Diazabicyclo octane 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 diseases, disorders, or conditions selected from cardiovascular disorders, pulmonary disorders, renal disorders, liver disorders, and pigmented scleroderma. (Formula I) # imgabs0 #

Description

[0001] Cross-references to related applications

[0002] This application claims priority to Polish Patent Application No. P.440789, filed March 29, 2022, and U.S. Provisional Patent Application Serial No. 63 / 324,713, filed March 29, 2022, the contents of which are incorporated herein by reference. Background Technology

[0003] Cardiovascular disease (CVD) is a leading cause of death and morbidity worldwide (The Global Burden of Disease: 2004 Update, in World Health Organization; 2004). Despite improvements resulting from treatment of risk factors (Circulation. 2017; 135(10):e146.), nearly half of the U.S. population will have CVD by 2030.

[0004] Cardiac injury, valvular heart disease (e.g., aortic stenosis), vascular hypertension, and aging are major factors contributing to pressure overload of the heart's pumping function. Left ventricular hypertrophy is a normal cardiac response to such pressure overload. Hypertrophy enables cardiomyocytes to generate the additional force required to compensate for the increased pressure load and maintain necessary pumping function. At least 10% of the population in industrialized societies suffers from severe hypertension, which not only leads 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, leading to diastolic dysfunction and concentric remodeling of the left ventricle, but in many cases systolic function remains unaffected until late life (2). However, initially appropriate and compensatory left ventricular remodeling can progress to a pathophysiological stage as ischemic and other damaged cardiomyocytes degenerate, fibrosis begins and develops, and the chambers dilate, leading to a progressive decline in cardiac pumping function (3-9).

[0005] The adaptive remodeling processes leading to heart failure can be conceptually divided into hypertrophic changes in cardiomyocytes and alterations in the normal patterns of the extracellular matrix (ECM) network. Changes in both systolic and diastolic function can be attributed to these two types (10). The cardiac ECM provides structural support to the myocardium and produces cytokines, growth factors, and regulatory proteins that regulate myocardial function (11). The emergence of adverse ECM remodeling represents a significant etiological milestone in the progression of frank heart failure. Normal basement membrane fibronectin, laminin, and collagen bind cardiomyocytes to the interstitial ECM and facilitate transmembrane signaling via integrin receptors (12), where collagen fibers structurally organize myocytes and myofibrils to allow for optimal force generation and transmission. However, when collagen fibrils and struts are lost, cardiomyocyte contractile slippage, chamber dilation, and worsening of systolic dysfunction can occur (13). Similarly, as the disease is promoted by exacerbating the aforementioned factors, fibrillary collagen accumulates in the left ventricular myocardium, leading to increased myocardial stiffness (2,14,15).

[0006] The extracellular matrix of the heart, like other structural components of the skeleton and body, undergoes a continuous process of synthesis, degradation, and resynthesis to maintain proper structure and strength. While this healthy remodeling of the cardiac ECM requires healthy proteolysis, proteolysis is also involved in undesirable remodeling as part of disease processes, including progressive heart failure. Notably, increased activation and expression of matrix metalloproteinases (MMPs) (zinc-dependent proteases) are associated with heart failure and therefore with the remodeling process of progressive pump failure (16–18). The mammalian MMP superfamily comprises 25 members, including matrix lysins, gelatinases, collagenases, matrix-dissolving factors, membrane-type MMPs, and others (19). Their various functions are endogenously regulated by tissue inhibitors of metalloproteinases (TIMPs: TIMP1–4), which typically bind nonvalently with low selectivity to form a 1:1 complex with both active and pro-form MMPs. Each cardiac ECM protein acts as a substrate for at least one cardiac MMP (20), which also inactivates and activates ECM-derived cytokines and growth factors (21,22).

