Diazabicyclooctane derivatives useful as matrix metalloproteinase inhibitors

Abstract

Provided herein are compounds that are MMP inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of a disease, disorder or condition selected from cardiovascular disorders, pulmonary disorders, renal disorders, hepatic disorders, and pigmented scleroderma. [Case 1] TIFF2024537545000193.tif52159

Description

[Background technology]

[0001] Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide (The Global Burden of Disease: 2004 Update. In: World Health Organization; 2004). Despite improvements through treatment of risk factors (Circulation. 2017; 135(10): e146.), nearly half of the US population is expected to suffer from CVD by 2030.

[0002] Cardiac injury, valvular heart disease such as aortic stenosis, vascular hypertension, and aging are major factors that lead to pressure overload of the cardiac pump function. Left ventricular hypertrophy is the heart's normal response to such pressure overload. Hypertrophy allows cardiomyocytes to generate the additional force required to compensate for the increased pressure load and maintain essential pumping function. At least 10% of the population in industrialized societies suffer from severe hypertension, which can lead not only to left ventricular hypertrophy and secondary heart failure, but also to myocardial infarction and fatal arrhythmias (1). Aging is another common cause of pump pressure overload, resulting in left ventricular diastolic dysfunction and concentric remodeling, although systolic function is often unaffected until late-life aging (2). However, initially appropriate compensatory left ventricular remodeling can progress to a pathophysiological stage, where degeneration of ischemic and other damaged cardiomyocytes initiates and progresses fibrosis, causing ventricle dilation and a gradual decline in cardiac pump function (3-9).

[0003] The maladaptive remodeling process leading to heart failure can be conceptually categorized as hypertrophic changes in cardiomyocytes and alterations in the normal patterning of the extracellular matrix (ECM) network. Alterations in both systolic and diastolic function can be attributed to these two categories (10). The cardiac ECM provides structural support for the myocardium and produces cytokines, growth factors, and regulatory proteins that modify myocardial function (11). The emergence of adverse ECM remodeling represents a critical pathogenetic milestone in the progression to overt heart failure. Normal basement membrane fibronectin, laminin, and collagen connect cardiomyocytes to the interstitial ECM and facilitate transmembrane signaling via integrin receptors (12), and collagen fibers structurally organize myocytes and myofibers to enable optimal force generation and transmission. However, loss of collagen fibrils and struts can lead to misaligned cardiomyocyte contractions, ventricular dilatation, and worsening systolic dysfunction (13). Additionally, as the disease progresses due to the worsening of the above-mentioned factors, fibrous collagen accumulates in the left ventricular myocardium, increasing myocardial stiffness (2, 14, 15).

[0004] The cardiac extracellular matrix, like skeletal bone and other structural elements of the body, undergoes continuous processes of synthesis, degradation, and resynthesis to maintain proper structure and strength. Healthy proteolysis is necessary for healthy remodeling of this cardiac ECM, but proteolysis is also involved in adverse remodeling as part of disease processes, including progressive heart failure. Notably, increased activation and expression of zinc-dependent proteases, matrix metalloproteinases (MMPs), have been associated with heart failure and thus implicated in the remodeling process of progressive pump failure (16-18). The mammalian MMP superfamily contains 25 members, including stromelysins, gelatinases, collagenases, matrilysins, membrane-type MMPs, and other MMPs (19). Their diverse functions are endogenously regulated by tissue inhibitors of metalloproteinases (TIMPs: TIMPs 1-4), which generally bind noncovalently to both activated and pro-forms of MMPs, forming 1:1 complexes with low selectivity. Each myocardial ECM protein serves as a substrate for at least one cardiac MMP ( 20 ), which also inactivates and activates ECM-derived cytokines and growth factors ( 21 , 22 ).

[0005] The involvement of MMPs in myocardial pathological remodeling, which leads to and worsens heart failure, has been characterized in both animal disease models and human plasma and left ventricle (8, 16-18, 23-46). While the majority of MMP substrates are accessible from the extracellular space, more recently, intracellular roles for MMPs in regulating calcium handling, which is critical for excitation-contraction coupling, and direct effects on sarcomere function have been reported (47-53). In humans, elevated levels of MMP2 and MMP9 have been strongly associated with diastolic dysfunction or heart failure in multiple studies (54-61).

[0006] Evidence is emerging, both through genetic and pharmacological intervention, that MMPs not only contribute to but also cause pathological left ventricular and global cardiac remodeling, leading to reduced pump function and disease. Nonselective pharmacological inhibition of MMPs has been demonstrated to significantly reduce pathological remodeling associated with various disease triggers in animal models (28, 40, 62-69). Data suggesting that selective MMP inhibition, particularly preservation of MMP1 activity, benefits cardiac remodeling have been generated for MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-3 (70-74). The strongest evidence has generated the therapeutic hypothesis that selective inhibition of at least MMP-2 and MMP-9 may facilitate the reduction of adverse cardiac function following various interventions that cause cardiac pump failure (59, 75, 76).

[0007] MMP9 mice are protected from diastolic dysfunction and fibrosis (77) and post-infarction remodeling (59)(75). It has been demonstrated that MMP2 expression, like MMP9 expression, is elevated during pressure-overload hypertrophy in both spontaneously hypertensive rats (66) and Dahl salt-sensitive hypertensive rats (43). Most compellingly, while both MMP2- and MMP9-overexpressing transgenic mice develop pathological myocardial fibrosis (78, 79), mice lacking the genes for MMP2 and MMP9 are structurally and functionally protected in disease models of heart failure, a finding that has been successfully recapitulated with prototypic pharmacological inhibitors that block MMP2 and / or MMP9 action (80, 81).

[0008] TACE / ADAM17 (Tumor necrosis factor-α-converting enzyme; A Disintegrin And Metalloproteinase 17) is a soluble or membrane-bound metalloproteinase primarily involved in the activation of pro-TNF-α and also targets proteins such as fractalkine, amyloid precursor protein, and CD40. ADAM17 / TACE is involved in cancer, vascular disorders, and inflammatory diseases such as rheumatoid arthritis and focal ischemic injury. The catalytic domain of ADAM17 / TACE can cleave pro-TNF-α and has been used in inhibitor screening. [References] 1. Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J. 2001;141(3):334-41. Epub 2001 / 03 / 07. doi: 10.1067 / mhj.2001.113218. PubMed PMID: 11231428. 2. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholder in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107(2):346-54. Epub 2003 / 01 / 23. doi: 10.1161 / 01.cir.0000048893.62841.f7. PubMed PMID: 12538439. 3. Weber KT. Fibrosis and hypertensive heart disease. Current opinion in cardiology. 2000;15(4):264-72. 4. Diez J, Lopez B, Gonzalez A, Querejeta R. Clinical aspects of hypertensive myocardial fibrosis. Current opinion in cardiology. 2001;16(6):328-35. 5. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 2011;124(3):304-13. Epub 2011 / 06 / 29. doi: 10.1161 / circulationaha.111.022889. PubMed PMID: 21709064;PMCID: PMC5843948. 6. Jugdutt BI. Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Current Drug Targets-Cardiovascular & Hematological Disorders. 2003;3(1):1-30. 7. Katz AM. Pathophysiology of heart failure: identifying targets for pharmacotherapy. Medical Clinics. 2003;87(2):303-16. 8. Janicki JS, Brower GL, Gardner JD, Chancey AL, Stewart JA. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. Heart failure reviews. 2004;9(1):33-42. 9. Jessup M, Brozena S. Heart failure. The New England journal of medicine. 2003;348(20):2007-18. Epub 2003 / 05 / 16. doi: 10.1056 / NEJMra021498. PubMed PMID: 12748317. 10. Redfield MM, Jacobsen SJ, Burnett JC, Jr., Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. Jama. 2003;289(2):194-202. Epub 2003 / 01 / 09. doi: 10.1001 / jama.289.2.194. PubMed PMID: 12517230. 11. Jacob MP. Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomedicine & pharmacotherapy. 2003;57(5-6):195-202. 12. Ross RS. The extracellular connections: the role of integrins in myocardial remodeling. Journal of cardiac failure. 2002;8(6):S326-S31. 13. Janicki JS, Brower GL. The role of myocardial fibrillar collagen in ventricular remodeling and function. Journal of cardiac failure. 2002;8(6):S319-S25. 14. Ferrari AU, Radaelli A, Centola M. Invited review: aging and the cardiovascular system. Journal of applied physiology (Bethesda, Md : 1985). 2003;95(6):2591-7. Epub 2003 / 11 / 06. doi: 10.1152 / japplphysiol.00601.2003. PubMed PMID: 14600164. 15. Martos R, Baugh J, Ledwidge M, O’Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007;115(7):888-95. Epub 2007 / 02 / 07. doi: 10.1161 / circulationaha.106.638569. PubMed PMID: 17283265. 16. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circulation research. 2002;90(5):520-30. 17. DeLeon-Pennell KY, Meschiari CA, Jung M, Lindsey ML. Matrix metalloproteinases in myocardial infarction and heart failure. Progress in molecular biology and translational science. 2017;147:75-100. 18. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiological reviews. 2007;87(4):1285-342. 19. Iyer RP, Patterson NL, Fields GB, Lindsey ML. The history of matrix metalloproteinases: milestones, myths, and misperceptions. American Journal of Physiology-Heart and Circulatory Physiology. 2012;303(8):H919-H30. 20. Brauer PR. MMPs--role in cardiovascular development and disease. Frontiers in bioscience: a journal and virtual library. 2006;11:447-78. 21. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annual review of cell and developmental biology. 2001;17:463-516. Epub 2001 / 11 / 01. doi: 10.1146 / annurev.cellbio.17.1.463. PubMed PMID: 11687497;PMCID: PMC2792593. 22. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Critical reviews in biochemistry and molecular biology. 2002;37(6):375-536. 23. Dixon JA, Spinale FG. Myocardial remodeling: cellular and extracellular events and targets. Annual review of physiology. 2011;73:47-68. 24. Spinale FG, Villarreal F. Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochemical pharmacology. 2014;90(1):7-15. 25. Spinale FG, Zile MR. Integrating the myocardial matrix into heart failure recognition and management. Circulation research. 2013;113(6):725-38. 26. Cleutjens JP, Creemers EE. Integration of concepts: cardiac extracellular matrix remodeling after myocardial infarction. Journal of cardiac failure. 2002;8(6):S344-S8. 27. Iwanaga Y, Aoyama T, Kihara Y, Onozawa Y, Yoneda T, Sasayama S. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. Journal of the American College of Cardiology. 2002;39(8):1384-91. 28. Li YY, McTiernan CF, Feldman AM. Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovascular research. 2000;46(2):214-24. 29. Nagatomo Y, Carabello BA, Coker ML, McDermott PJ, Nemoto S, Hamawaki M, Spinale FG. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. American Journal of Physiology-Heart and Circulatory Physiology. 2000;278(1):H151-H61. 30. Peterson JT, Li H, Dillon L, Bryant JW. Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovascular research. 2000;46(2):307-15. 31. Reinhardt D, Sigusch H, Henβe J, Tyagi S, Koerfer R, Figulla H. Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart. 2002;88(5):525-30. 32. Shastry S, Hayden MR, Lucchesi PA, Tyagi SC. Matrix metalloproteinase in left ventricular remodeling and heart failure. Current cardiology reports. 2003;5(3):200-4. 33. Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, Goldberg AT, Zellner JL, Crumbley AJ. A matrix metalloproteinase induction / activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation. 2000;102(16):1944-9. 34. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circulation research. 1998;82(4):482-95. 35. Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley III AJ, Spinale FG. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation. 1998;97(17):1708-15. 36. Chapman RE, Spinale FG. Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications. American Journal of Physiology-Heart and Circulatory Physiology. 2004;286(1):H1-H10. 37. Fedak PW, Altamentova SM, Weisel RD, Nili N, Ohno N, Verma S, Lee T-YJ, Kiani C, Mickle DA, Strauss BH. Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3. American Journal of Physiology-Heart and Circulatory Physiology. 2003;284(2):H626-H34. 38. Lindsey ML. MMP induction and inhibition in myocardial infarction. Heart failure reviews. 2004;9(1):7-19. 39. Lindsey ML, Mann DL, Entman ML, Spinale FG. Extracellular matrix remodeling following myocardial injury. Annals of medicine. 2003;35(5):316-26. 40. Miura S, Ohno I, Suzuki J, Suzuki K, Okada S, Okuyama A, Nawata J, Ikeda J, Shirato K. Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by β-adrenergic stimulation in rats. Journal of cardiovascular pharmacology. 2003;42(2):174-81. 41. Nishikawa N, Yamamoto K, Sakata Y, Mano T, Yoshida J, Miwa T, Takeda H, Hori M, Masuyama T. Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation. Cardiovascular research. 2003;57(3):766-74. 42. Pauschinger M, Chandrasekharan K, Schultheiss H-P. Myocardial remodeling in viral heart disease: possible interactions between inflammatory mediators and MMP-TIMP system. Heart failure reviews. 2004;9(1):21-31. 43. Sakata Y, Yamamoto K, Mano T, Nishikawa N, Yoshida J, Hori M, Miwa T, Masuyama T. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: its inhibition as a primary effect of angiotensin-converting enzyme inhibitor. Circulation. 2004;109(17):2143-9. 44. Sierevogel M, Pasterkamp G, De Kleijn D, Strauss B. Matrix metalloproteinases: a therapeutic target in cardiovascular disease. Current pharmaceutical design. 2003;9(13):1033-40. 45. Tao Z-Y, Cavasin MA, Yang F, Liu Y-H, Yang X-P. Temporal changes in matrix metalloproteinase expression and inflammatory response associated with cardiac rupture after myocardial infarction in mice. Life sciences. 2004;74(12):1561-72. 46. Wilson EM, Moainie SL, Baskin JM, Lowry AS, Deschamps AM, Mukherjee R, Guy TS, St John-Sutton MG, Gorman III JH, Edmunds Jr LH. Region-and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling. Circulation. 2003;107(22):2857-63. 47. Ali MA, Cho WJ, Hudson B, Kassiri Z, Granzier H, Schulz R. Titin is a target of matrix metalloproteinase-2: implications in myocardial ischemia / reperfusion injury. Circulation. 2010;122(20):2039-47. Epub 2010 / 11 / 03. doi: 10.1161 / circulationaha.109.930222. PubMed PMID: 21041693;PMCID: PMC3057897. 48. Ali MA, Fan X, Schulz R. Cardiac sarcomeric proteins: novel intracellular targets of matrix metalloproteinase-2 in heart disease. Trends in cardiovascular medicine. 2011;21(4):112-8. Epub 2012 / 06 / 12. doi: 10.1016 / j.tcm.2012.03.008. PubMed PMID: 22681966. 49. Fan X, Hughes BG, Ali MA, Chan BY, Launier K, Schulz R. Matrix metalloproteinase-2 in oncostatin M-induced sarcomere degeneration in cardiomyocytes. American journal of physiology Heart and circulatory physiology. 2016;311(1):H183-9. Epub 2016 / 05 / 21. doi: 10.1152 / ajpheart.00229.2016. PubMed PMID: 27199120. 50. Lovett DH, Chu C, Wang G, Ratcliffe MB, Baker AJ. A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium. Front Physiol. 2014;5:363. Epub 2014 / 10 / 14. doi: 10.3389 / fphys.2014.00363. PubMed PMID: 25309453;PMCID: PMC4174733. 51. Rouet-Benzineb P, Buhler JM, Dreyfus P, Delcourt A, Dorent R, Perennec J, Crozatier B, Harf A, Lafuma C. Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation. European journal of heart failure. 1999;1(4):337-52. Epub 2000 / 08 / 11. doi: 10.1016 / s1388-9842(99)00048-3. PubMed PMID: 10937947. 52. Sawicki G, Leon H, Sawicka J, Sariahmetoglu M, Schulze CJ, Scott PG, Szczesna-Cordary D, Schulz R. Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2. Circulation. 2005;112(4):544-52. Epub 2005 / 07 / 20. doi: 10.1161 / circulationaha.104.531616. PubMed PMID: 16027249. 53. Wang GY, Bergman MR, Nguyen AP, Turcato S, Swigart PM, Rodrigo MC, Simpson PC, Karliner JS, Lovett DH, Baker AJ. Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility. Cardiovasc Res. 2006;69(3):688-96. Epub 2005 / 09 / 27. doi: 10.1016 / j.cardiores.2005.08.023. PubMed PMID: 16183043. 54. Chancey AL, Brower GL, Peterson JT, Janicki JS. Effects of matrix metalloproteinase inhibition on ventricular remodeling due to volume overload. Circulation. 2002;105(16):1983-8. 55. Cox MJ, Hawkins UA, Hoit BD, Tyagi SC. Attenuation of oxidative stress and remodeling by cardiac inhibitor of metalloproteinase protein transfer. Circulation. 2004;109(17):2123-8. 56. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England journal of medicine. 2014;371(11):993-1004. Epub 2014 / 09 / 02. doi: 10.1056 / NEJMoa1409077. PubMed PMID: 25176015. 57. Mukherjee R, Brinsa TA, Dowdy KB, Scott AA, Baskin JM, Deschamps AM, Lowry AS, Escobar GP, Lucas DG, Yarbrough WM. Myocardial infarct expansion and matrix metalloproteinase inhibition. Circulation. 2003;107(4):618-25. 58. Peterson JT, Hallak H, Johnson L, Li H, O’Brien PM, Sliskovic DR, Bocan TM, Coker ML, Etoh T, Spinale FG. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation. 2001;103(18):2303-9. 59. Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH, Lopez-Anaya A, McClure KF, Mitchell PG, Libby P, Lee RT. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation. 1999;99(23):3063-70. 60. Spinale FG, Coker ML, Bond BR, Zellner JL. Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovascular research. 2000;46(2):225-38. 61. Spinale FG, Coker ML, Krombach SR, Mukherjee R, Hallak H, Houck WV, Clair MJ, Kribbs SB, Johnson LL, Peterson JT. Matrix metalloproteinase inhibition during the development of congestive heart failure: effects on left ventricular dimensions and function. Circulation research. 1999;85(4):364-76. 62. King MK, Coker ML, Goldberg A, McElmurray III JH, Gunasinghe HR, Mukherjee R, Zile MR, O’Neill TP, Spinale FG. Selective matrix metalloproteinase inhibition with developing heart failure: effects on left ventricular function and structure. Circulation research. 2003;92(2):177-85. 63. Lindsey ML, Gannon J, Aikawa M, Schoen FJ, Rabkin E, Lopresti-Morrow L, Crawford J, Black S, Libby P, Mitchell PG. Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation. 2002;105(6):753-8. 64. Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J. Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation. 2003;108(12):1487-92. 65. Yarbrough WM, Mukherjee R, Escobar GP, Mingoia JT, Sample JA, Hendrick JW, Dowdy KB, McLean JE, Lowry AS, O’Neill TP. Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling. Circulation. 2003;108(14):1753-9. 66. Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D’Armiento J. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. The Journal of clinical investigation. 2000;106(7):857-66. 67. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. The Journal of clinical investigation. 2000;106(1):55-62. 68. Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka-Yoshida K, Itoh T, Takeshita A. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. American Journal of Physiology-Heart and Circulatory Physiology. 2003;285(3):H1229-H35. 69. Heymans S, Lupu F, Terclavers S, Vanwetswinkel B, Herbert J-M, Baker A, Collen D, Carmeliet P, Moons L. Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. The American journal of pathology. 2005;166(1):15-25. 70. Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin Y-F, Lindsey ML. Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovascular research. 2012;96(3):444-55. 71. Toba H, Cannon PL, Yabluchanskiy A, Iyer RP, D’Armiento J, Lindsey ML. Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis. American journal of physiology Heart and circulatory physiology. 2017;312(3):H375-h83. Epub 2016 / 12 / 25. doi: 10.1152 / ajpheart.00633.2016. PubMed PMID: 28011588;PMCID: PMC5402013. 72. Bergman MR, Teerlink JR, Mahimkar R, Li L, Zhu BQ, Nguyen A, Dahi S, Karliner JS, Lovett DH. Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction. American journal of physiology Heart and circulatory physiology. 2007;292(4):H1847-60. Epub 2006 / 12 / 13. doi: 10.1152 / ajpheart.00434.2006. PubMed PMID: 17158653. 73. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H. Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension (Dallas, Tex : 1979). 2006;47(4):711-7. Epub 2006 / 03 / 01. doi: 10.1161 / 01.hyp.0000208840.30778.00. PubMed PMID: 16505197. 74. Heymans S, Lupu F, Terclavers S, Vanwetswinkel B, Herbert JM, Baker A, Collen D, Carmeliet P, Moons L. Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Am J Pathol. 2005;166(1):15-25. Epub 2005 / 01 / 06. doi: 10.1016 / s0002-9440(10)62228-6. PubMed PMID: 15631996;PMCID: PMC1602291. 75. Hayashidani, S., et al. (2003). “Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction.” American Journal of Physiology-Heart and Circulatory Physiology 285(3): H1229-H1235. 76 Heymans, S., et al. (2005). “Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice.” The American journal of pathology 166(1): 15-25. 77. Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin YF, Lindsey ML. Cardiovasc Res. 2012 Dec 1;96(3):444-55. doi: 10.1093 / cvr / cvs275. Epub 2012 Aug 22. 78. Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis. Toba H, Cannon PL, Yabluchanskiy A, Iyer RP, D’Armiento J, Lindsey ML. Am J Physiol Heart Circ Physiol. 2017 Mar 1;312(3):H375-H383. doi: 10.1152 / ajpheart.00633.2016. 79. Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction. Bergman MR, Teerlink JR, Mahimkar R, Li L, Zhu BQ, Nguyen A, Dahi S, Karliner JS, Lovett DH. Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1847-60. doi: 10.1152 / ajpheart.00434.2006 80. Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H. Hypertension. 2006 Apr;47(4):711-7. doi: 10.1161 / 01.HYP.0000208840.30778.00. Epub 2006 Feb 27. PMID: 16505197 81. Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Heymans S, Lupu F, Terclavers S, Vanwetswinkel B, Herbert JM, Baker A, Collen D, Carmeliet P, Moons L. Am J Pathol. 2005 Jan;166(1):15-25. doi: 10.1016 / S0002-9440(10)62228-6.

