.2).sub.mNR.sup.3 heteroaryl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.mNR.sup.3 heterocyclyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.mNR.sup.3C.sub.3-C.sub.8 cycloalkyl aryl, --(CH.sub.2).sub.m NR.sup.3C.sub.9-C.sub.10 bicyclic carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged carbocyclyl, --(CH.sub.2).sub.mNR.sup.3 bridged heterocyclyl,

##STR00005##

[0058] any of which can be substituted with 0-3 R.sup.4 groups;

[0059] m is 2;

[0060] R.sup.4 is hydrogen, halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-2 haloalkyl, phenoxy, aryl or benzyl;

[0061] said --C.sub.3-6 cycloalkyl is substituted with 0-3 R.sup.a; said aryl is substituted with 0-4 R.sup.a

[0062] or a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR.sup.b, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a;

[0063] R.sup.a is, independently at each occurrence, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or C.sub.1-4 haloalkoxy;

[0064] r is 0 or 1;

[0065] X is CH.sub.2 or O;

[0066] and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

[0067] In a fourth aspect, the present invention includes a compound of Formula (III);

##STR00006##

wherein

[0068] R.sup.3 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxyalkyl, C.sub.2-4 hydroxyalkyl, C.sub.1-4 haloalkyl, --CH.sub.2-heterocyclyl or --(CH.sub.2) CONH.sub.2;

[0069] R.sup.2 is

##STR00007##

[0070] any of which can be substituted with 0-1 R.sup.4 groups;

[0071] r is 0 or 1;

[0072] R.sup.4 is hydrogen, halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-2 haloalkyl, phenoxy, aryl or benzyl;

[0073] and/or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

[0074] In another aspect, the present invention provides a compound selected from the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[0075] In another aspect, the present invention provides a compound selected from any subset list of compounds within the scope of the prior aspect.

II. Other Embodiments of the Invention

[0076] In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[0077] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[0078] In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[0079] In another embodiment, the present invention provides a pharmaceutical composition as defined above further comprising additional therapeutic agent(s).

[0080] In another embodiment, the present invention provides a process for making a compound of the present invention.

[0081] In another embodiment, the present invention provides an intermediate for making a compound of the present invention.

[0082] In another embodiment, the present invention provides a compound of the present invention, for use in therapy, alone, or optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[0083] In another embodiment, the present invention provides a compound of the present invention for use in therapy, for the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX, alone, or optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[0084] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[0085] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX, comprising administering to a patient in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention and the second therapeutic agent is one other type of therapeutic agent.

[0086] In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX, alone, or optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[0087] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

[0088] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO and/or EPX.

[0089] Examples of diseases or disorders associated with the activity of MPO and/or EPX that may be prevented, modulated, or treated according to the present invention include, but are not limited to, atherosclerosis, coronary heart disease, coronary artery disease, coronary vascular disease, cerebrovascular disorders, peripheral vascular disease, dyslipidemias and the sequelae thereof, cardiovascular disorders, angina, ischemia, cardiac ischemia, heart failure, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia.

[0090] In one embodiment, examples of diseases or disorders include, but are not limited to, atherosclerosis, coronary artery disease, acute coronary syndrome, dyslipidemias and the sequelae thereof, heart failure, lung diseases including asthma, COPD and cystic fibrosis, and neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, transient ischemic attack and stroke. In one embodiment, examples of diseases or disorders include atherosclerosis, coronary heart disease, cerebrovascular disorders and dyslipidemias and the sequelae thereof. In one embodiment, examples of diseases or disorders include coronary artery disease and acute coronary syndrome. In one embodiment, examples of diseases or disorders include dyslipidemias and the sequelae thereof. In one embodiment, examples of diseases or disorders include heart failure. In one embodiment, examples of diseases or disorders include lung diseases including asthma, COPD and cystic fibrosis. In one embodiment, examples of diseases or disorders include neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, and stroke.