[0007] The relationship between MMPs and pathological myocardial remodeling leading to and exacerbating heart failure has been characterized in both animal disease models and in human plasma and left ventricle (8, 16-18, 23-46). While most substrates of MMPs are available from the extracellular space, more recent studies have reported intracellular roles for MMPs in calcium processing, which is important for regulating excitation-contraction coupling and direct effects on sarcomere function (47-53). In humans, elevated MMP2 and MMP9 levels have been strongly associated with diastolic dysfunction or heart failure in numerous studies (54-61).

[0008] Through both genetic and pharmacological interventions, evidence has been generated that MMPs are not only associated with pathological left ventricular and global cardiac remodeling leading to reduced pump function and disease, but are also the cause of pathological left ventricular and global cardiac remodeling leading to reduced pump function and disease. In animal models, non-selective pharmacological inhibition of MMPs has been shown to significantly reduce pathological remodeling associated with multiple disease triggers (28, 40, 62-69). Data show that selective MMP inhibition, particularly sparing MMP1, provides a benefit for existing cardiac remodeling for MMP-1, MMP-2, MMP-9, TIMP 1, and TIMP-3 (70-74). The strongest evidence leads to the therapeutic hypothesis that selective inhibition of at least MMP-2 and MMP-9 promotes less adverse cardiac function following multiple interventions leading to cardiac pump failure (59, 75, 76).

[0009] MMP9 mice are protected from diastolic dysfunction and fibrosis accumulation (77) and post-infarction remodeling (59)(75). Both MMP2 and MMP9 expression have been shown to be elevated in both spontaneously hypertensive (66) and Dahl salt-sensitive hypertensive rats (43) during stress overload hypertrophy. Most convincingly, both transgenic MMP2-overexpressing and transgenic MMP9-overexpressing mice developed pathological fibrotic myocardium (78, 79), while MMP2 and MMP9 gene-deficient mice were structurally and functionally protected in disease models of heart failure, a finding well summarized by prototypical drug inhibitors that block the action of MMP2 and / or MMP9 (80, 81).

[0010] TACE / ADAM17 (tumor necrosis factor-α convertase; integrin and metalloproteinase 17) is a soluble or membrane-bound metalloproteinase that primarily activates proTNF-α, while also targeting proteins such as fractal chemokines, amyloid precursor protein, and CD40. ADAM17 / TACE is involved in cancer, vascular disorders, and inflammatory diseases (e.g., rheumatoid arthritis and focal ischemic injury). The catalytic domain of ADAM17 / TACE can cleave proTNF-α and is used for inhibitor screening.

[0011] References

[0012] 1. Vakili BA, Okin PM, Devereux RB. Prognostic implications of leftventricular hypertrophy. Am Heart J. 2001;141(3):334-41. Epub 2001 / 03 / 07.doi:10.1067 / mhj.2001.113218. PubMed PMID: 11231428.

[0013] 2.Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders incardiovascular 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.PubMedPMID:12538439.

[0014] 3. Weber KT. Fibrosis and hypertensive heart disease. Current opinion incardiology. 2000; 15(4): 264-72.

[0015] 4. Díez J, López B, González A, Querejeta R. Clinical aspects of hypertensive myocardial fibrosis. Current opinion in cardiology. 2001;16(6):328-35.

[0016] 5.Jessup M,Greenberg B,Mancini D,Cappola T,Pauly DF,Jaski B,Yaroshinsky A,Zsebo KM,Dittrich H,Hajjar RJ.Calcium Upregulation byPercutaneous Administration of Gene Therapy in Cardiac Disease(CUPID):a phase2trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase inpatients with advanced heart failure.Circulation.2011;124(3):304-13.Epub2011 / 06 / 29.doi:10.1161 / circulationaha.111.022889.PubMed PMID:21709064;PMCID:PMC5843948.

[0017] 6.Jugdutt BI.Remodeling of the myocardium and potential targets inthe collagen degradation and synthesis pathways.Current Drug Targets-Cardiovascular&Hematological Disorders.2003;3(1):1-30.