[0009] There is a strong need to develop therapeutic treatment options specifically aimed at reversing the underlying cause of heart failure (HF), which is an abnormality in the heart's pumping function. However, the current standard of care for HF and other CVDs does not correct the underlying defect that causes loss of pumping function, which is the loss of functional heart muscle cells, or cardiomyocytes. Rather, existing pharmacologic therapies target non-cardiac peripheral features of the cardiovascular system, including reducing preload and afterload by targeting blood pressure, reducing blood volume (aldosterone antagonists, diuretics), or lowering lipids that contribute to vascular disease.

[0010] Selective inhibition of matrix metalloproteinases provides a valuable therapeutic treatment option for treating a variety of disorders associated with abnormal activity of matrix metalloproteinases, including, but not limited to, cardiovascular disorders, pulmonary disorders, renal disorders, hepatic disorders, and pigmented scleroderma.

[0011] Cardiovascular disorders of interest include, among others, cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, abnormal myocardial contractility, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19 associated myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological remodeling of the myocardium, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, and right ventricular hypertrophy.

[0012] Lung disorders of concern include idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), and emphysema.

[0013] Relevant renal disorders include polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, and chronic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schoenlein purpura, and post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, tubular injury after sepsis, acute ischemic renal injury, contrast-induced renal injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, and tubulointerstitial fibrosis.

[0014] Liver disorders of interest include alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia and reperfusion injury, viral hepatitis, drug-induced liver injury, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, acute liver failure, and biliary atresia. Summary of the Invention

[0015] The present disclosure provides, for example, compounds and compositions that are MMP inhibitors, as well as their use as medicinal agents, processes for their preparation, and pharmaceutical compositions comprising the disclosed compounds as at least one active ingredient. The present disclosure also provides the use of the disclosed compounds as and / or in the manufacture of medicaments for MMP inhibition in warm-blooded animals, such as humans, for the treatment of heart failure and other CVD.

[0016] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] wherein [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; X is -C(=O)- or -S(=O)2-; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)NH-, or -N(R 5 )- and where nitrogen is for bonding to Y [ka] When the above point of attachment is Y cannot be -O-; If Y is asymmetric, [ka] are written in the order corresponding to R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 )2, R 2 is -C(=O)NH(OH), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , —CH(NH)C(═O)OH, —C-C heteroaryl, —C(═O)—C-C heteroaryl, or —C(═O)NH—C-C heteroaryl; Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from R 5 is hydrogen or -C1-C6 alkyl, Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3.

[0017] In some embodiments, the present invention provides [ka] is phenyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] is phenyl. In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where Y is -O-. In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where X is -S(=O)2-. In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where X is -C(=O)-.

[0018] In some embodiments, the present invention provides a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , R 4 , n, p, and q are as defined in formula (I).

[0019] In some embodiments, the present invention provides a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , R 4 , n, p, and q are as defined in formula (I).

[0020] In some embodiments, the present invention provides a compound of formula (Ic): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] is a C2-C9 heterocycloalkyl ring, Y is a direct bond, —O—, or —CH—; R 1 , R 2 , R 3 , R 4 , n, p, and q are as defined in formula (I).

[0021] In some embodiments, the present invention provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] R 1 , R 3 , R 4 , p, q, X and Y are as defined in formula (I).

[0022] In some embodiments, the present invention provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] R 1 , R 3 , R 4, p, q, and Y are as defined in formula (I).

[0023] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently selected from: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments, the present invention provides compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently selected from: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —C(═O)NH(OH). 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In some embodiments, the present invention provides a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0024] In some embodiments, the present invention provides the following compound: [Table 1] TIFF2024537545000019.tif239159TIFF2024537545000020.tif239159TIFF2024537545000021.tif241159TIFF2024537545000022.tif223159, or a pharmaceutically acceptable salt or solvate thereof.

[0025] In another aspect, disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or binder and a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0026] In another aspect, disclosed herein is a method of treating a mammal in need thereof, comprising: Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, myocardial contractility abnormalities, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-associated myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, Polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, and chronic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schoenlein purpura, and postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced kidney injury, tubular injury after sepsis, acute ischemic kidney injury, contrast-induced kidney injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, tubulointerstitial fibrosis, Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia and reperfusion injury, viral hepatitis, drug-induced liver injury, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, acute liver failure, biliary atresia, and pigmented scleroderma A method of treating a disease, disorder, or condition selected from the group consisting of:

[0027] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0028] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, and a reference to "the cell" includes a reference to one or more cells (or cells) and their equivalents. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a numerical value or numerical range, means that the referenced numerical value or numerical range is approximate within experimental variability (or within statistical experimental error), and therefore, the numerical value or numerical range may vary by 1% to 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") does not exclude the possibility that in other particular embodiments, an embodiment, such as, for example, any material, composition, method, or process described herein, "consists of" or "consists essentially of" the described features.

[0029] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the following meanings.

[0030] Terms used herein may be preceded and / or followed by a single dash "-" or a double dash "=" to indicate the attachment order of bonds between a designated substituent and its parent moiety. A single dash indicates a single bond, and a double dash indicates a double bond. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety. Furthermore, unless otherwise indicated by a dash, substituents are intended to be read "left to right." For example, (C1-C6)-alkoxycarbonyloxy and -OC(O)O(C1-C6)alkyl represent the same functional group. Similarly, arylalkyl and -alkylaryl represent the same functional group.

[0031] In the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside cover of Handbook of Chemistry and Physics, 67th ed., 1986-87.

[0032] As used herein, C1-C x is C1-C2, C1-C3…C1-C x Includes C1-C x refers to the number of carbon atoms that make up the moiety it designates (excluding optional substituents).

[0033] The terms "hydrogen," "hydrogen atom," and the symbol "H," when used in the context of substituents on structural formulae such as Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), refer to a hydrogen atom attached to the remainder of the molecule or group in question. For simplicity, hydrogen atoms attached to carbon atoms are not shown in structural formulae. Each carbon atom is understood to be attached to enough hydrogen atoms to provide four bonds to the carbon atom.

[0034] A "saturated" or "fully saturated" compound means that the referenced chemical structure contains no carbon-carbon multiple bonds. For example, saturated cycloalkyl groups, as defined herein, include cyclohexyl, cyclopropyl, and the like.

[0035] "Unsaturated" or "partially saturated" compounds mean that the referenced chemical structure may contain one or more carbon-carbon multiple bonds, but is not aromatic. For example, unsaturated cycloalkyl groups as defined herein include cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

[0036] "Amino" refers to the -NH2 radical.

[0037] "Cyano" refers to the -CN radical.

[0038] "Nitro" refers to the -NO2 radical.

[0039] "Oxa" refers to the -O- radical.

[0040] "Oxo" refers to the =O radical.

[0041] "Thioxo" refers to the =S radical.

[0042] "Imino" refers to the =NH radical.

[0043] "Oximo" refers to the =N-OH radical.

[0044] It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution, subject to the substituted atom and the allowed valence of the substituent, results in a stable compound that does not spontaneously undergo transformation, such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0045] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, (cycloalkyl)alkoxyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, aminosulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, heterocyclylalkyl, aromatic or heteroaromatic moiety, aminoalkyl, haloalkyl, fluoroalkyl (such as trifluoromethyl), haloalkoxyl, cyano, or other substituents described above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. As used herein, heteroatoms such as nitrogen may have hydrogen substituents and / or permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0046] "Alkyl" or "alkylene" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., -C1-C 15 In certain embodiments, alkyl includes 1 to 13 carbon atoms (e.g., -C1-C 13alkyl). In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., —C1-C8 alkyl). In other embodiments, alkyl contains 1 to 6 carbon atoms (e.g., —C1-C6 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., —C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., —C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., —C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., —C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., —C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., —C5-C6 alkyl). 15 In other embodiments, alkyl contains 5 to 8 carbon atoms (e.g., —C5-C8 alkyl). In other embodiments, alkyl contains 2 to 5 carbon atoms (e.g., —C2-C5 alkyl). In other embodiments, alkyl contains 3 to 5 carbon atoms (e.g., —C3-C5 alkyl). In other embodiments, alkyl groups are selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the rest of the molecule by a single bond. An alkylene is a diradical, attached to two portions of the molecule by two single bonds, as in methylene (—CH2—) or ethylene (—CH2CH2— or —CH(—CH3)—). Unless stated otherwise specifically in the specification, alkyl groups may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a)2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (wherein t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0047] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0048] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond, and examples include ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-R f , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (wherein t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0049] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkynyl contains from 2 to 8 carbon atoms. In other embodiments, alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond, and examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, alkynyl groups may also contain the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O-R ... a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (wherein t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0050] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 6 to 18 carbon atoms, and at least one of the rings within the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise stated specifically in this specification, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") refers to any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b-S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain.

[0051] "Aryloxy" refers to a radical attached through an oxygen atom of the formula --O-aryl, where aryl is as defined above.

[0052] "Aralkyl" is a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0053] "Aralkyloxy" refers to a radical attached through an oxygen atom of the formula -O-aralkyl, where aralkyl is defined above.