[0091] The compounds of the present invention may be employed in combination with additional therapeutic agent(s) selected from one or more, preferably one to three, of the following therapeutic agents: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, diuretics, mineralocorticoid receptor antagonists, calcium channel blockers, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents.

[0092] In another embodiment, additional therapeutic agent(s) used in combined pharmaceutical compositions or combined methods or combined uses, are selected from one or more, preferably one to three, of the following therapeutic agents in treating atherosclerosis: anti-hyperlipidemic agents, plasma high-density lipoprotein (HDL)-raising agents, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), acyl-coenzyme A: cholesterol acytransferase (ACAT) inhibitors, cholesterylester transfer protein (CETP) inhibitors, liver X receptor (LXR) agonists, anti-probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (e.g., cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B.sub.6, vitamin B.sub.12, anti-oxidant vitamins, .beta.-blockers, diuretics, mineralocorticoid receptor antagonists, calcium channel blockers, anti-diabetes agents, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, factor Xa inhibitors, anti-thrombotic agents, renin inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

[0093] In another embodiment, additional therapeutic agent(s) used in combined pharmaceutical compositions or combined methods or combined uses, are selected from one or more, preferably one to three, of the following therapeutic agents in treating cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

[0094] The present invention may be embodied in other specific forms without parting from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

III. Chemistry

[0095] Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C.dbd.C double bonds, C.dbd.N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

[0096] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C.sub.1 to C.sub.10 alkyl" or "C.sub.1-10 alkyl" (or alkylene), is intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10 alkyl groups. Additionally, for example, "C.sub.1 to C.sub.6 alkyl" or "C.sub.1-6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C.sub.0 alkyl" or "C.sub.0 alkylene" is used, it is intended to denote a direct bond.

[0097] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C.sub.2 to C.sub.6 alkenyl" or "C.sub.2-6 alkenyl" (or alkenylene), is intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

[0098] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain. For example, "C.sub.2 to C.sub.6 alkynyl" or "C.sub.2-6 alkynyl" (or alkynylene), is intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0099] The term "alkoxy" or "alkyloxy" refers to an --O-alkyl group. "C.sub.1 to C.sub.6 alkoxy" or "C.sub.1-6 alkoxy" (or alkyloxy), is intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S-- and ethyl-S--.

[0100] "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more fluorine atoms.

[0101] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C.sub.1 to C.sub.6 haloalkoxy" or "C.sub.1-6 haloalkoxy", is intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S--, and pentafluoroethyl-S--.

[0102] The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. "C.sub.3 to C.sub.7 cycloalkyl" or "C.sub.3-7 cycloalkyl" is intended to include C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".

[0103] As used herein, "carbocycle", "carbocyclyl", or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, [2.2.2]bicyclooctane, and tetrahydronaphthyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0104] As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0105] "Aryl" groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and described, for example, in Lewis, R. J., ed., Hawley's Condensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc., New York (2007). "C.sub.6 or C.sub.10 aryl" or "C.sub.6-10 aryl" refers to phenyl and naphthyl.

[0106] The term "benzyl", as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group.

[0107] As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N--O and S(O).sub.p, wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.

[0108] Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0109] Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

[0110] Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0111] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).

[0112] The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.

[0113] Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

[0114] As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N.fwdarw.O and S(O).sub.p, wherein p is 0, 1 or 2).

[0115] Examples of 5- to 6-membered heteroaryls include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0116] Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0117] The term "counter ion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), ammonium (R.sub.nNH.sub.m+ where n=0-4 and m=0-4) and the like.

[0118] When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.

[0119] As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Greene, T. W. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.

[0120] As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. When a substituent is keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N, or N.dbd.N).

[0121] In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N.fwdarw.O) derivative.

[0122] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.

[0123] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.

[0124] Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0125] As a person of ordinary skill in the art would be able to understand, a ketone (--CH--C.dbd.O) group in a molecule may tautomerize to its enol form (--C.dbd.C--OH). Thus, this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them.