[0018] 7.Katz AM.Pathophysiology of heart failure:identifying targets forpharmacotherapy.Medical Clinics.2003;87(2):303-16.

[0019] 8.Janicki JS,Brower GL,Gardner JD,Chancey AL,Stewart JA.The dynamicinteraction between matrix metalloproteinase activity and adverse myocardialremodeling.Heart failure reviews.2004;9(1):33-42.

[0020] 9.Jessup M,Brozena S.Heart failure.The New England journal ofmedicine.2003;348(20):2007-18.Epub 2003 / 05 / 16.doi:10.1056 / NEJMra021498.PubMedPMID:12748317.

[0021] 10.Redfield MM,Jacobsen SJ,Burnett JC,Jr.,Mahoney DW,Bailey KR,Rodeheffer RJ.Burden of systolic and diastolic ventricular dysfunction in thecommunity: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.

[0022] 11.Jacob MP.Extracellular matrix remodeling and matrixmetalloproteinases in the vascular wall during aging and in pathologicalconditions.Biomedicine&pharmacotherapy.2003;57(5-6):195-202.

[0023] 12.Ross RS.The extracellular connections:the role of integrins inmyocardial remodeling.Journal of cardiac failure.2002;8(6):S326-S31.

[0024] 13.Janicki JS,Brower GL.The role of myocardial fibrillar collagen inventficular remodeling and function.Journal of cardiac failure.2002;8(6):S319-S25.

[0025] 14.Ferrari AU,Radaelli A,Centola M.Invited review:aging and thecardiovascular 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.

[0026] 15.Martos R,Baugh J,Ledwidge M,O′Loughlin C,Conlon C,Patle A,DonnellySC,McDonald K.Diastolic heart failure:evidence of increased myocardialcollagen turnover linked to diastolic dysfunction.Circulation.2007;115(7):888-95.Epub 2007 / 02 / 07.doi:10.1161 / circulationaha.106.638569.PubMed PMID:17283265.

[0027] 16.Spinale FG.Matrix metalloproteinases:regulation and dysregulationin the failing heart.Circulation research.2002;90(5):520-30.

[0028] 17.DeLeon-Pennell KY,Meschiari CA,Jung M,Lindsey ML.Matrixmetalloproteinases in myocardial infarction and heart failure.Progress inmolecular biology and translational science.2017;147:75-100.

[0029] 18.Spinale FG.Myocardial matrix remodeling and the matrixmetalloproteinases:influence on cardiac form and function.Physiologicalreviews.2007;87(4):1285-342.

[0030] 19.Iyer RP,Patterson NL,Fields GB,Lindsey ML.The history of matrixmetalloproteinases:milestones,myths,and misperceptions.American Journal ofPhysiology-Heart and Circulatory Physiology.2012;303(8):H919-H30.

[0031] 20.Brauer PR.MMPs--role in cardiovascular development anddisease.Frontiers in bioscience:a journal and virtual library.2006;11:447-78.

[0032] 21.Sternlicht MD,Werb Z.How matrix metalloproteinases regulate cellbehavior.Annual review of cell and developmental biology.2001;17:463-516.Epub2001 / 11 / 01.doi:10.1146 / annurev.cellbio.17.1.463.PubMed PMID:11687497;PMCID:PMC2792593.

[0033] 22.Van den Steen PE,Dubois B,Nelissen I,Rudd PM,Dwek RA,OpdenakkerG.Biochemistry and molecular biology of gelatinase B or matrixmetalloproteinase-9(MMP-9).Critical reviews in biochemistry and molecularbiology.2002;37(6):375-536.

[0034] 23.Dixon JA,Spinale FG.Myocardial remodeling:cellular andextracellular events and targets.Annual review of physiology.2011;73:47-68.

[0035] 24.Spinale FG,Villarreal F.Targeting matrix metalloproteinases inheart disease:lessons from endogenous inhibitors.Biochemicalpharmacology.2014;90(1):7-15.