[0054] "Aralkenyl" refers to a group of the formula -R d -aryl radical, where R dis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0055] "Aralkynyl" refers to a group of the formula -R e -aryl radical, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0056] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems having from 3 to 15 carbon atoms. In certain embodiments, cycloalkyls contain from 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain from 5 to 7 carbon atoms. A cycloalkyl is attached to the remainder of the molecule by a single bond. A cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl contains from 3 to 8 carbon atoms (e.g., -C3-C8 cycloalkyl). In other embodiments, a cycloalkyl contains from 3 to 7 carbon atoms (e.g., -C3-C7 cycloalkyl). In other embodiments, a cycloalkyl contains from 3 to 6 carbon atoms (e.g., -C3-C6 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 5 carbon atoms (e.g., —C3-C5 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 4 carbon atoms (e.g., —C3-C4 cycloalkyl). Partially unsaturated cycloalkyls are also referred to as “cycloalkenyls.” Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in this specification, the term “cycloalkyl” includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b -OR a , -R b -OC(O)-R a , -Rb -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain.

[0057] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0058] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.

[0059] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0060] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above.

[0061] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. "C2-C9 heterocycloalkyl" refers to a heterocycloalkyl radical as defined above containing 2 to 9 carbon atoms and 1 to 4 heteroatoms. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused, spiro, or bridged ring systems. Heteroatoms in a heterocycloalkyl radical are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. A heterocycloalkyl radical is partially saturated or fully saturated. In some embodiments, a heterocycloalkyl is attached to the remainder of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in this specification, the term “heterocycloalkyl” includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a)2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain.

[0062] "Heteroaryl" refers to a radical derived from a 5-18-membered aromatic ring radical containing 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring within the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring(s). Unless stated otherwise specifically in this specification, the term “heteroaryl” includes alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a(where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain.

[0063] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen and wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0064] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The -C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0065] "Heteroaryloxy" refers to a radical attached through an oxygen atom of the formula --O-heteroaryl, where heteroaryl is defined above.

[0066] "Heteroarylalkyl" refers to a group of the formula -Rc - refers to a heteroaryl radical, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0067] "Heteroarylalkoxy" refers to a group of the formula -OR c - refers to a radical attached through an oxygen atom of a heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0068] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are contemplated by the present disclosure. When a compound described herein contains an alkene double bond, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans) unless otherwise specified. Similarly, all possible isomers, including their racemic and optically pure forms, and all tautomeric forms, are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers about a central ring, such as ortho, meta, and para isomers about a benzene ring.

[0069] "Tautomer" refers to a molecule in which a proton transfer from one atom of the molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following: [ka]

[0070] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that instances in which the event or circumstance occurs and instances in which it does not occur are included in the description. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that both substituted and unsubstituted aryl radicals are included in the description.

[0071] The term "prodrug" includes compounds that are metabolized after administration to become pharmacologically active drugs (R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chp. 8). Prodrugs can be used to improve how a compound is absorbed, distributed, metabolized, or excreted.

[0072] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0073] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0074] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from the addition of inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0075] "I C 50 " refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures that maximal response.

[0076] As used herein, "subject" refers to a warm-blooded animal, e.g., a mammal, preferably a human, or a human child, that is afflicted with or susceptible to one or more of the diseases and disorders described herein.

[0077] The term "mammal" refers to a human, non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy that reduces the severity of a condition in one species of mammal can predict the effectiveness of that therapy in another species of mammal.

[0078] An "effective amount" refers to an amount sufficient to achieve a desired biological effect. By selecting from among various active compounds and considering factors such as potency, relative bioavailability, the patient's weight, sex, age, medical history, severity of adverse side effects, and preferred mode of administration, combined with the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that is effective in treating a particular subject while causing little or no undesirable toxicity. The effective amount for a particular application may vary depending on factors such as the disease or condition being treated, the particular compound of the present invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the present invention and / or other therapeutic agent without necessitating undue experimentation. Generally, it is preferable to use a maximum dose, i.e., the highest safe dose according to any medical judgment. Multiple doses per day may be contemplated to achieve an appropriate systemic level of the compound. The appropriate systemic level may be determined, for example, by measuring peak or sustained plasma levels of the drug in the patient. "Dose" and "administration" are used interchangeably herein.

[0079] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved with the eradication or amelioration of one or more physiological symptoms of the underlying disorder, such that an improvement is observed in the patient even if the patient still suffers from the underlying disorder. For prophylactic benefit, the composition is administered to a patient at risk of developing a particular disease or who reports one or more physiological symptoms of the disease, even if the patient has not been diagnosed with the disease.

[0080] compound The compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) described herein are MMP inhibitors. In some embodiments, the compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) described herein, and compositions comprising these compounds, are useful for treating cardiovascular diseases, disorders or conditions, particularly heart failure.

[0081] In some embodiments, the present invention provides a compound of formula (I): [ka] A compound of the formula: [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; X is -C(=O)- or -S(=O)2-; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)NH-, or -N(R 5 )- and where nitrogen is for bonding to Y [ka] When the above point of attachment is Y cannot be -O-; If Y is asymmetric, [ka] are written in the order corresponding to R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 )2, R 2 is -C(=O)NH(OH), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , —CH(NH)C(═O)OH, —C-C heteroaryl, —C(═O)—C-C heteroaryl, or —C(═O)NH—C-C heteroaryl; Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from R 5 is hydrogen or -C1-C6 alkyl, Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0082] In some embodiments, the present invention provides [ka] is phenyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] C3-C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl ring, or a pharmaceutically acceptable salt or solvate thereof.

[0083] In some embodiments, the present invention provides [ka] is phenyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] C3-C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl ring, or a pharmaceutically acceptable salt or solvate thereof.

[0084] In some embodiments, the present invention provides [ka] is phenyl, [ka] is phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0085] In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein X is -C(=O)-. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein X is -S(=O)-.

[0086] In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where Y is -O-. In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where Y is -CHO-. In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where Y is -OCH-. In some embodiments, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where Y is -N(R 5 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 )- and R 5 is -C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 ) and R 5 is methyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) and R 5 is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

[0087] In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where p is 0. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where p is 1. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where p is 2.

[0088] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is methyl. In some embodiments, the present invention provides3 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is trifluoromethyl. In some embodiments, the present invention provides 3 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 and each R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0089] In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where q is 0. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where q is 1. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where q is 2.

[0090] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is methyl. In some embodiments, the present invention provides 4In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is trifluoromethyl. In some embodiments, the present invention provides 4 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 and each R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), wherein each R 4 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0091] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising:1 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)OR 6 and R 6 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)OR 6 and R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In another embodiment, R is methyl, ethyl, n-propyl, isobutyl, or t-butyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is methyl. In still further embodiments, R 6 is ethyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 and R 9 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR6 and R 6 -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(=O)N(R 6 )2, and each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(=O)N(R 6 )2, and each R 6 is hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0092] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some embodiments, the present invention provides a compound of formula (I), wherein R 2 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (I), wherein R 2 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (I), wherein R 2 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (I), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (I), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (I), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0093] In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where n is 1. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where n is 2. In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, where n is 0.

[0094] In some embodiments, the present invention provides a compound of formula (Ia): [ka] A compound of the formula: R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 )2, R2 is -C(=O)NH(OH), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , —CH(NH)C(═O)OH, —C-C heteroaryl, —C(═O)—C-C heteroaryl, or —C(═O)NH—C-C heteroaryl; Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, OR 6 , -N(R 6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0095] In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 0. In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1. In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 2.

[0096] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 In some embodiments, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is methyl. In some embodiments, the present invention provides 3 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is trifluoromethyl. In some embodiments, the present invention provides 3 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 and each R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein each R 3is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0097] In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where q is 0. In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where q is 1. In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where q is 2.

[0098] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4In some embodiments, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is methyl. In some embodiments, the present invention provides 4 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is trifluoromethyl. In some embodiments, the present invention provides 4 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 and each R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein each R 4 is -C(=O)N(R6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0099] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 and R 6 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 and R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In another embodiment, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In still further embodiments, R 6 is ethyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 and R 9 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is ethylene-OR 9In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0100] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —CH(NH)C(═O)OH. 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0101] In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, the present invention provides compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0102] In some embodiments, the present invention provides a compound of formula (Ib): [ka] A compound of formula (I) having the structure: R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 )2, R 2 is -C(=O)NH(OH), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , —CH(NH)C(═O)OH, —C-C heteroaryl, —C(═O)—C-C heteroaryl, or —C(═O)NH—C-C heteroaryl; Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, OR 6 , -N(R 6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R9 )2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0103] In some embodiments, the present invention provides compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where p is 0. In some embodiments, the present invention provides compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where p is 1. In some embodiments, the present invention provides compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where p is 2.

[0104] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is methyl. In some embodiments, the present invention provides 3 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is trifluoromethyl. In some embodiments, the present invention provides 3 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 and each R 6In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0105] In some embodiments, the present invention provides compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0106] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is methyl. In some embodiments, the present invention provides 4 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is trifluoromethyl. In some embodiments, the present invention provides 4 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 and each R 6In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein each R 4 is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0107] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 and R 6 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 and R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In another embodiment, the compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof is provided, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In still further embodiments, R 6 is ethyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6-C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 and R 9 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is hydrogen and -C1-C6 alkylene-OR 9In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0108] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some embodiments, the present invention provides a compound of formula (I), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0109] In some embodiments, the present invention provides compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, the present invention provides compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, the present invention provides compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0110] In some embodiments, the present invention provides a compound of formula (Ic): [ka] A compound of formula (I) having the structure: [ka] is a C2-C9 heterocycloalkyl ring, [ka] is selected from -S(=O)2-, Y, and optionally (R 4 ) q is bound to Y is a direct bond, —O—, or —CH—; where nitrogen is for bonding to Y [ka] When the above point of attachment is Y cannot be -O-; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6)2, R 2 is -C(=O)NH(OH), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , —CH(NH)C(═O)OH, —C-C heteroaryl, —C(═O)—C-C heteroaryl, or —C(═O)NH—C-C heteroaryl; Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, OR 6 , -N(R 6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0111] In some embodiments, the present invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is a direct bond. In some embodiments, the present invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments, the present invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2-.

[0112] In some embodiments, the present invention provides compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where p is 0. In some embodiments, the present invention provides compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where p is 1. In some embodiments, the present invention provides compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where p is 2.

[0113] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is methyl. In some embodiments, the present invention provides 3 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is trifluoromethyl. In some embodiments, the present invention provides 3 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 and each R 6In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0114] In some embodiments, the present invention provides compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where q is 0. In some embodiments, the present invention provides compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where q is 1. In some embodiments, the present invention provides compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where q is 2.

[0115] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is methyl. In some embodiments, the present invention provides 4 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is trifluoromethyl. In some embodiments, the present invention provides 4 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 and each R 6In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein each R 4 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0116] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 and R 6 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 and R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In another embodiment, the compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof is provided, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In still further embodiments, R 6 is ethyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6-C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 and R 9 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is hydrogen and -C1-C6 alkylene-OR 9In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0117] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] In some embodiments, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0118] In some embodiments, the present invention provides compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, the present invention provides compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, the present invention provides compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0119] In some embodiments, the present invention provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; X is -C(=O)- or -S(=O)2-; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)NH-, or -N(R 5 )- and where nitrogen is for bonding to Y [ka] When the above point of attachment is Y cannot be -O-; If Y is asymmetric, [ka] are written in the order corresponding to R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 )2, Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from R 5 is hydrogen or -C1-C6 alkyl, Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3.

[0120] In some embodiments, the present invention provides [ka] In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] C3-C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl ring, or a pharmaceutically acceptable salt or solvate thereof.

[0121] In some embodiments, the present invention provides [ka] In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] C3-C 10In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl ring, or a pharmaceutically acceptable salt or solvate thereof.

[0122] In some embodiments, the present invention provides [ka] is phenyl, [ka] is phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0123] In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein X is -C(=O)-. In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein X is -S(=O)-.

[0124] In some embodiments, the present invention provides compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, where Y is -O-. In some embodiments, the present invention provides compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, where Y is -CHO-. In some embodiments, the present invention provides compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, where Y is -OCH-. In some embodiments, the present invention provides compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, where Y is -N(R 5In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 )- and R 5 is -C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 ) and R 5 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) and R 5 is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

[0125] In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, where p is 0. In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, where p is 1. In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, where p is 2.

[0126] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is methyl. In some embodiments, the present invention provides 3 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is trifluoromethyl. In some embodiments, the present invention provides 3 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 and each R 6In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II), wherein each R 3 is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, where q is 0. In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, where q is 1. In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, where q is 2.

[0128] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is methyl. In some embodiments, the present invention provides 4 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is trifluoromethyl. In some embodiments, the present invention provides 4 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 and each R 6In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II), wherein each R 4 is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0129] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II), wherein R 1 -C(=O)OR 6 and R 6 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II), wherein R 1 -C(=O)OR 6 and R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In another embodiment, R is methyl, ethyl, n-propyl, isobutyl, or t-butyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is methyl. In still further embodiments, R 6 is ethyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6-C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (II), wherein R 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 and R 9 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(=O)N(R 6 )2, and each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(=O)N(R 6 )2, and each R 6 is hydrogen and -C1-C6 alkylene-OR 9In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (II), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0130] In some embodiments, the present invention provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; [ka] is phenyl, C3-C 10 a cycloalkyl ring, a C2-C9 heterocycloalkyl ring, or a C2-C9 heteroaryl ring; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)NH-, or -N(R 5 )- and where nitrogen is for bonding to Y [ka] When the above point of attachment is Y cannot be -O-; If Y is asymmetric, [ka] are written in the order corresponding to R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 )2, Each R 3 and each R 4 are each halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 7 , -NR 6 SO2R 7 , -SO2R 7 , and -SO2N(R 6 ) independently selected from R 5 is hydrogen or -C1-C6 alkyl, Each R 6 is hydrogen, -C1-C6 alkyl, -CF3, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9 )2, and —C1-C6 alkylene-C2-C9 heterocycloalkyl; Each R 7 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-N(R 9)2, independently selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 are independently selected from hydrogen and —C1-C6 alkyl; each occurrence of C2-C9 heterocycloalkyl and C2-C9 heteroaryl is optionally substituted with -C1-C6 alkyl or CF3; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3.

[0131] In some embodiments, the present invention provides [ka] In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] C3-C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl ring, or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments, the present invention provides [ka] In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein [ka] C3-C 10 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl ring, or a pharmaceutically acceptable salt or solvate thereof.

[0133] In some embodiments, the present invention provides [ka] is phenyl, [ka] is phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0134] In some embodiments, the present invention provides compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, where Y is -O-. In some embodiments, the present invention provides compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, where Y is -CHO-. In some embodiments, the present invention provides compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, where Y is -OCH-. In some embodiments, the present invention provides compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, where Y is -N(R 5 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 )- and R 5is -C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 ) and R 5 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) and R 5 is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

[0135] In some embodiments, the present invention provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, where p is 0. In some embodiments, the present invention provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, where p is 1. In some embodiments, the present invention provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, where p is 2.

[0136] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is methyl. In some embodiments, the present invention provides 3 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 3 is trifluoromethyl. In some embodiments, the present invention provides 3 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 and each R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3-C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III), wherein each R 3 is -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0137] In some embodiments, the present invention provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, where q is 0. In some embodiments, the present invention provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, where q is 1. In some embodiments, the present invention provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, where q is 2.