[0126] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0127] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

[0128] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Allen, L. V., Jr., ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference.

[0129] In addition, compounds of the present invention may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of Formula (I) or Formula (II)) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

[0130] (a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);

[0131] b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991);

[0132] c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

[0133] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);

[0134] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

[0135] f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

[0136] Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield Formula (I) or Formula (II) compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of Formula (I) or Formula (II) include C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C.sub.1-6 alkanoyloxy-C.sub.1-6 alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C.sub.1 to C.sub.6 alkoxycarbonyloxy-C.sub.1 to C.sub.6 alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well-known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

[0137] Preparation of prodrugs is well known in the art and described in, for example, King, F. D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced, 2006); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice of Medicinal Chemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

[0138] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include .sup.13C and .sup.14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.

[0139] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain a N-halo, S(O).sub.2H, or S(O)H group.

[0140] The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0141] Abbreviations as used herein, are defined as follows: "1.times." for once, "2.times." for twice, "3.times." for thrice, ".degree. C." for degrees Celsius, "aq" for aqueous, "Col" for column, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, ".mu.L" for microliter or microliters, "N" for normal, "M" for molar, "nM" for nanomolar, "mol" for mole or moles, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, "aq" for "aqueous", "sat" or "sat'd" for saturated, "MW" for molecular weight, "mw" or ".mu.wave" for microwave, "mp" for melting point, "Wt" for weight, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, ".sup.1H" for proton, ".delta." for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and ".alpha.", ".beta.", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

TABLE-US-00001 Ac acetic AcOH acetic acid, ACN (or acetonitrile MeCN) APF aminophenyl fluorescein Aq. aqueous BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn benzyl Boc tert-butyl carbonyl Boc.sub.2O di-tert-butyl dicarbonate Bu butyl dba (Pd.sub.2(dba)3) dibenzylideneacetone DCM dichloromethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide DPPA DPPA: diphenyl phosphoryl azide dppf 1,1'-bis(diphenylphosphino)ferrocene (DtBPF)PdCl.sub.2 1.1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride EDC 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide ELSD evaporative light scattering detector EPX eosinophil peroxidase Et ethyl EtOH ethanol EtOAc ethyl acetate HATU 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU 2-(1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate i-Bu isobutyl IBCF isobutylchloroformate i-Pr isopropyl KHMDS LAH lithium aluminum hydride m-CPBA meta-chloroperbenzoic acid Me methyl MeOH methanol MPO myeloperoxidase NMM N-methylmorpholine NMO N-methyl morpholine N-oxide NMP N-methylpyrrolidone PCC pyridinium chlorochromate Ph phenyl Pr propyl Psia pounds per square inch absolute psia absolute pressure in pounds per square inch rt Room temperature t-Bu tert-butyl tetrakis tetrakis(triphenylphosphine) palladium T3P propylphosphonic anhydride TBDMS-Cl t-butyldimethylchlorosilane TBDMS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TCA trichloroacetic acid TEA triethylamine TES triethylsilyl TFA trifluoroacetic acid TFAA trifluoroacetic acid anhydride THF tetrahydrofuran TIPS triisopropylsilyl TIPS-Cl tri-isopropylsilyl chloride TMAD N,N,N',N'-tetramethylazodicarbonamide (1,1'azobis(N,N-dimethylformamide)) TMS trimethylsilyl TPAP tetrapropylammonium perruthenate Tr trityl (triphenylmethyl) Ts tosyl Xphos 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl

Synthesis

[0142] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

[0143] A particularly useful compendium of synthetic methods which may be applicable to the preparation of compounds of the present invention may be found in Larock, R. C., Comprehensive Organic Transformations, VCH, New York (1989). Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

[0144] It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 3rd Edition, Wiley-Interscience (1999)).

[0145] Compounds having the general Formula (I):


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