[0036] 25.Spinale FG,Zile MR.Integrating the myocardial matrix into heartfailure recognition and management.Circulation research.2013;113(6):725-38.

[0037] 26.Cleutjens JP,Creemers EE.Integration of concepts:cardiacextracellular matrix remodeling after myocardial infarction.Journal ofcardiac failure.2002;8(6):S344-S8.

[0038] 27.Iwanaga Y,Aoyama T,Kihara Y,Onozawa Y,Yoneda T,SasayamaS.Excessive activation of matrix metalloproteinases coincides with leftventricular remodeling during transition from hypertrophy to heart failure inhypertensive rats.Journal of the American College of Cardiology.2002;39(8):1384-91.

[0039] 28.Li YY,McTiernan CF,Feldman AM.Interplay of matrixmetalloproteinases,tissue inhibitors of metalloproteinases and theirregulators in cardiac matrix remodeling.Cardiovascular research.2000;46(2):214-24.

[0040] 29.Nagatomo Y,Carabello BA,Coker ML,McDermott PJ,Nemoto S,Hamawaki M,Spinale FG.Differential effects of pressure or volume overload on myocardialMMP levels and inhibitory control.American Journal of Physiology-Heart andCirculatory Physiology.2000;278(1):H151-H61.

[0041] 30.Peterson JT,Li H,Dillon L,Bryant JW.Evolution of matrixmetalloprotease and tissue inhibitor expression during heart failureprogression in the infarcted rat.Cardiovascular research.2000;46(2):307-15.

[0042] 31.Reinhardt D,Sigusch H,Henβe J,Tyagi S, R,Figulla H.Cardiacremodelling in end stage heart failure:upregulation of matrixmetalloproteinase(MMP)irrespective of the underlying disease,and evidence fora direct inhibitory effect of ACE inhibitors on MMP.Heart.2002;88(5):525-30.

[0043] 32.Shastry S,Hayden MR,Lucchesi PA,Tyagi SC.Matrix metalloproteinasein left ventricular remodeling and heart failure.Current cardiologyreports.2003;5(3):200-4.

[0044] 33.Spinale FG,Coker ML,Heung LJ,Bond BR,Gunasinghe HR,Etoh T,GoldbergAT,Zellner JL,Crumbley AJ.A matrix metalloproteinase induction / activationsystem exists in the human left ventricular myocardium and is upregulated inheart failure.Circulation.2000;102(16):1944-9.

[0045] 34.Spinale FG,Coker ML,Thomas CV,Walker JD,Mukherjee R,Hebbar L.Time-dependent changes in matrix metalloproteinase activity and expression duringthe progression of congestive heart failure:relation to ventricular andmyocyte function.Circulation research.1998;82(4):482-95.

[0046] 35.Thomas CV,Coker ML,Zellner JL,Handy JR,Crumbley III AJ,SpinaleFG.Increased matrix metalloproteinase activity and selective upregulation inLV myocardium from patients with end-stage dilatedcardiomyopathy.Circulation.1998;97(17):1708-15.

[0047] 36.Chapman RE,Spinale FG.Extracellular protease activation andunraveling of the myocardial interstitium:critical steps toward clinicalapplications.American Journal of Physiology-Heart and CirculatoryPhysiology.2004;286(1):H1-H10.

[0048] 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 humanheart failure:a possible regulatory role for TIMP-3.American Journal ofPhysiology-Heart and Circulatory Physiology.2003;284(2):H626-H34.

[0049] 38.Lindsey ML.MMP induction and inhibition in myocardialinfarction.Heart failure reviews.2004;9(1):7-19.

[0050] 39.Lindsey ML,Mann DL,Entman ML,Spinale FG.Extracellular matrixremodeling following myocardial injury.Annals of medicine.2003;35(5):316-26.