[0138] In some embodiments, the present invention provides a method for treating a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of at least one of: 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R 6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 , and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is methyl. In some embodiments, the present invention provides 4 In a further embodiment, R is -C1-C6 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof. 4 is trifluoromethyl. In some embodiments, the present invention provides 4 But, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2, and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -OR 6 In a further embodiment, R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 and each R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4-C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III), wherein each R 4 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0139] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 1 is -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 , -C1-C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 , or -S(=O)2N(R6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III), wherein R 1 -C(=O)OR 6 and R 6 is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III), wherein R 1 -C(=O)OR 6 and R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C1-C6 alkyl. 6 In another embodiment, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In still further embodiments, R 6 is ethyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (III), wherein R 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-OR 9and R 9 In a further embodiment, R is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 and R 6 -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, and each R 6 is hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (III), wherein R 1 is -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments described herein, the disclosed compounds are the following compounds: [Table 2] TIFF2024537545000094.tif236159TIFF2024537545000095.tif241159TIFF2024537545000096.tif242148TIFF2024537545000097.tif229159TIFF2024537545000098.tif47159, or a pharmaceutically acceptable salt or solvate thereof.

[0141] In certain embodiments, the disclosed compound utilized by one or more of the foregoing methods is one of the genus, subgenus, or specific compounds described herein, such as a compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) described herein.

[0142] Preparation of compounds The compounds used in the methods described herein are made according to the procedures disclosed herein or by known organic synthesis techniques, starting from commercially available chemicals and / or compounds described in the chemical literature. Commercially available chemicals include Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc.(Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).

[0143] Suitable reference books and monographs detailing the synthesis of, or providing references to articles describing the preparation of, reactants useful in the preparation of the compounds described herein include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and monographs detailing the synthesis of, or providing references to articles describing the preparation of, reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC“Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN:0-471-19031-4, March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley&Sons, ISBN:0-471-60180-2, Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN:3-527-29871-1, Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN:0-471-93022-9, Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X (8 volumes in total), "Organic Reactions" (1942-2000) John Wiley & Sons (over 55 volumes in total), and "Chemistry of Functional Groups" John Wiley & Sons (73 volumes in total).

[0144] Specific and similar reactants are also identified by the catalogs of known chemicals compiled by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries and online databases (further details can be contacted at the American Chemical Society, Washington, DC). Known chemicals not commercially available in catalogs are optionally prepared by custom chemical synthesis companies, and many of the standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0145] Further forms of the compounds disclosed herein Isomers Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds exist as tautomers. The compounds described herein encompass all possible tautomers within the formulae described herein. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that does not result in racemization.

[0146] Labeled Compounds In some embodiments, the compounds described herein exist in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein except for the replacement of one or more atoms by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, e.g., 2 H, 3 H, 13 C. 14 C. l5 N, 16 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Incorporating radioactive isotopes such as 1C are useful in drug and / or substrate tissue distribution assays. 3 H) isotopes and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2Substitution with heavy isotopes, such as H, offers certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof are prepared by any suitable method.

[0147] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0148] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0149] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases and acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt thereby formed.

[0150] Prodrug In some embodiments, the compounds described herein are formulated as drugs that are converted to active forms in vivo to alter the biodistribution or pharmacokinetics of a particular drug. For example, a carboxylic acid group can be esterified with a methyl or ethyl group, etc., to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, by reduction, oxidation, or hydrolysis to expose the anionic group. The anionic group can be esterified with a moiety (e.g., an acyloxymethyl ester) that is cleaved to yield an intermediate that subsequently decomposes to yield the active drug. The prodrug moiety can be metabolized in vivo by esterases or other mechanisms to yield the carboxylic acid. Alternatively, other functional groups can be modified to form prodrugs. For example, an amine group can be converted to an in vivo cleavable carbamate or amide.

[0151] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0152] Solvates contain either stoichiometric or non-stoichiometric solvents and, in some embodiments, are formed during the process of crystallization using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0153] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are administered in a manner consistent with the selected route of administration and the methods described in, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 2011). st and / or a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on standard pharmaceutical practice as described in "Therapeutic Drugs and Pharmaceuticals," Ed. Mack Pub. Co., Easton, PA (2005)."

[0154] Thus, provided herein are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt described herein in combination with one or more pharmaceutically acceptable carriers. A carrier(s) (or excipient(s)) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0155] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt thereof.

[0156] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), or a pharmaceutically acceptable salt thereof.

[0157] In certain embodiments, the compounds described herein are substantially pure, in the sense that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as contaminating intermediates or by-products made in one or more of the steps of the synthetic method.

[0158] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0159] Exemplary pharmaceutical compositions are used as medicinal preparations in solid, semi-solid, or liquid form, containing one or more compounds of the present disclosure as an active ingredient in a mixture with an organic or inorganic carrier or excipient suitable for, for example, topical, enteral, or parenteral application. In some embodiments, the active ingredient is formulated with a conventional non-toxic, pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0160] In some embodiments, the compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) described herein are administered to a subject in a biologically compatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. By "biologically compatible form suitable for topical administration" is meant a form of the compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) administered in which the therapeutic effects of the inhibitor outweigh any toxic effects. The administration of the compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) described herein can be in any pharmacological form containing a therapeutically effective amount of the compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III), alone or in combination with a pharmaceutically acceptable carrier.

[0161] Topical administration of a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) can be provided in the form of an aerosol, semi-solid pharmaceutical composition, powder, or solution. The term "semi-solid composition" refers to an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are described in Chapter 17 of "The Theory and Practice of Industrial Pharmacy," Lachman, Lieberman, and Kanig (published by Lea and Febiger) (1970) and Chapter 67 of "Remington's Pharmaceutical Sciences," 15th Edition (1975) (published by Mack Publishing Company).

[0162] Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches may provide absorption enhancers, such as DMSO, to increase absorption of the compound. Patches may also include those that control the rate of drug delivery to the skin. Patches may offer various delivery systems, including reservoir systems or integrated systems. Reservoir designs may have four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of drug molecules, a reservoir of drug molecules, and a waterproof backing. Such designs deliver a uniform amount of drug over a specified period of time, and the delivery rate must be below the saturation limit for various types of skin. Integrated designs typically have only three layers: an adhesive layer, a polymer matrix containing the compound, and a waterproof backing. This design delivers a saturating amount of drug to the skin, allowing delivery to be controlled by the skin. If the amount of drug in the patch decreases below the saturation level, the delivery rate decreases.

[0163] In one embodiment, the topical composition may take the form of, for example, a hydrogel based on polyacrylic acid or polyacrylamide, or as an ointment, such as the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500), which contains, for example, polyethylene glycol (PEG) as a carrier, or as an emulsion, in particular a water-in-oil or oil-in-water microemulsion optionally containing liposomes. Suitable penetration enhancers (entrainers) include sulfoxide derivatives such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO), and transcutol (diethylene glycol monoethyl ether) or cyclodextrin; and pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and their fatty acid esters; urea derivatives such as dodecyl urea, 1,3-didodecyl urea, and 1,3-diphenyl urea; terpenes such as D-limonene, menthone, α-terpineol, carbol, limonene oxide, or 1,8-cineole.

[0164] Ointments, pastes, creams, and gels can also contain excipients such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known methods commonly used to make aerosol medicines. Generally, such methods involve pressurizing a container of the solution, usually with an inert carrier gas, or providing a pressurizing means, and passing the pressurized gas through a small orifice. Sprays can further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0165] In some embodiments for preparing solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical carrier, such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of the disclosed compounds or their non-toxic, pharmaceutically acceptable salts. When these preformulation compositions are referred to as homogeneous, this means that the active ingredient is dispersed evenly throughout the composition, so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0166] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions may be formulated with one or more pharmaceutically acceptable carriers, e.g., sodium citrate or dicalcium phosphate, and / or (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) crospovidone, croscarmellose sodium, (4) disintegrating agents such as cereals, dairy products, and the like; (5) disintegrating agents such as cereals, dairy products, and the like; (6) dissolution retarders such as paraffin; (7) absorption accelerators such as quaternary ammonium compounds; (8) wetting agents such as docusate sodium, cetyl alcohol, and glycerol monostearate; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. For capsules, tablets, and pills, the compositions may also contain buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, for example.

[0167] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. In some embodiments, molded tablets are made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms such as dragees, capsules, pills, and granules are stamped or prepared with coatings and shells, such as enteric coatings and other coatings.

[0168] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, liquid dosage forms contain, in addition to the subject compositions, an inert diluent, such as water or other solvent, a solubilizing agent and an emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0169] In some embodiments, suspensions contain, in addition to the subject compositions, suspending agents such as, for example, ethoxylated isostearoyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0170] In some embodiments, powders and sprays contain, in addition to the subject compositions, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, sprays further contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0171] Alternatively, the compositions and compounds disclosed herein may be administered by aerosol. This can be accomplished by preparing aqueous aerosols, liposomal preparations, or solid particles containing the compounds. In some embodiments, non-aqueous (e.g., fluorocarbon propellant) suspensions are used. In some embodiments, sonic nebulizers are used to minimize exposure of the drug to shear, which can result in degradation of the compounds contained in the subject compositions. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject compositions with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0172] Pharmaceutical compositions suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders to be reconstituted immediately before use into sterile injectable solutions or dispersions, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0173] Examples of suitable aqueous or non-aqueous carriers used in pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0174] The dosage of a composition comprising at least one compound described herein will vary depending on the condition of the patient (eg, human), i.e., the stage of the disease, general health, age, and other factors.

[0175] Pharmaceutical compositions are administered as appropriate for the disease to be treated (or prevented). The appropriate dose and suitable duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provides a sufficient amount of the composition(s) to provide therapeutic and / or prophylactic benefit (e.g., an increased frequency of complete or partial remission, or an increased disease-free interval and / or overall survival, or an improved clinical outcome such as a reduced severity of symptoms). Optimal dosages are generally determined using experimental models and / or clinical trials. In some embodiments, optimal dosages depend on the patient's size, weight, or blood volume.

[0176] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0177] method In some embodiments, disclosed herein is a method for treating a mammal in need thereof, Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, myocardial contractility abnormalities, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-associated myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, Polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, diabetic nephropathy, glomerulonephritis, hereditary kidney disease, and chronic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schoenlein purpura, and postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, tubular injury after sepsis, acute ischemic renal injury, contrast-induced renal injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, tubulointerstitial fibrosis, Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia and reperfusion injury, viral hepatitis, drug-induced liver injury, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, acute liver failure, biliary atresia, and pigmented scleroderma A method of treating a disease, disorder, or condition selected from the group consisting of:

[0178] In some embodiments, disclosed herein is a method of treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof.

[0179] In some embodiments, disclosed herein is a method of treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to said mammal in need thereof a therapeutically effective amount of a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof.

[0180] In some embodiments, disclosed herein is a method of treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof.

[0181] In some embodiments, disclosed herein is a method of treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof.

[0182] In some embodiments, disclosed herein is a method of treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof.

[0183] Concomitant use of medicines Combination therapy is also contemplated herein, for example, by administering the disclosed compounds and an additional active agent together as part of a specific treatment regimen to provide a beneficial effect due to the interaction of these therapeutic agents. Beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combined use of therapeutic agents. The combined administration of these therapeutic agents typically occurs over a predetermined period of time (usually weekly, monthly, or yearly, depending on the combination selected). Combination therapy is intended to encompass not only the administration of multiple or at least two therapeutic agents substantially simultaneously, but also the sequential administration of multiple therapeutic agents, i.e., administration of each therapeutic agent at different times.

[0184] Substantially simultaneous administration can be achieved, for example, by administering to a subject a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent) or multiple separate formulations (e.g., capsules) for each therapeutic agent. Substantially simultaneous administration can also be achieved by administering to a subject a novel chemical entity consisting of a compound of the present disclosure linked to one or more additional active agents via a chemical bond or linker. Sequential or substantially simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, and other therapeutic agents in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection.

[0185] In some embodiments, disclosed herein is a method for treating a mammal in need thereof, Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, myocardial contractility abnormalities, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-associated myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, Polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, diabetic nephropathy, glomerulonephritis, hereditary kidney disease, and chronic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schoenlein purpura, and postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, tubular injury after sepsis, acute ischemic renal injury, contrast-induced renal injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, tubulointerstitial fibrosis, Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia and reperfusion injury, viral hepatitis, drug-induced liver injury, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, acute liver failure, biliary atresia, and pigmented scleroderma 1. A method of treating a disease, disorder, or condition selected from the group consisting of: and further comprising administering one or more additional pharmaceutical agents to the mammal. In some embodiments, disclosed are methods for treating a cardiovascular disease, disorder, or condition in a mammal in need of treatment, comprising administering to the mammal in need of treatment a therapeutically effective amount of a compound of Formula (I), and further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments, disclosed are methods for treating a cardiovascular disease, disorder, or condition in a mammal in need of treatment, comprising administering to the mammal in need of treatment a therapeutically effective amount of a compound of Formula (Ia), and further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments, disclosed are methods for treating a cardiovascular disease, disorder, or condition in a mammal in need of treatment, comprising administering to the mammal in need of treatment a therapeutically effective amount of a compound of Formula (Ib), and further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments, disclosed are methods of treating a cardiovascular disease, disorder, or condition in a mammal in need of treatment, comprising administering to the mammal in need of treatment a therapeutically effective amount of a compound of Formula (Ic), and further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments, disclosed are methods of treating a cardiovascular disease, disorder, or condition in a mammal in need of treatment, comprising administering to the mammal in need of treatment a therapeutically effective amount of a compound of Formula (II), and further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments, disclosed are methods of treating a cardiovascular disease, disorder, or condition in a mammal in need of treatment, comprising administering to the mammal in need of treatment a therapeutically effective amount of a compound of Formula (III), and further comprising administering to the mammal one or more additional pharmaceutical agents.

[0186] Combination therapy also includes the administration of the above-mentioned therapeutic agent in combination with other biologically active ingredients and non-drug therapy.When combination therapy further includes non-drug therapy, the non-drug therapy can be carried out at an appropriate time, as long as the beneficial effect from the interaction of the combination of the therapeutic agent and the non-drug therapy can be achieved.For example, in appropriate cases, the beneficial effect can also be achieved when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, for example, for several days or even weeks.

[0187] The components of the combination are administered to a patient simultaneously or sequentially. It will be understood that multiple components are administered simultaneously because they are in the same pharmaceutically acceptable carrier. Alternatively, the active ingredients are present in separate pharmaceutical carriers, as in conventional oral dosage forms, which are administered simultaneously or sequentially. [Example]

[0188] The present invention is further illustrated by the following examples, which should not be construed in any way as limiting the scope of the claims provided herein.

[0189] List of abbreviations As used above, and throughout the present specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings: s: Single line d: double line t: Mie line q:Quarter m: multiplet brs: wide single line dd: Double line of double lines td:double line triple line dt: Triple line double line ℃: Celsius ACN: acetonitrile Bn: Benzyl BOC or Boc: tert-butoxycarbonyl (Boc)2O: di-tert-butyl dicarbonate BOP-Cl: Bis(2-oxo-3-oxazolidinyl)phosphinic chloride CDI: 1,1'-carbonyldiimidazole Cy: Cyclohexyl DCE: dichloroethane (ClCH2CH2Cl) DCM: dichloromethane (CH2Cl2) DEAD: Diethyl azodicarboxylate DIPEA: N,N-diisopropylethylamine DMAP: 4-(N,N-dimethylamino)pyridine DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide DMSO: dimethyl sulfoxide equiv: equivalent (plural) Et: Ethyl EtOH: ethanol EA or EtOAc: Ethyl acetate g: grams(s) h: hour(s) HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography J: NMR coupling constant in Hertz LAH: Lithium aluminum hydride LCMS: Liquid chromatography / mass spectrometry Me: Methyl MeOH: Methanol mL: milliliter(s) μL: microliter(s) mmol: millimoles (multiple) μmol: micromol(s) MS: Mass spectrometry NaH: Sodium hydride (60% dispersion in mineral oil) NMM: N-methylmorpholine NMR: nuclear magnetic resonance PDA: Photodiode array detector Pd / C: 10% palladium / activated carbon, 50% water PMB: p-methoxybenzyl p-TSA: p-toluenesulfonic acid monohydrate RT or rt: room temperature TBDMS: tert-butyldimethylsilyl TEA: Triethylamine TBAF: Tetrabutylammonium fluoride TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography

[0190] Unless otherwise defined, the purity of a solid material is expressed as the ratio of the weight of the component in question to the total weight multiplied by 100 (wt%), the purity of a liquid is expressed as the ratio of the volume of the component in question to the total volume multiplied by 100 (vol%), and the concentration of a solution is expressed as the weight of the solute (in grams) to the total volume of the solution (in mL) multiplied by 100 (% w / v). The yield of a reactant is expressed as the ratio of the weight of the product in question to the theoretical yield of that product (%) multiplied by 100. The composition of a mixed solvent is expressed as the proportion of the volume parts of the constituent solvents (e.g., 80:20 or 3:2:1).