[0051] 40.Miura S,Ohno I,Suzuki J,Suzuki K,Okada S,Okuyama A,Nawata J,IkedaJ,Shirato K.Inhibition of matrix metalloproteinases prevents cardiachypertrophy induced byβ-adrenergic stimulation in rats.Journal ofcardiovascular pharmacology.2003;42(2):174-81.

[0052] 41.Nishikawa N,Yamamoto K,Sakata Y,Mano T,Yoshida J,Miwa T,Takeda H,Hori M,Masuyama T.Differential activation of matrix metalloproteinases inheart failure with and without ventricular dilatation.Cardiovascularresearch.2003;57(3):766-74.

[0053] 42.Pauschinger M,Chandrasekharan K,Schultheiss H-P.Myocardialremodeling in viral heart disease:possible interactions between inflammatorymediators and MMP-TIMP system.Heart failure reviews.2004;9(1):21-31.

[0054] 43.Sakata Y,Yamamoto K,Mano T,Nishikawa N,Yoshida J,Hori M,Miwa T,Masuyama T.Activation of matrix metalloproteinases precedes left ventricularremodeling in hypertensive heart failure rats:its inhibition as a primaryeffect of angiotensin-converting enzyme inhibitor.Circulation.2004;109(17):2143-9.

[0055] 44.Sierevogel M,Pasterkamp G,De Kleijn D,Strauss B.Matrixmetalloproteinases:a therapeutic target in cardiovascular disease.Currentpharmaceutical 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 andinflammatory response associated with cardiac rupture after myocardialinfarction in mice.Life sciences.2004;74(12):1561-72.

[0056] 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-specificinduction of matrix metalloproteinases in post-myocardial infarctionremodeling.Circulation.2003;107(22):2857-63.

[0057] 47.Ali MA,Cho WJ,Hudson B,Kassiri Z,Granzier H,Schulz R.Titin is atarget 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.PubMedPMID:21041693;PMCID:PMC3057897.

[0058] 48.Ali MA,Fan X,Schulz R.Cardiac sarcomeric proteins:novelintracellular targets of matrix metalloproteinase-2 in heart disease.Trendsin cardiovascular medicine.2011;21(4):112-8.Epub 2012 / 06 / 12.doi:10.1016 / j.tcm.2012.03.008.PubMed PMID:22681966.

[0059] 49.Fan X,Hughes BG,Ali MA,Chan BY,Launier K,Schulz R.Matrixmetalloproteinase-2in oncostatin M-induced sarcomere degeneration incardiomyocytes.American journal of physiology Heartand circulatoryphysiology.2016;311(1):H183-9.Epub 2016 / 05 / 21.doi:10.1152 / ajpheart.00229.2016.PubMed PMID:27199120.

[0060] 50.Lovett DH,Chu C,Wang G,Ratcliffe MB,Baker AJ.A N-terminaltruncated intracellular iso form of matrix metalloproteinase-2 impairscontractility of mouse myocardium.Front Physiol.2014;5:363.Epub 2014 / 10 / 14.doi:10.3389 / fphys.2014.00363.PubMed PMID:25309453;PMCID:PMC4174733.

[0061] 51.Rouet-Benzineb P,B uhler JM,Dreyfus P,Delcourt A,Dorent R,PerennecJ,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 ofheart failure.1999;1(4):337-52.Epub 2000 / 08 / 11.doi:10.1016 / s1388-9842(99)00048-3.PubMed PMID:10937947.

[0062] 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 rathearts subjected to ischemia-reperfusion injury:a new intracellular targetfor matrix metalloproteinase-2.Circulation.2005;112(4):544-52.Epub 2005 / 07 / 20.doi:10.1161 / circulationaha.104.531616.PubMed PMID:16027249.

[0063] 53.Wang GY,Bergman MR,Nguyen AP,Turcato S,Swigart PM,Rodrigo MC,Simpson PC,Karliner JS,Lovett DH,Baker AJ.Cardiac transgenic matrixmetalloproteinase-2 expression directly induces impairedcontractility.Cardiovasc Res.2006;69(3):688-96.Epub 2005 / 09 / 27.doi:10.1016 / j.cardiores.2005.08.023.PubMed PMID:16183043.

[0064] 54.Chancey AL,Brower GL,Peterson JT,Janicki JS.Effects of matrixmetalloproteinase inhibition on ventricular remodeling due to volumeoverload.Circulation.2002;105(16):1983-8.

[0065] 55.Cox MJ,Hawkins UA,Hoit BD,Tyagi SC.Attenuation of oxidative stressand remodeling by cardiac inhibitor of metalloproteinase proteintransfer.Circulation.2004;109(17):2123-8.

[0066] 56.McMurray JJ,Packer M,Desai AS,Gong J,Lefkowitz MP,Rizkala AR,Rouleau JL,Shi VC,Solomon SD,Swedberg K,Zile MR.Angiotensin-neprilysininhibition versus enalapril in heart failure.The New England journal ofmedicine.2014;371(11):993-1004.Epub 2014 / 09 / 02.doi:10.1056 / NEJMoa1409077.PubMed PMID:25176015.

[0067] 57.Mukherjee R,Brinsa TA,Dowdy KB,Scott AA,Baskin JM,Deschamps AM,Lowry AS,Escobar GP,Lucas DG,Yarbrough WM.Myocardial infarct expansion andmatrix metalloproteinase inhibition.Circulation.2003;107(4):618-25.

[0068] 58.Peterson JT,Hallak H,Johnson L,Li H,O’Brien PM,Sliskovic DR,BocanTM,Coker ML,Etoh T,Spinale FG.Matrix metalloproteinase inhibition attenuatesleft ventricular remodeling and dysfunction in a rat model of progressiveheart failure.Circulation.2001;103(18):2303-9.

[0069] 59.Rohde LE,Ducharme A,Arroyo LH,Aikawa M,Sukhova GH,Lopez-Anaya A,McClure KF,Mitchell PG,Libby P,Lee RT.Matrix metalloproteinase inhibitionattenuates early left ventricular enlargement after experimental myocardialinfarction in mice.Circulation.1999;99(23):3063-70.

[0070] 60.Spinale FG,Coker ML,Bond BR,Zellner JL.Myocardial matrixdegradation and metalloproteinase activation in the failing heart:a potentialtherapeutic target.Cardiovascular research.2000;46(2):225-38.

[0071] 61.Spinale FG,Coker ML,Krombach SR,Mukherjee R,Hallak H,Houck WV,Clair MJ,Kribbs SB,Johnson LL,Peterson JT.Matrix metalloproteinase inhibitionduring the development of congestive heart failure:effects on leftventricular dimensions and function.Circulation research.1999;85(4):364-76.

[0072] 62.King MK,Coker ML,Goldberg A,McElmurray III JH,Gunasinghe HR,Mukherjee R,Zile MR,O’Neill TP,Spinale FG.Selective matrix metalloproteinaseinhibition with developing heart failure:effects on left ventricular functionand structure.Circulation research.2003;92(2):177-85.

[0073] 63.Lindsey ML,Gannon J,Aikawa M,Schoen FJ,Rabkin E,Lopresti-Morrow L,Crawford J,Black S,Libby P,Mitchell PG.Selective matrix metalloproteinaseinhibition reduces left ventricular remodeling but does not inhibitangiogenesis after myocardial infarction.Circulation.2002;105(6):753-8.

[0074] 64.Villarreal FJ,Griffin M,Omens J,Dillmann W,Nguyen J,Covell J.Earlyshort-term treatment with doxycycline modulates postinfarction leftventricular remodeling.Circulation.2003;108(12):1487-92.

[0075] 65.Yarbrough WM,Mukherjee R,Escobar GP,Mingoia JT,Sample JA,HendrickJW,Dowdy KB,McLean JE,Lowry AS,O’Neill TP.Selective targeting and timing ofmatrix metalloproteinase inhibition in post-myocardial infarctionremodeling.Circulation.2003;108(14):1753-9.