[0191] Overview Commercially available chemicals include Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz&Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc.Chemicals were obtained from standard commercial sources, including Merck (Rockville, MD), and WuXi (Shanghai, China). Dry solvents such as DCM, diethyl ether, and toluene were obtained from Finar and used as received, while THF was dried over sodium (monitored by the color of the benzophenone ketyl radical) and freshly distilled before use. Liquids and solutions were transferred via syringe or cannula. All reactions were carried out in flame-dried or oven-dried glassware under a nitrogen / argon atmosphere with magnetic stirring. Merck silica gel 60 F. 254 All reactions were monitored by thin-layer chromatography (TLC) using precoated plates (0.25 mm) and UV light, iodine, potassium permanganate stain, p-anisaldehyde stain, or phosphomolybdic acid stain; GC / FID; LCMS; or 1 H NMR was used for visualization. The crude compounds were purified by trituration; silica gel (60-120, 100-200, or 230-400 mesh) chromatography; and CombiFlash normal or reverse phase.

[0192] Analysis method proton( 1 H) and carbon ( 13C) NMR spectra were recorded on a Bruker Ascend-400 spectrometer operating at 400 MHz for proton and 100 MHz for carbon, using CDCl3, DMSO-d6, CD3CN, or DO as solvents. Chemical shifts are expressed in parts per million (δ, ppm), and coupling constants (J) are listed in Hertz. For proton spectra, the solvent peak was used as the reference peak. LCMS was performed on a Shimadzu LCMS-2020, an Agilent 6420 Triple Quad LC / MS, or an Agilent Infinity Lab LC / MSD XT using a PDA detector under electrospray ionization (ESI) conditions in both positive and negative modes. HPLC was performed on a Shimadzu LC-2010 and an Agilent 1290 Infinity II using a PDA detector. Preparative HPLC was performed on a Shimadzu semi-preparative or Agilent 1260 Infinity II using a PDA detector. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated.

[0193] The operating conditions for chromatography and mass spectrometry are summarized in Tables 1-3 below. [Table 3] [Table 4] [Table 5]

[0194] chemical synthesis Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized. Column and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ scale) and coupling constants (J) are listed in Hertz. For proton spectra, the solvent peak was used as the reference peak.

[0195] Exemplary synthetic methods for making compounds according to the present disclosure are provided below.

[0196] Preparation Example 1: Synthesis of 2-methoxyethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-1-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 1) The synthesis of the title compound is presented in Synthetic Scheme 1 below.

[0197] [ka] Methyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (1A) (200 mg, 0.76 mmol) was dissolved in acetone (5 mL) under a nitrogen atmosphere and cooled to 0-5 °C. K2CO3 (317 mg, 2.29 mmol) was added, and the mixture was stirred for 20 min. Then, 4-(4-chlorophenoxy)-3,5-difluorobenzenesulfonyl chloride (1B) (317 mg, 2.29 mmol) was added at the same temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with water (10 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography to give compound (1C) (200 mg, 64%) as a colorless gum. LCMS: 563.3 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.2 Hz, 2H), 7.32 - 7.25 (m, 7H), 6.90 (d, J = 4.8 Hz, 2H), 4.17 (m, 1H), 3.73 (s, 3H), 3.61 (q, 2H), 3.06 (d, J = 11.6 Hz, 1H), 2.79 (d, J = 11.6 Hz, 1H), 2.73 - 2.68 (m, 2H), 2.34 - 2.31 (m, 1H), 2.28 - 2.19 (m, 1H), 1.99 - 1.94 (m, 2H).

[0198] To a stirred solution of compound (1C) (600 mg, 1.06 mmol) in 1,2-dichloroethane (6 mL) was added 1-chloroethyl chloroformate (2 mL) slowly at room temperature. The reaction mixture was then heated at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with NaHCO solution (20 mL), and extracted with DCM (50 mL). The organic layer was washed with water (10 mL), dried over anhydrous NaSO, and concentrated to dryness under reduced pressure. The residue was treated with MeOH (5 mL) and heated at 70° C. for an additional hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound (1D) (150 mg, 30%) as a colorless gum. LCMS: 473.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 3.2 Hz, 2H), 7.29 (d, J = 4.4 Hz, 2H), 6.90 (d, J = 4.8 Hz, 2H), 4.18 - 4.11 (m, 1H), 3.76 (s, 3H), 3.37 - 3.34 (m, 2H), 3.08 (d, J = 12.8 Hz, 1H), 2.73 (dd, J = 10.4 Hz, 1H), 2.37 - 2.31 (m, 1H), 2.29 - 2.24 (m, 1H), 2.22 - 2.20 (m, 2H), 2.03 - 2.01 (m, 1H).

[0199] A stirred solution of compound 1D (350 mg, 0.74 mmol) in acetone (15 mL) was cooled to 0-5 °C under a nitrogen atmosphere. To this solution was added K2CO3 (306 mg, 2.22 mmol). The mixture was stirred at 0-5 °C for 20 minutes, and then 2-methoxyethyl carbonochloridate (0.17 mL, 1.11 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound 1E (370 mg, 87%) as a colorless gum. LCMS: 575.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.8 Hz, 2H), 7.29 (d, J = 4.8 Hz, 2H), 6.91 (d, J = 4.8 Hz, 2H), 4.52 - 4.51 (m, 2H), 4.44 - 4.38 (m, 2H), 4.30 - 4.28 (m, 1H), 4.24 - 4.21 (m, 1H), 3.65 (s, 3H), 3.56 - 3.51 (m, 3H), 3.40 - 3.39 (m, 1H), 3.36 (s, 3H), 2.30 - 2.19 (m, 1H), 2.09 - 1.98 (m, 2H).

[0200] To a stirred solution of compound 1E (150 mg, 0.261 mmol) in a 1:1 mixture of THF / water (5 mL) at 0° C. was added LiOH.HO (54 mg, 1.30 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then cooled to 0° C., neutralized with a saturated aqueous solution of citric acid, and extracted with ethyl acetate (50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give compound 1F (130 mg, 89%) as a brown gum. LCMS: 561.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 2.4 Hz, 2H), 6.89 (d, J = 4.8 Hz, 2H), 4.31 - 4.28 (m, 2H), 4.19 - 4.11 (m, 2H), 3.61 - 3.53 (m, 4H), 3.38 (s, 3H), 2.30 - 2.37 (m, 2H), 2.15 - 2.08 (m, 3H).

[0201] To a stirred solution of compound (1F) (110 mg, 0.19 mmol) in DMF (3 mL) was added HATU (89.5 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for an additional 30 minutes. DIPEA (0.1 mL, 0.58 mmol) was then added, followed by a solution of O-(tert-butyldimethylsilyl)hydroxylamine (106 mg, 0.39 mmol) in DMF (2 mL). The reaction was monitored by TLC, diluted with ice-cold water (20 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and treated with a solution of TBAF (1 M in THF) (2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-methoxyethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-1-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 1) (16 mg) as a pale pink solid. LCMS: 576.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.18 (brs, 1H) 7.65 (d, J = 5.6 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 9.2 Hz, 2H), 4.34 - 4.30 (m, 4H), 4.01 - 3.91 (m, 1H), 3.61 - 3.53 (m, 4H), 3.47 (s, 3H), 2.37 (m, 1H), 2.13 - 2.06 (m, 2H).

[0202] Several compounds according to the present disclosure were prepared according to the synthetic route shown in general synthetic schemes 2 or 3 and described in further detail in preparative example 2 below.

[0203] [ka] [ka] Preparation Example 2: 2-Methoxyethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-1-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 2) [ka] Step 1: Synthesis of ethyl 3-benzyl-8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] Ethyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (0.4 g, 1.45 mmol) was dissolved in acetone (5 mL) under a nitrogen atmosphere and cooled to 0-10 °C. K2CO3 (1.0 g, 7.25 mmol) was added to the reaction mixture and stirred at the same temperature for 20 minutes. 3,5-Difluoro-4-(4-fluorophenoxy)benzenesulfonyl chloride (0.705 g, 2.18 mmol) was dissolved in acetone (4 mL) and added to the reaction mixture at the same temperature. Water (0.1 mL) was then added, and the reaction mixture was stirred at room temperature for 10 hours. The reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by silica gel column chromatography (100-200 mesh, 5-10% EtOAc in hexane) to give 3-benzyl-8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (0.3 g, 0.53 mmol, 36% yield) as a colorless sticky gum. MS (ESI): m / z 561.0 [M+H] + .

[0204] Synthesis of ethyl 3-benzyl-8-((4-(4-cyano-2-methylphenyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a solution of ethyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (300 mg, 1.094 mmol) in THF (5 mL) was added DIPEA (0.58 mL, 3.28 mmol) and stirred at 0-10 °C under a nitrogen atmosphere for 20 minutes. 4-(4-cyano-2-methylphenyl)piperazine-1-sulfonyl chloride (491 mg, 1.64 mmol) was dissolved in THF (3 mL) and added to the reaction mixture at the same temperature. The reaction mixture was then stirred at 60 °C for 48 hours. The reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by silica gel column chromatography (100-200 mesh, 5-10% EtOAc in hexane) to give ethyl 3-benzyl-8-((4-(4-cyano-2-methylphenyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (250 mg, 0.46 mmol, 42% yield) as a yellow sticky gum. MS (ESI): m / z 538.1 [M+H] + .

[0205] Similarly, the following intermediates were prepared following the same or similar procedures as those described above. [Table 6] TIFF2024537545000109.tif125159

[0206] Step 2: Synthesis of ethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 3-benzyl-8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (0.3 g, 0.53 mmol) in MeOH (6 mL) was added (Boc)O (0.5 mL, 2.142 mmol), followed by Pd / C (120 mg, 40 wt%) under N atmosphere. The reaction mixture was stirred at room temperature (RT) under H balloon pressure for 6 h. The reaction was monitored by TLC until completion. The reaction mixture was filtered through a celite bed and washed with MeOH (20 mL). The organic layer was evaporated under reduced pressure to give 3-(tert-butyl) 1-ethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (0.25 g, 0.43 mmol, 81% yield) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 515.0 [Mt-Bu+H] + .

[0207] To a stirred solution of 3-(tert-butyl) 1-ethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (0.25 g, 0.43 mmol) in DCM (5 mL) at 0-10 °C, trifluoroacetic acid (0.33 mL, 4.38 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. The reaction mixture was evaporated to dryness, and the residue was diluted with ethyl acetate (40 mL) and washed with saturated NaHCO3 solution (2 × 10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (0.2 g, 0.42 mmol, 97% yield) as a colorless sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 471.0 [M+H] +.

[0208] Synthesis of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 3-benzyl-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (800 mg, 1.3 mmol) in MeOH (8 mL) was added (Boc)O (0.6 mL, 2.6 mmol) and 1,2-dichlorobenzene (0.28 mL, 2.6 mmol) at room temperature. This solution was then treated with Pd / C (240 mg, 30 wt%) at room temperature. The resulting solution was stirred under H balloon pressure at room temperature for 1 hour while being monitored by TLC until completion. The reaction mixture was filtered through a pad of Celite and washed with methanol (25 mL). The filtrate was concentrated under reduced pressure to give 3-(tert-butyl) 1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (900 mg, 1.53 mmol, quantitative) as a colorless semi-solid, which was used directly in the next step without further purification. MS (ESI): m / z 487 [M-100+H] + ; 1 H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 6.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.44 - 4.13 (m, 3H), 3.90 - 3.70 (m, 2H), 3.60 - 3.20 (m, 2H), 2.52 - 2.20 (m, 2H), 2.19 - 2.00 (m, 2H), 1.50 (s, 9H), 1.31 (t, J = 6.8 Hz, 3H).

[0209] To a stirred solution of 3-tert-butyl 1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (1.0 g, 1.7 mmol) in DCM (10 mL) at 0-10 °C, trifluoroacetic acid (1.5 mL, 17 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated to dryness, then diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (2 × 100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (600 mg, 1.23 mmol, 72% yield over two steps) as an off-white solid, which was used directly in the next step without further purification. MS (ESI): m / z 487.0 [M+H] + .

[0210] Synthesis of ethyl 8-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 8-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (400 mg, 0.724 mmol) in 8 mL of EtOAc was added Pd / C (120 mg, 30 wt%) at room temperature. The resulting solution was stirred at room temperature under a H balloon atmosphere for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad and washed with 25 mL of EtOAc. The filtrate was concentrated under reduced pressure to give ethyl 8-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (260 mg, 0.60 mmol, 83% yield) as a colorless semisolid. This was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 4.21 (q, J = 7.2 Hz, 2H), 3.99 - 3.91 (m, 1H), 3.52 - 3.45 (m, 4H), 3.42 - 3.36 (m, 2H), 3.22 - 3.18 (m, 4H), 2.93 (d, J = 12.8 Hz, 1H), 2.62 (d, J = 12.0 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.20 - 2.09 (m, 3H), 1.90 - 1.80 (m, 1H), 1.47 (s, 9H), 1.31 (t, J = 6.8 Hz, 3H).

[0211] Synthesis of ethyl 8-((4-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 3-benzyl-8-((4-(benzyloxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (600 mg, 1.13 mmol) in MeOH (5 mL) was added (Boc)2O (0.5 mL, 2.27 mmol) at room temperature. This solution was then treated with Pd / C (180 mg, 30 wt%) at room temperature and stirred at room temperature for 5 hours under an H2 atmosphere from a balloon. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad and washed with methanol (25 mL). The filtrate was concentrated under reduced pressure to give 3-(tert-butyl) 1-ethyl 8-((4-hydroxypiperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (450 mg, 1.00 mmol, 88% yield) as a colorless semi-solid, which was used directly in the next step without further purification. MS (ESI): m / z 448.4 [M+H] + .

[0212] To a DMSO solution (5 mL) of 3-(tert-butyl)1-ethyl 8-((4-hydroxypiperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (100 mg, 0.22 mmol) at 0° C., sodium hydride (16 mg, 0.67 mmol) was added portionwise. The mixture was then stirred at the same temperature for 10 minutes, and then 2,5-difluoropyridine (127 mg, 1.1 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted into diethyl ether (3×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (100-200 mesh, 10% EtOAc in hexane) to give 3-(tert-butyl) 1-ethyl 8-((4-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (60 mg, 0.11 mmol, 49% yield) as a colorless liquid. MS (ESI): m / z 543.3 [M+H] + .

[0213] To a solution of 3-(tert-butyl) 1-ethyl 8-((4-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (160 mg, 0.29 mmol) in DCM (5 mL) at 0-5 °C, trifluoroacetic acid (0.25 mL, 2.95 mmol) was added dropwise and stirred at room temperature for 16 h. Completion of the reaction was monitored by TLC. The volatiles were evaporated under reduced pressure, and the residue was diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 (2 × 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give ethyl 8-((4-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (130 mg, 0.29 mmol, 100% yield) as a pale red liquid, which was used directly in the next step without further purification. MS (ESI): m / z 443.1 [M+H] + .

[0214] Similarly, the following intermediates were prepared following the same or similar procedures as those described above. [Table 7]

[0215] Step 3: Synthesis of 1-ethyl 3-(2-methoxyethyl) 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a stirred solution of ethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (0.2 g, 0.43 mmol) in DCM (5 mL) at 0-10 °C, DIPEA (0.29 mL, 1.4 mmol) and 2-methoxyethyl chloroformate (0.09 mL, 0.8 mmol) were added under N atmosphere. The reaction mixture was then stirred at room temperature for 6 h and monitored by TLC. The reaction mixture was quenched with ice-cold water (5 mL) and extracted into EtOAc (2 × 20 mL). The combined organic layers were washed with ice-cold water (2 x 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1-ethyl 3-(2-methoxyethyl) 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (0.3 g, 0.52 mmol, quantitative) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 573.0 [M+H] + .

[0216] Synthesis of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-(2-morpholinoacetyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (250 mg, 0.5133 mmol) in DCM (5 mL) was added DIPEA (1.0 mL, 5.133 mmol) and 2-chloroacetyl chloride (0.25 mL, 3.08 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 4 hours, at which point TLC indicated complete consumption of the starting material. The reaction mixture was cooled to 0° C., and then morpholine (0.25 mL, 5.133 mmol) was added. The resulting reaction mixture was allowed to slowly warm to room temperature while being monitored by TLC and stirred for 16 hours. The reaction mixture was quenched with water (20 mL) at 0° C. and extracted with DCM (3×10 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 50% EtOAc in hexane) to give ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-(2-morpholinoacetyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (200 mg, 0.326 mmol, 63% yield) as a colorless liquid. MS (ESI): m / z 614.2 [M+H] + .

[0217] Synthesis of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-(2-(piperidin-1-yl)acetyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (0.150 g, 0.308 mmol) in anhydrous DMF (2 mL) at 0-10 °C, HATU (0.140 g, 0.369 mmol) and DIPEA (0.26 mL, 1.54 mmol) were added. The reaction mixture was stirred at the same temperature for 20 min, and 2-(piperidin-1-yl)acetic acid (0.053 g, 0.369 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 16 h, and monitored by TLC. The reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with ice-cold water (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-(2-(piperidin-1-yl)acetyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (160 mg, 0.26 mmol, 84% yield) as a brown sticky gum. MS (ESI): m / z 612.2 [M+H] + .

[0218] Synthesis of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-((2-morpholinoethyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (250 mg, 0.5144 mmol) in DCM (5 mL), triethylamine (0.143 mL, 1.028 mmol) was added at 0-10 °C, and stirring was continued for another 30 min at 0-10 °C. 2-Chloroethane-1-sulfonyl chloride (0.08 mL, 0.771 mmol) was added and stirred at the same temperature for 20 min. Morpholine (134 mg, 1.543 mmol) was then added to the reaction mixture at 0 °C, and the resulting solution was slowly warmed to room temperature over 30 min while being monitored by TLC and stirred for 16 h. The reaction mixture was quenched with water (10 mL) at 0 °C and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 0-10% MeOH in DCM) to give ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-((2-morpholinoethyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (290 mg, 0.431 mmol, 84% yield) as a brown sticky gum. MS (ESI): m / z 664.3 [M+H] + ; 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 7.2 Hz, 2H), 4.38 - 4.30 (m, 1H), 4.25 - 4.19 (m, 2H), 4.04 (d, J = 12.0 Hz, 1H), 3.79 - 3.74 (m, 4H), 3.64 - 3.58 (m, 3H), 3.17 (t, J = 7.2 Hz, 2H), 2.85 - 2.75 (m, 2H), 2.60 - 2.45 (m, 4H), 2.38 - 2.20 (m, 2H), 2.12 - 1.95 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0219] Synthesis of 1-ethyl 3-(2-(4-methylpiperazin-1-yl)ethyl) 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a stirred solution of ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (300 mg, 0.616 mmol) in DCM (10 mL) was added DIPEA (0.2 mL, 1.23 mmol) at 0° C. and stirred for 10 min. 2-Chloroethyl carbonochloridate (0.1 mL, 0.924 mmol) was added to the reaction mixture at the same temperature, and the mixture was allowed to warm to room temperature slowly over 30 min while being monitored by TLC and stirred for 4 h. The reaction was quenched with water (10 mL) at 0° C. and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-(2-chloroethyl) 1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (400 mg, crude) as an off-white semi-solid, which was used directly in the next step without further purification. MS (ESI): m / z 593.2 [M+H] + .

[0220] To a stirred DMF solution (2.0 mL) of 3-(2-chloroethyl)1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (400 mg, obtained crude from the previous step) at 0° C., KCO (279 mg, 2.02 mmol) and KI (12 mg, 0.067 mmol) were added. The reaction mixture was stirred for 30 min, and 1-methylpiperazine (0.5 mL, 1.349 mmol) was added at the same temperature. The reaction mixture was then slowly heated to 60° C. with TLC monitoring and stirred for 16 h. After completion of the reaction, the reaction mixture was cooled to 0° C., quenched with water (10 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by reverse-phase Combiflash (C-18 column, 5% ACN / deionized water) to give 1-ethyl 3-(2-(4-methylpiperazin-1-yl)ethyl) 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (100 mg, 0.152 mmol, 24% yield over two steps) as a brown sticky gum. MS (ESI): m / z 657.2 [M+H] + .

[0221] Synthesis of ethyl 8-((6-(3-fluorophenyl)pyridin-3-yl)sulfonyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of ethyl 8-((6-(3-fluorophenyl)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (140 mg, 0.334 mmol) in MeOH (2.0 mL) was added formaldehyde (70 mg, 2.33 mmol) and Pd / C (50 mg, 30 wt%) under an inert atmosphere. The reaction mixture was stirred at room temperature under a H atmosphere (1 atm, balloon) for 16 hours with TLC monitoring. The reaction mixture was filtered through a Celite pad and washed with methanol. The filtrate was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and filtered to give ethyl 8-((6-(3-fluorophenyl)pyridin-3-yl)sulfonyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (90 mg, 0.207 mmol, 61% yield) as a colorless gum. MS (ESI): m / z 434.0 [M+H] + .

[0222] Synthesis of 1-ethyl 3-(2-methoxyethyl)8-((4-(4-fluorobenzyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a stirred solution of ethyl 8-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (360 mg, 0.833 mmol) in DCM (5 mL) at 0–10° C. was added DIPEA (0.6 mL, 3.33 mmol). The reaction mixture was stirred for 15 min, and 2-methoxyethyl carbonochloridate (0.14 mL, 1.20 mmol) was added at 0° C. The resulting solution was slowly warmed to room temperature over 30 min while being monitored by TLC and stirred for an additional 2 h. The reaction mixture was quenched with water (10 mL) at 0° C. and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60–120 mesh, 0–80% EtOAc in hexane) to give 1-ethyl 3-(2-methoxyethyl) 8-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (400 mg, 0.749 mmol, 89% yield) as a pale red liquid. 1 H NMR (400 MHz, CDCl3): δ 4.30 - 4.18 (m, 4H), 4.05 - 3.96 (m, 1H), 3.83 - 3.68 (m, 2H), 3.65 - 3.57 (m, 2H), 3.56 - 3.45 (m, 4H), 3.38 (s, 3H), 3.30 - 3.17 (m, 4H), 2.40 - 2.28 (m, 2H), 2.18 - 1.98 (m, 3H), 1.81 - 1.70 (m, 1H), 1.47 (s, 9H), 1.31 (t, J = 6.4 Hz, 3H).

[0223] To a stirred solution of 1-ethyl 3-(2-methoxyethyl) 8-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (400 mg, 0.749 mmol) in DCM (5 mL) at 0-5 °C, trifluoroacetic acid (0.5 mL, 7.490 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. Completion of the reaction was monitored by TLC. The volatiles were evaporated under reduced pressure, and the residue was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 (2 × 10 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1-ethyl 3-(2-methoxyethyl) 8-(piperazin-1-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (300 mg, 0.806 mmol, 93% yield) as a colorless sticky gel, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 4.30 - 4.20 (m, 4H), 4.15 - 3.95 (m, 1.5H), 3.81 - 3.70 (m, 1.5H), 3.65 - 3.50 (m, 3H), 3.38 (s, 3H), 3.31 - 3.20 (m, 4H), 2.96 - 2.90 (m, 4H), 2.40 - 2.29 (m, 1H), 2.20 - 1.95 (m, 3H), 1.70 - 1.60 (m, 1H), 1.65 - 1.55 (m, 1H), 1.31 (t, J = 6.4Hz, 3H).

[0224] To a stirred solution of 1-ethyl 3-(2-methoxyethyl) 8-(piperazin-1-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (350 mg, 0.806 mmol) in acetonitrile (8 mL) was added triethylamine (0.46 mL, 3.22 mmol) at 0 °C under a N atmosphere. After 10 min, 4-fluorobenzyl chloride (0.1 mL, 0.887 mmol) was slowly added to the reaction mixture at the same temperature. The reaction mixture was then allowed to warm to room temperature and stirred for 16 h while being monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine solution (10 mL), dried over NaSO, filtered, and concentrated to give the crude compound. The crude compound was purified by reverse-phase Combiflash chromatography (C-18 column, 10-20% ACN / deionized water) to give 1-ethyl 3-(2-methoxyethyl) 8-((4-(4-fluorobenzyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (150 mg, 0.276 mmol, 34% yield) as a colorless sticky gel. MS (ESI): m / z 543.2 [M+H] + .

[0225] Synthesis of 1-ethyl 3-(2-methoxyethyl) 8-((4-((2-chloro-4-fluorobenzyl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a solution of ethyl 3-benzyl-8-((4-((2-chloro-4-fluorobenzyl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (200 mg, 0.349 mmol) in DCE (5.0 mL) stirred at room temperature was added 2-methoxyethyl chloroformate (0.04 ml, 3.49 mmol) under N atmosphere. The reaction mixture was heated to 85 °C with TLC monitoring and stirred for 24 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (100–200 mesh, 10–20% EtOAc in hexane) to give 1-ethyl 3-(2-methoxyethyl) 8-((4-((2-chloro-4-fluorobenzyl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (150 mg, 0.256 mmol, 73% yield) as a colorless sticky gum. 1 H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.8 Hz, 2H), 7.52 - 7.48 (m, 1H), 7.19 (dd, J = 2.4, 8.4 Hz, 1H), 7.06 - 6.99 (m, 3H), 5.30 (s, 2H), 4.32 - 4.02 (m, 6H), 3.92 - 3.78 (m, 1H), 3.65 - 3.49 (m, 4H), 3.36 (s, 3H), 2.32 - 2.20 (m, 1H), 2.05 - 1.87 (m, 2H), 1.74 - 1.60 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H).

[0226] Similarly, the following intermediates were prepared following the same or similar procedures as those described above. [Table 8] TIFF2024537545000124.tif228159

[0227] Step 4: Synthesis of 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid [ka] To a stirred solution of 1-ethyl 3-(2-methoxyethyl) 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (0.30 g, 0.52 mmol) in a 1:1:1 mixture of THF:MeOH:HO (2 mL:2 mL:2 mL) at 0 °C was added LiOH.HO (132 mg, 3.16 mmol). The reaction mixture was stirred at room temperature for 24 h with TLC monitoring. The volatiles were evaporated under reduced pressure, diluted with water (5 mL), and cooled to 0–10 °C. The pH of the reaction mixture was adjusted to approximately 4–5 with 10% aqueous citric acid and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (160 mg, 0.29 mmol, 56% yield) as a pale yellow sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 545.0 [M+H] + .

[0228] Similarly, the following intermediates were prepared following the same or similar procedures as those described above. [Table 9] TIFF2024537545000127.tif242156TIFF2024537545000128.tif221159

[0229] Step 5: Synthesis of 2-methoxyethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-1-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a stirred solution of 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-3-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (0.15 g, 0.28 mmol) in anhydrous DMF (2 mL) at 0–10° C., HATU (0.125 g, 0.33 mmol) and DIPEA (0.25 mL, 1.3 mmol) were added. The reaction mixture was stirred at the same temperature for 20 min, and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.04 g, 0.33 mmol) was added. The reaction mixture was allowed to warm to room temperature while being monitored by TLC and stirred for 6 h. Upon completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with ice-cold water (2 × 5 mL), dried over NaSO, filtered, and evaporated under reduced pressure to give 2-methoxyethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-1-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.31 mmol, quantitative) as a brown sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 641.9 [M−H] - .

[0230] Similarly, the following intermediates were prepared following the same or similar procedures as those described above. [Table 10] TIFF2024537545000131.tif240159TIFF2024537545000132.tif200159

[0231] Step 8: Synthesis of 3-(tert-butyl) 1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a stirred solution of ethyl 3-benzyl-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (800 mg, 1.39 mmol) in MeOH (8 mL) was added (Boc)O (0.6 mL, 2.6 mmol) and 1,2-dichlorobenzene (0.28 mL, 2.6 mmol) at room temperature. Pd / C (240 mg, 30 wt%) was then added to the reaction mixture at room temperature under an inert atmosphere. The reaction mixture was stirred under a H atmosphere (1 atm, balloon) for 1 h at room temperature while being monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a Celite pad and washed with methanol (25 mL). The filtrate was concentrated under reduced pressure to give 3-(tert-butyl) 1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (900 mg, 1.55 mmol, quantitative) as a colorless semi-solid, which was used directly in the next step without further purification. MS (ESI): m / z 487 [M-100+H] + .

[0232] Step 9: Synthesis of 3-(tert-butoxycarbonyl)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid [ka] To a stirred solution of 3-(tert-butyl) 1-ethyl 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (100 mg, 0.17 mmol, crude from the previous step) in a 3:2:1 mixture of THF:MeOH:HO (3 mL:2 mL:1 mL) at 0 °C, LiOH.HO (36 mg, 0.85 mmol) was added and stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with 10% aqueous citric acid and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-(tert-butoxycarbonyl)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (65 mg, 0.116 mmol, 68% yield) as a brown sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 556.9 [M−H] - .

[0233] Step 10: Synthesis of tert-butyl 1-((benzyloxy)carbamoyl)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a stirred solution of 3-(tert-butoxycarbonyl)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (570 mg, 0.95 mmol) in DMF (10 mL) was added HATU (434 mg, 1.14 mmol) and stirred at room temperature for an additional 30 min. The temperature of the reaction mixture was lowered to 0-10 °C, and DIPEA (0.8 mL, 4.76 mmol) was added and stirred at the same temperature for 10 min. Benzylhydroxylamine hydrochloride (181 mg, 1.14 mmol) was added to the reaction mixture at 0-10 °C. The resulting solution was slowly warmed to room temperature over 30 min while monitoring by TLC and stirred for 16 h. The reaction mixture was quenched with water (20 mL) at 0 °C, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 10% EtOAc in hexane) to give tert-butyl 1-((benzyloxy)carbamoyl)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 0.60 mmol, 48% yield over three steps) as an off-white solid. MS (ESI): m / z 662.2 [M−H] - .

[0234] Step 11: Synthesis of N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide [ka] To a stirred solution of tert-butyl 1-((benzyloxy)carbamoyl)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 0.63 mmol) in DCM (5 mL) at 0-5 °C, trifluoroacetic acid (0.23 mL, 3.06 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h with TLC monitoring. The reaction mixture was evaporated to dryness, then diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 (2 × 10 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (300 mg, 0.53 mmol, 84% yield) as an off-white solid, which was used directly in the next step without further purification.