[0076] 66.Kim HE,Dala1 SS,Young E,Legato MJ,Weisfeldt ML,D’ArmientoJ.Disruption of the myocardial extracellular matrix leads to cardiacdysfunction.The Journal of clinical investigation.2000;106(7):857-66.

[0077] 67.Ducharme A,Frantz S,Aikawa M,Rabkin E,Lindsey M,Rohde LE,SchoenFJ,Kelly RA,Werb Z,Libby P.Targeted deletion of matrix metalloproteinase-9attenuates left ventricular enlargement and collagen accumulation afterexperimental myocardial infarction.The Journal of clinicalinvestigation.2000;106(1):55-62.

[0078] 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 attenuatesearly LV rupture and late remodeling after experimental myocardialinfarction.American Journal of Physiology-Heart and CirculatoryPhysiology.2003;285(3):H1229-H35.

[0079] 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 LVremodeling and dysfunction after acute pressure overload in mice.The Americanjournal of pathology.2005;166(1):15-25.

[0080] 70.Chiao YA,Ramirez TA,Zamilpa R,Okoronkwo SM,Dai Q,Zhang J,Jin Y-F,Lindsey ML.Matrix metalloproteinase-9 deletion attenuates myocardial fibrosisand diastolic dysfunction in ageing mice.Cardiovascular research.2012;96(3):444-55.

[0081] 71.Toba H,Cannon PL,Yabluchanskiy A,Iyer RP,D′Armiento J,LindseyML.Transgenic overexpression of macrophage matrix metalloproteinase-9exacerbates age-related cardiac hypertrophy,vessel rarefaction,inflammation,and fibrosis.American journal of physiology Heart and circulatoryphysiology.2017;312(3):H375-h83.Epub 2016 / 12 / 25.doi:10.1152 / ajpheart.00633.2016.PubMed PMID:28011588;PMCID:PMC5402013.

[0082] 72.Bergman MR,Teerlink JR,Mahimkar R,Li L, Zhu BQ,Nguyen A,Dahi S,Karliner JS,Lovett DH.Cardiac matrix metalloproteinase-2 expressionindependently induces marked ventricular remodeling and systolicdysfunction.American journal of physiology Heart and circulatoryphysiology.2007;292(4):H 1847-60.Epub 2006 / 12 / 13.doi:10.1152 / ajpheart.00434.2006.PubMed PMID:17158653.

[0083] 73.Matsusaka H,Ide T,Matsushima S,Ikeuchi M,Kubota T,Sunagawa K,Kinugawa S,Tsutsui H.Targeted deletion of matrix metalloproteinase 2ameliorates myocardial remodeling in mice with chronic pressureoverload.Hypertension(Dallas,Tex:1979).2006;47(4):711-7.Epub2006 / 03 / 01.doi:10.1161 / 01.hyp.0000208840.30778.00.PubMed PMID:16505197.

[0084] 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 LVremodeling and dysfunction after acute pressure overload in mice.Am JPathol.2005;166(1):15-25.Epub2005 / 01 / 06.doi:10.1016 / s0002-9440(10)62228-6.PubMed PMID:15631996;PMCID:PMC 1602291.

[0085] 75.Hayashidani,S.,et al.(2003)."Targeted deletion of MMP-2 attenuatesearly LV rupture and late remodeling after experimental myocardialinfarction."American Journal of Physiology-Heart and Circulatory Physiology285(3):H 1229-H 1235.

[0086] 76 Heymans,S.,et al.(2005)."Loss or inhibition of uPA or MMP-9attenuates LV remodeling and dysfunction after acute pressure overload inmice."The American journal of pathology 166(1):15-25.

[0087] 77.Matrix metalloproteinase-9 deletion attenuates myocardial fibrosisand 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.