[0235] MS (ESI): 563.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): 11.23 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.45 - 7.32 (m, 7H), 7.11 (d, J = 12.4 Hz, 2H), 4.82 (d, J = 10.8 Hz, 1H), 4.78 (d, J = 10.8 Hz, 1H), 4.21 (d, J = 5.2 Hz, 1H), 3.10 (d, J = 12.8 Hz, 1H), 2.97 (d, J = 12.4 Hz, 1H), 2.75 - 2.55 (m, 3H), 2.11 - 1.95 (m, 2H), 1.81 - 1.70 (m, 2H).

[0236] Step 12: Synthesis of N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-isonicotinoyl-3,8-diazabicyclo[3.2.1]octane-1-carboxamide [ka] Following a procedure similar to that described for Step 3 of Method I in Preparative Example 2, N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-isonicotinoyl-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (70 mg, 0.105 mmol, 59% yield) was obtained as a pale red liquid. MS (ESI): m / z 669.0 [M+H] + .

[0237] Synthesis of N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-(morpholino-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide [ka] Following a procedure similar to that described for Step 3 of Method G in Preparative Example 2, semi-pure N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (100 mg, 0.147 mmol, 83% yield) was obtained as a colorless viscous liquid, which was used directly in the next step without further purification. MS (ESI): m / z 677.0 [M+H] + .

[0238] Similarly, the following intermediates were prepared following the same or similar procedures as those described above. [Table 11]

[0239] Step 6: Synthesis of 2-methoxyethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-1-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 2) [ka] To a stirred solution of 2-methoxyethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-1-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.2 g, 0.31 mmol) in DCM (4 mL) at 0-10 °C, trifluoroacetic acid (0.3 mL, 3.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 h with TLC monitoring. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (2 × 5 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by RP preparative HPLC (Table 2, Method 2) and the relevant fractions were combined and lyophilized to give 2-methoxyethyl 8-((3,5-difluoro-4-(4-fluorophenoxy)phenyl)sulfonyl)-1-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 2, 25 mg, 0.044 mmol, 14% yield) as an off-white solid. MS (ESI): m / z 560.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6): δ 10.72 (brs, 1H), 9.00 (brs, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.24 - 7.19 (m, 2H), 7.13 - 7.09 (m, 2H), 4.50 - 4.41 (m, 1H), 4.21 - 4.12 (m, 2H), 4.10 - 3.96 (m, 1H), 3.89 - 3.78 (m, 1H), 3.53 (t, J = 4.8 Hz, 2H), 3.49 - 3.40 (m, 1H), 3.40 - 3.30 (m, 1H), 3.27 (s, 3H), 2.20 - 2.10 (m, 1H), 1.95 - 1.80 (m, 2H), 1.61 - 1.51 (m, 1H).

[0240] Synthesis of 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-isonicotinoyl-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 3) [ka] To a stirred solution of N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3-isonicotinoyl-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (70 mg, 0.10 mmol) in MeOH (3 mL) was added 1,2-dichlorobenzene (0.02 mL, 0.20 mmol), followed by Pd / C (21 mg, 30 wt%) at room temperature under an inert atmosphere. The reaction mixture was stirred under H atmosphere (1 atm, balloon) for 16 hours while being monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a Celite pad and washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by RP preparative HPLC (Table 2, Method 1) and the relevant fractions were combined and lyophilized to give 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-isonicotinoyl-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 3, 13 mg, 0.022 mmol, 22% yield) as an off-white solid. MS (ESI): m / z 579.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 0.5H), 10.62 (s, 0.5H), 9.07 (s, 0.5H), 8.95 (s, 0.5H), 8.69 (d, J = 4.4 Hz, 2H), 7.89 - 7.80 (m, 2H), 7.48 - 7.43 (m, 4H), 7.10 (d, J = 9.2 Hz, 2H), 4.67 - 4.60 (m, 1H), 4.41 - 4.37 (m, 1H), 3.78 - 3.67 (m, 1H), 3.44 - 3.33 (m, 2H), 2.20 - 2.09 (m, 1H), 2.00 - 1.48 (m, 3H).

[0241] Likewise, the following examples were prepared following the same or similar processes as those described above. [Table 12] TIFF2024537545000143.tif229159TIFF2024537545000144.tif203159 TIFF2024537545000145.tif191159 TIFF2024537545000146.tif196159 TIFF2024537545000147.tif197159 TIFF2024537545000148.tif192159 TIFF2024537545000149.tif74159

[0242] Step 7: Synthesis of rel-(1R,5S)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 26) and rel-(1S,5R)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 27) [ka] 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (20 mg, 0.034 mmol) was purified by chiral preparative HPLC (Table 2, Method 4) to give rel-(1R,5S)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl) as an off-white solid. Both peaks were separated: rel-(1S,5R)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 26, 3 mg, 0.0051 mmol, 15% yield) and rel-(1S,5R)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 27, 3 mg, 0.0051 mmol, 15% yield), which was obtained as an off-white solid.

[0243] rel-(1R,5S)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 26): MS (ESI): m / z 587.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 6.4 Hz, 2H), 7.32 - 7.26 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.31 (d, J = 6.4 Hz, 1H), 4.15 - 4.00 (m, 2H), 3.73 - 3.50 (m, 7H), 3.30 - 3.19 (m, 4H), 2.31 - 2.22 (m, 2H), 2.10 - 2.01 (m, 1H), 1.83 - 1.76 (m, 2H).

[0244] rel-(1S,5R)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 27): MS (ESI): m / z 587.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ 7.65 - 7.60 (m, 2H), 7.32 - 7.27 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.34 - 4.30 (m, 1H), 4.10 - 4.00 (m, 1H), 3.72 - 3.48 (m, 7H), 3.30 - 3.19 (m, 4H), 2.32 - 2.23 (m, 2H), 2.09 - 2.00 (m, 1H), 1.88 - 1.78 (m, 2H).

[0245] Likewise, the following examples were prepared following the same or similar processes as those described above. [Table 13] TIFF2024537545000152.tif70159

[0246] Several compounds according to the present disclosure were prepared according to the synthetic route shown in general synthetic scheme 4 and described in further detail in preparative example 3 below.

[0247] [ka] Preparation Example 3: Synthesis of 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 32) [ka] Step 13: Synthesis of 3-benzyl-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid [ka] To a stirred solution of methyl 3-benzyl-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (200 mg, 0.35 mmol) in a 3:2:1 mixture of THF:MeOH:HO (3 mL:2 mL:1 mL) at 0 °C was added NaOH (71 mg, 1.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h while being monitored by TLC. The reaction mixture was neutralized with 10% aqueous citric acid and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-benzyl-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (180 mg, 0.33 mmol, 93% yield) as a brown sticky gel, which was used directly in the next step without further purification. MS (ESI): m / z 549.0 [M+H] + .

[0248] Step 14: Synthesis of 3-benzyl-N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide [ka] To a stirred solution of 3-benzyl-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (180 mg, 0.32 mmol) in anhydrous DCM (5 mL) was added HATU (150 mg, 0.39 mmol) and stirred at room temperature for 30 min. The reaction mixture was then cooled to 0-10 °C, and DIPEA (0.3 mL, 1.64 mmol) and benzylhydroxylamine hydrochloride (63 mg, 0.39 mmol) were added. The reaction mixture was allowed to warm slowly to room temperature while being monitored by TLC and stirred for 16 h. The reaction was quenched with water (20 mL) at 0 °C, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 20% EtOAc in hexane) to give 3-benzyl-N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (110 mg, 0.15 mmol, 47% yield) as a colorless viscous liquid. MS (ESI): m / z 654.1 [M+H] + .

[0249] Step 15: Synthesis of 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 32) [ka] To a stirred solution of 3-benzyl-N-(benzyloxy)-8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (70 mg, 0.1 mmol) in MeOH (3 mL) was added 1,2-dichlorobenzene (0.02 mL, 0.2 mmol) and Pd / C (21 mg, 30 wt%) at room temperature under a nitrogen atmosphere. The solution was degassed with N and flushed with H, then stirred at room temperature under a H atmosphere (1 atm, balloon) for 30 min with TLC monitoring. The reaction mixture was filtered through a Celite pad and washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give 70 mg of crude compound. The crude compound was purified by RP preparative HPLC (Table 2, Method 1) and lyophilized to give 8-((4-(4-chlorophenoxy)-3,5-difluorophenyl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-1-carboxamide (Example 32) (21 mg, 0.44 mmol, 42% yield) as an off-white solid. MS (ESI): m / z 474.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.54 (brs, 1H), 8.88 (brs, 1H), 8.83 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.25 - 4.20 (m, 1H), 3.12 (d, J = 12.8 Hz, 1H), 2.98 (d, J = 12.4 Hz, 1H), 2.75 (d, J = 12.8 Hz, 1H), 2.60 (d, J = 11.6 Hz, 1H), 2.10 - 2.03 (m, 2H), 1.81 - 1.73 (m, 2H) (-NH protons not observed).

[0250] Several compounds according to the present disclosure were prepared according to the synthetic route shown in general synthetic scheme 5 and described in further detail in preparative example 4 below.

[0251] [ka] Preparation Example 4: Synthesis of 2-methoxyethyl 1-(hydroxycarbamoyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 33) [ka] Step 16: Synthesis of ethyl 3-benzyl-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of 4-(4-(trifluoromethoxy)phenoxy)benzoic acid (350 mg, 1.17 mmol) in DCM (3.5 mL) was added BOP-Cl (736 mg, 2.93 mmol) and EtN (0.4 mL, 3.52 mmol) at room temperature, and the mixture was stirred for 10 min. The reaction was then cooled to 0–10 °C, and ethyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (321 mg, 1.17 mmol) was added. The resulting solution was slowly warmed to room temperature over 30 min and stirred for 16 h while being monitored by TLC. The reaction mixture was quenched with water (10 mL) at 0 °C and then extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 50% EtOAc in hexane) to give ethyl 3-benzyl-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (300 mg, 0.54 mmol, 46% yield) as a colorless liquid. MS (ESI): m / z 555.0 [M+H] + .

[0252] Synthesis of ethyl 3-benzyl-8-(4-(4-chlorophenoxy)-3,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of 4-(4-chlorophenoxy)-3,5-difluorobenzoic acid (300 mg, 1.098 mmol) in DMF (5 mL) was added HATU (500 mg, 1.31 mmol) at room temperature. The reaction was stirred for 30 min and cooled to 0–10 °C. DIPEA (0.9 mL, 5.47 mmol) was added and stirred at the same temperature for 10 min. Ethyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (373 mg, 1.31 mmol) was then added, and the resulting solution was slowly warmed to room temperature over 30 min and stirred for 16 h. The reaction was quenched with water (20 mL) at 0 °C and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 5% EtOAc in hexane) to give ethyl 3-benzyl-8-(4-(4-chlorophenoxy)-3,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (250 mg, 4.62 mmol, 42% yield) as an off-white solid. MS (ESI): m / z 541.0 [M+H] + .

[0253] Step 17: Synthesis of 3-(tert-butyl) 1-ethyl 8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a stirred solution of ethyl 3-benzyl-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (300 mg, 0.541 mmol) in MeOH (4 mL) was added (Boc)O (0.26 mL, 1.083 mmol), followed by Pd / C (150 mg, 50 wt%) at room temperature under an inert atmosphere. The resulting solution was then stirred at room temperature under a H atmosphere (1 atm, balloon) for 3 h with TLC monitoring. The reaction mixture was filtered through a Celite pad and washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give 3-(tert-butyl) 1-ethyl 8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (300 mg, 0.53 mmol, 98% yield) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 565.0 [M+H] + .

[0254] Synthesis of 3-(tert-butyl) 1-ethyl 8-(4-(4-chlorophenoxy)-3,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] To a stirred solution of ethyl 3-benzyl-8-(4-(4-chlorophenoxy)-3,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (200 mg, 0.37 mmol) in MeOH (5 mL) was added (Boc)O (0.8 mL, 3.70 mmol), 1,2-dichlorobenzene (0.07 mL, 0.74 mmol), and Pd / C (60 mg, 30 wt%) at room temperature. The resulting solution was stirred at room temperature under a H atmosphere (1 atm, balloon) for 4 h with TLC monitoring. The reaction mixture was filtered through a Celite pad and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give 3-(tert-butyl) 1-ethyl 8-(4-(4-chlorophenoxy)-3,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (200 mg, 0.36 mmol, 97% yield) as a colorless semi-solid, which was used directly in the next step without further purification. MS (ESI): m / z 451 [M-Boc+H] + .

[0255] Step 18: Synthesis of ethyl 8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate [ka] To a stirred solution of 3-tert-butyl 1-ethyl 8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (300 mg, 0.62 mmol) in DCM (3.5 mL) at 0-5 °C, trifluoroacetic acid (0.47 mL, 6.20 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h with TLC monitoring. After evaporation of the volatiles, it was diluted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous NaHCO (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give ethyl 8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylate (246 mg, 0.53 mmol, 85% yield) as a colorless gum. This was used directly in the next step without further purification. MS (ESI): m / z 465.0 [M+H] + .

[0256] Similarly, the following intermediates were prepared following the same procedures as those described above: [Table 14]

[0257] Step 19: Synthesis of 1-ethyl 3-(2-methoxyethyl)8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate [ka] Following a procedure similar to that described in Step 3 of Method G of Preparative Example 2, 1-ethyl 3-(2-methoxyethyl) 8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1,3-dicarboxylate (300 mg, 0.53 mmol, quantitative) was obtained as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 567.0 [M+H] + .

[0258] Similarly, the following intermediates were prepared following the same procedures as those described above: [Table 15]

[0259] Step 20: Synthesis of 3-((2-methoxyethoxy)carbonyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid [ka] Following a procedure similar to that described for Step 9 of Preparative Example 2, 3-((2-methoxyethoxy)carbonyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (200 mg, 0.37 mmol, 70% yield) was obtained as a brown sticky gum, which was used in the next step without further purification. MS (ESI): m / z 539.0 [M+H] + .

[0260] Similarly, the following intermediates were prepared following the same procedures as those described above: [Table 16]

[0261] Step 21: Synthesis of 2-methoxyethyl 1-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a stirred solution of 3-((2-methoxyethoxy)carbonyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-1-carboxylic acid (200 mg, 0.37 mmol) in DCM (2 mL) was added BOP-Cl (233 mg, 0.92 mmol) and DIPEA (0.19 mL, 1.11 mmol), and the reaction was stirred at room temperature for 10 min. The reaction mixture was cooled to 0-10 °C, and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (56 mg, 0.48 mmol) was added. The resulting solution was allowed to warm slowly to room temperature over 30 min while being monitored by TLC and stirred for 16 h. The reaction was quenched with water (10 mL) at 0 °C and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (60-120 mesh, 10% MeOH in DCM) to give 2-methoxyethyl 1-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (160 mg, 0.25 mmol, 67% yield) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 636.0 [M−H] - .

[0262] Similarly, the following intermediates were prepared following the same procedures as those described above: [Table 17]

[0263] Step 22: Synthesis of 2-methoxyethyl 1-(hydroxycarbamoyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 33) [ka] To a stirred solution of 2-methoxyethyl 1-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (150 mg, 0.23 mmol) in MeOH (1.5 mL) was added p-TSA (40 mg, 0.23 mmol) at 0–5°C and stirred at room temperature for 16 h. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated to dryness, diluted with ethyl acetate (15 mL), and washed with saturated aqueous NaHCO3 (2 × 10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by RP preparative HPLC (Table 2, Method 3) and the relevant fractions were combined and lyophilized to give 2-methoxyethyl 1-(hydroxycarbamoyl)-8-(4-(4-(trifluoromethoxy)phenoxy)benzoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Example 33) (3.0 mg, 0.005 mmol, 2.3% yield) as a pale pink solid. MS (ESI): m / z 554.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6): δ 10.55 (brs, 1H), 8.57 (brs, 1H), 7.47 - 7.42 (m, 4H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.75 - 4.65 (m, 0.5H), 4.35 - 4.10 (m, 3.5H), 3.75 - 3.50 (m, 4H), 3.26 (s, 3H), 3.15 - 2.85 (m, 2H), 2.60 - 2.50 (m, 1H), 2.10 - 1.90 (m, 2H), 1.90 - 1.40 (m, 2H).

[0264] Similarly, the following compounds of formula (IV) were prepared according to the same procedure as above: [Table 18]

[0265] Biological Examples Matrix metalloproteinase inhibition assay The inhibitory activity of the compounds of the present invention was evaluated in a 96-well microplate format using MMP1, MMP2, MMP9, and MMP13 colorimetric assay kits and a TACE fluorometric assay kit from Enzo Life Sciences, Inc. The inhibitory effect of the compounds of the present invention on ADAM10 activity was evaluated in a 96-well microplate format using a fluorometric assay from AnaSpec, Inc.

[0266] The MMP-1 Colorimetric Drug Discovery Kit (product number BML-AK404) is a complete assay system designed to screen for inhibitors of matrix metalloproteinase 1 using a thiopeptide as a chromogenic substrate (Ac-PLG-[2-mercapto-4-methylpentanoyl]-LG-OC2H5). In this thiopeptide, the peptide bond at the MMP cleavage site is replaced with a thioester bond. Hydrolysis of this bond by MMPs generates a sulfhydryl group, which reacts with DTNB [5,5'-dithiobis(2-nitrobenzoic acid), Ellman's reagent] to form 2-nitro-5-thiobenzoic acid, which can be detected spectrophotometrically.

[0267] The MMP-2 Colorimetric Drug Discovery Kit (product number BML-AK408) is a complete assay system designed to screen for MMP-2 inhibitors using a thiopeptide as a chromogenic substrate (Ac-PLG-[2-mercapto-4-methylpentanoyl]-LG-OC2H5). In this thiopeptide, the peptide bond at the MMP cleavage site is replaced with a thioester bond. Hydrolysis of this bond by MMPs generates a sulfhydryl group, which reacts with DTNB [5,5'-dithiobis(2-nitrobenzoic acid), Ellman's reagent] to form 2-nitro-5-thiobenzoic acid, which can be detected spectrophotometrically.

[0268] The MMP-9 Colorimetric Drug Discovery Kit (product number BML-AK410) is a complete assay system designed to screen for inhibitors of matrix metalloproteinase 9 using a thiopeptide as a chromogenic substrate (Ac-PLG-[2-mercapto-4-methylpentanoyl]-LG-OC2H5). In this thiopeptide, the peptide bond at the MMP cleavage site is replaced with a thioester bond. Hydrolysis of this bond by MMPs generates a sulfhydryl group, which reacts with DTNB [5,5'-dithiobis(2-nitrobenzoic acid), Ellman's reagent] to form 2-nitro-5-thiobenzoic acid, which can be detected spectrophotometrically.

[0269] The MMP-13 Colorimetric Drug Discovery Kit (product number BML-AK412) is a complete assay system designed to screen for inhibitors of matrix metalloproteinase 13 using a thiopeptide as a chromogenic substrate (Ac-PLG-[2-mercapto-4-methylpentanoyl]-LG-OC2H5). In this thiopeptide, the peptide bond at the MMP cleavage site is replaced with a thioester bond. Hydrolysis of this bond by MMPs generates a sulfhydryl group, which reacts with DTNB [5,5'-dithiobis(2-nitrobenzoic acid), Ellman's reagent] to form 2-nitro-5-thiobenzoic acid, which can be detected spectrophotometrically.

[0270] The TACE Fluorometric Drug Discovery Kit (product number BML-AK310) is a complete assay system designed to screen ADAM17 (TACE) inhibitors using a quenched fluorogenic peptide: Mca-PLAQAV-Dpa-RSSSR-NH2. The fluorescence of Mca is quenched by the Dpa group until protease cleavage separates the two moieties, increasing the fluorescence of Mca.

[0271] The SensoLyte® 520 ADAM10 Activity Assay Kit (product number AS-72226) is a complete assay system designed to screen for ADAM10 inhibitors using a FRET-based peptide substrate containing the 5-FAM / QXL™ 520 fluorophore / quencher pair. The fluorescence of 5-FAM is quenched by QXL™ 520 and restored upon cleavage of the peptide by active ADAM10.

[0272] The inhibitory activity of the compounds of the present invention against MMP1, MMP2, MMP9 and MMP13 was tested according to the manufacturer's assay protocol and measured using Tecan Infinite® 200 Pro F Nano + Absorbance at 415 nm was monitored using a microplate reader.

[0273] The inhibitory activity of the compounds of the present invention against TACE was tested according to the manufacturer's assay protocol and was measured using Tecan Infinite® 200 Pro F Nano + Fluorescence was monitored using a microplate reader at excitation / emission wavelengths = 320 nm / 420 nm.

[0274] The inhibitory activity of the compounds of the present invention against ADAM10 was tested according to the manufacturer's assay protocol and measured using Tecan Infinite® 200 Pro F Nano + Fluorescence was monitored using a microplate reader at excitation / emission wavelengths = 495 nm / 520 nm.

[0275] Inhibition curves were plotted and IC values ​​were calculated using GraphPad Prism 9 for Windows (GraphPad Software, San Diego, CA, USA). 50 The normalized values ​​were analyzed by determining the values.

[0276] I C 50 The calculated values ​​were divided into the following classes: A:<50nM, B:50~1000nM, C:>1000~10,000nM, D:>10,000nM.

[0277] The classes of inhibitory activity of exemplary compounds according to the invention are presented in Table 17. [Table 19] TIFF2024537545000175.tif223159 TIFF2024537545000176.tif206159 TIFF2024537545000177.tif109159

[0278] Prospective Example of a HFpEF Clinical Trial The therapeutic efficacy of compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) (hereinafter referred to as development candidates) will be confirmed in a randomized, double-blind, parallel-group, active-controlled study in patients with heart failure with preserved ejection fraction (HFpEF) in accordance with the literature (Lancet 2012;380:1387-95).

[0279] The study will include participants aged 40 years or older with a history of heart failure with a left ventricular ejection fraction (LVEF) of 45% or greater and associated signs or symptoms (dyspnea on exertion, orthopnea, paroxysmal dyspnea, and peripheral edema). Patients will be required to: ● Plasma NT-proBNP >400 pg / mL at screening; At the time of randomization, patients were receiving diuretic therapy and had a systolic blood pressure of less than 140 mmHg or 160 mmHg or less, or lower if taking three or more blood pressure medications; ● Estimated glomerular filtration rate (eGFR) of 1.73m at screening 2 at least 30 mL / min per ● and plasma potassium concentration should not exceed 5.2 mmol / L.

[0280] Patients were excluded if they had a history of LVEF <45% at any time, isolated right heart failure due to pulmonary disease, dyspnea due to noncardiac causes (such as pulmonary disease, anemia, or severe obesity), primary valvular or myocardial disease, or coronary artery or cerebrovascular disease that would require revascularization within 3 months of screening or would likely require revascularization during the study.

[0281] Patients who meet the enrollment criteria will be randomly assigned (1:1) to treatment with either the investigational drug or valsartan using a central interactive voice response system. Treatments will be identical in appearance. Investigators and participants will be masked to treatment throughout the study.

[0282] The double-blind design will last for 36 weeks, including a 12-week main study period and a 24-week extension period.

[0283] The primary endpoint of the study is the change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), assessed at week 12. Secondary endpoints include changes in echocardiographic measures (left ventricular volume and ejection fraction, left atrial volume, measures of diastolic function) and blood pressure, as well as changes in New York Heart Association (NYHA) class, clinical composite assessment, and quality of life (Kansas City Cardiomyopathy Questionnaire; KCCQ).

[0284] NT-proBNP will be measured at screening, randomization, weeks 4, 12, and 36, or at the end-of-study or early termination visit. Efficacy assessment of NT-proBNP will be measured in a central laboratory using commercially available reagents (e.g., Elecsys NT-proBNP immunoassay, Roche Diagnostics, Indianapolis, IN, USA).

[0285] Echocardiography will be performed at screening, randomization, week 12, and week 36, or at the end-of-study or early termination visit. Measurements will be performed three times as recommended by the American Society of Echocardiography.

[0286] The clinical composite assessment was based on a composite of NYHA functional class, patient global assessment, and serious adverse clinical events. Patients were classified as improved if there was an improvement in NYHA functional class or patient global assessment (or both) and no serious cardiovascular adverse events at the endpoint visit. Patients were rated as worsened if there was a serious cardiac adverse event during double-blind treatment at the endpoint visit or if a worsening of NYHA class or patient global assessment was reported.

[0287] The trial size of 300 patients randomized into two groups ensures at least 80% power to detect a 25% reduction in the ratio of week 12 NT-proBNP to baseline NT-proBNP using a two-tailed t-test at an alpha level of 0.05 on the logarithm of this ratio between the development candidate and valsartan groups. This calculation assumes a common SD of 0.83 for the logarithmic scale of this ratio and a dropout rate of 10%. This sample size requires 132 patients to complete the study in each group.

Claims

1. Formula (II): 【Chemical 1】 A compound of the formula: 【Chemistry 2】 is phenyl, C ３ -C １０ Cycloalkyl ring, C ２ -C ９ heterocycloalkyl ring, or C ２ -C ９ is a heteroaryl ring, 【Chemistry 3】 is phenyl, C ３ -C １０ Cycloalkyl ring, C ２ -C ９ heterocycloalkyl ring, or C ２ -C ９ is a heteroaryl ring, X is -C(=O)- or -S(=O) ２ - and Y is a direct bond, —O—, or —CH ２ O-, -OCH ２ -, -CH ２ -, -C(=O)NH-, or -N(R ５ ) - and where nitrogen is for bonding to Y 【Chemistry 4】 When the above point of attachment is Y cannot be -O-; When Y is asymmetric, 【Chemistry 5】 are written in the order corresponding to R １ is hydrogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, —C １ -C ６ Alkylene-OR ６ , -C １ -C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ , or -S(=O) ２ N (R ６ ) ２ and Each R ３ and each R ４ are each a halogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ６ , -N(R ６ ) ２ , -CN, -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -NR ６ C(=O)R ７ , -NR ６ SO ２ R ７ , -SO ２ R ７ , and -SO ２ N (R ６ ) ２ are independently selected from R ５ is hydrogen or -C １ -C ６ is alkyl, Each R ６ is hydrogen, -C １ -C ６ Alkyl, —CF ３ , -C １ -C ６ Alkylene-OR ９ , -C １ -C ６ Alkylene-N(R ９ ) ２ , and -C １ -C ６ Alkylene-C ２ -C ９ heterocycloalkyl; Each R ７ is -C １ -C ６ Alkyl, —C １ -C ６ Alkylene-OR ９ , -C １ -C ６ Alkylene-N(R ９ ) ２ , -C ２ -C ９ heterocycloalkyl, —C ２ -C ９ Heteroaryl, —C １ -C ６ Alkylene-C ２ -C ９ heterocycloalkyl, and —C １ -C ６ Alkylene-C ２ -C ９ heteroaryl; Each R ９ is hydrogen and -C １ -C ６ alkyl; C ２ -C ９ Heterocycloalkyl and C ２ -C ９ Each occurrence of heteroaryl is -C １ -C ６ Alkyl or CF ３ are substituted appropriately with p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; The compound or a pharmaceutically acceptable salt or solvate thereof.

2. Formula (III): 【Chemistry 6】 10. The compound of claim 1 having the structure: 【Chemistry 7】 is phenyl, C ３ -C １０ Cycloalkyl ring, C ２ -C ９ heterocycloalkyl ring, or C ２ -C ９ is a heteroaryl ring, 【Chemistry 8】 is phenyl, C ３ -C １０ Cycloalkyl ring, C ２ -C ９ heterocycloalkyl ring, or C ２ -C ９ is a heteroaryl ring, Y is a direct bond, —O—, or —CH ２ O-, -OCH ２ -, -CH ２ -, -C(=O)NH-, or -N(R ５ ) - and where nitrogen is for bonding to Y 【Chemistry 9】 When the above point of attachment is Y cannot be -O-; When Y is asymmetric, 【Chemistry 10】 are written in the order corresponding to R １ is hydrogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, —C １ -C ６ Alkylene-OR ６ , -C １ -C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ , or -S(=O) ２ N (R ６ ) ２ and Each R ３ and each R ４ are each a halogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ６ , -N(R ６ ) ２ , -CN, -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -NR ６ C(=O)R ７ , -NR ６ SO ２ R ７ , -SO ２ R ７ , and -SO ２ N (R ６ ) ２ are independently selected from R ５ is hydrogen or -C １ -C ６ is alkyl, Each R ６ is hydrogen, -C １ -C ６ Alkyl, —CF ３ , -C １ -C ６ Alkylene-OR ９ , -C １ -C ６ Alkylene-N(R ９ ) ２ , and -C １ -C ６ Alkylene-C ２ -C ９ heterocycloalkyl; Each R ７ is -C １ -C ６ Alkyl, —C １ -C ６ Alkylene-OR ９ , -C １ -C ６ Alkylene-N(R ９ ) ２ , -C ２ -C ９ heterocycloalkyl, —C ２ -C ９ Heteroaryl, —C １ -C ６ Alkylene-C ２ -C ９ heterocycloalkyl, and —C １ -C ６ Alkylene-C ２ -C ９ heteroaryl; Each R ９ is hydrogen and -C １ -C ６ alkyl; C ２ -C ９ Heterocycloalkyl and C ２ -C ９ Each occurrence of heteroaryl is -C １ -C ６ Alkyl or CF ３ are substituted appropriately with p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; The compound or a pharmaceutically acceptable salt or solvate thereof.

3. Each R ３ is a halogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ６ , -N(R ６ ) ２ , -CN, -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -SO ２ R ７ , and -SO ２ N (R ６ ) ２ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

4. Each R ３ is a halogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ６ , and —C(═O)OR ６ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

5. Each R ３ is a halogen and -C １ -C ６ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein: R is independently selected from alkyl;

6. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

7. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

8. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

9. Each R ４ is a halogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ６ , -N(R ６ ) ２ , -CN, -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -SO ２ R ７ , and -SO ２ N (R ６ ) ２ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

10. Each R ４ is a halogen, -C １ -C ６ Alkyl, —C １ -C ６ Haloalkyl, -OR ６ , and —C(═O)OR ６ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, independently selected from:

11. Each R ４ is a halogen and -C １ -C ６ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein: R is independently selected from alkyl;

12. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

13. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

14. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

15. R １ is -C(=O)OR ６ 3. The compound according to any one of claims 1 to 2, wherein:

16. R ６ Ha-C １ -C ６ Alkyl, —C １ -C ６ Alkylene-OR ９ , or -C １ -C ６ Alkylene-N(R ９ ) ２ 3. The compound according to any one of claims 1 to 2, wherein:

17. R ６ Ha-C １ -C ６ Alkylene-OR ９ 3. The compound according to any one of claims 1 to 2, wherein:

18. R ９ Ha-C １ -C ６ The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

19. R ６ Ha-C １ -C ６ The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

20. The following compounds: 【Table 1】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt or solvate thereof.

21. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder and a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof.

22. in a mammal in need thereof Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, abnormal myocardial contractility, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-associated myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological remodeling of the myocardium, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, and right ventricular hypertrophy. Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, Polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, and chronic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schoenlein purpura, and post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced kidney injury, tubular injury after sepsis, acute ischemic kidney injury, contrast-induced kidney injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, tubulointerstitial fibrosis, Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia and reperfusion injury, viral hepatitis, drug-induced liver injury, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, acute liver failure, biliary atresia, and pigmented scleroderma 10. A method of treating a disease, disorder or condition selected from the group consisting of:

23. 23. The method of claim 22, wherein the disease, disorder, or condition being treated is heart failure.

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