[0088] 78.Transgenic overexpression of macrophage matrix metalloproteinase-9exacerbates age-related cardiac hypertrophy,vessel rarefaction,inflammation,and fibrosis.Toba H,Cannon PL,Yabluchanskiy A,Iyer RP,D'Armiento J,LindseyML.Am J Physiol Heart Circ Physiol.2017Mar 1;312(3):H375-H383.doi:10.1152 / ajpheart.00633.2016.

[0089] 79.Cardiac matrix metalloproteinase-2expression independently inducesmarked ventricular remodeling and systolic dysfunction.Bergman MR,TeerlinkJR,Mahimkar R,Li L,Zhu BQ,Nguyen A,Dahi S,Karliner JS,Lovett DH.Am J PhysiolHeart Circ Physiol.2007Apr;292(4):H 1847-60.doi:10.1152 / ajpheart.00434.2006

[0090] 80.Targeted deletion of matrix metalloproteinase 2amelioratesmyocardial remodeling in mice with chronic pressure overload.Matsusaka H,IdeT,Matsushima S,Ikeuchi M,Kubota T,Sunagawa K,Kinugawa S,TsutsuiH.Hypertension.2006Apr;47(4):711-7.doi:10.1161 / 01.HYP.0000208840.30778.00.Epub 2006Feb 27.PMID:16505197

[0091] 81.Loss or inhibition of uPA or MMP-9attenuates LV remodeling anddysfunction after acute pressure overload in mice.Heymans S,Lupu F,TerclaversS,Vanwetswinkel B,Herbert JM,Baker A,Collen D,Carmeliet P,Moons L.Am JPathol.2005Jan;166(1):15-25.doi:10.1016 / S0002-9440(10)62228-6.

[0092] There is a strong need to develop therapeutic treatment options specifically targeting the underlying causes of heart failure (HF), which is impaired cardiac pumping function. However, current standard of care for HF and other CVDs does not correct the underlying defects leading to this loss of pumping function, which is the loss of functional cardiomyocytes or myocardial cells. Instead, existing pharmacological treatments target non-cardiac peripheral features of the cardiovascular system, including reducing preload and afterload by targeting blood pressure, lowering blood volume (aldosterone antagonists, diuretics), or reducing lipids that contribute to vascular disease.

[0093] Selective inhibition of matrix metalloproteinases provides a valuable therapeutic option for treating a variety of disorders associated with abnormal matrix metalloproteinase activity, including but not limited to cardiovascular disorders, pulmonary disorders, renal disorders, hepatic disorders, and scleroderma pigmentosum.

[0094] The aim is to study cardiovascular disorders, particularly including cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, impaired cardiac contractility, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-related myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation-induced myocardial fibrosis, chemotherapeutic cardiomyopathy, vessel rarefaction, aortic valve sclerosis, calcific aortic stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, and right ventricular hypertrophy.

[0095] The lung disorders discussed include idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), and emphysema.

[0096] Suitable kidney disorders include polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, chronic allogeneic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, HIV-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schoenlein purpura, post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced kidney injury, post-septic tubular injury, acute ischemic kidney injury, contrast agent-induced kidney injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, and tubulointerstitial fibrosis.

[0097] The target liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, steatosis, 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

[0098] This disclosure provides, for example, compounds and compositions that are MMP inhibitors, their use as pharmaceutical agents, methods for their preparation, and pharmaceutical compositions comprising the disclosed compounds as at least one active ingredient. This disclosure also provides the use of the disclosed compounds as pharmaceuticals, and / or the use of the disclosed compounds in the preparation of pharmaceuticals for MMP inhibition in warm-blooded animals (e.g., humans) for the treatment of heart failure and other CVDs.

[0099] In one aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof:

[0100]

[0101] in:

[0102] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0103] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0104] X is -C(=O)- or -S(=O)2-;

[0105] Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R) 5 )-;

[0106] Where Y, if asymmetrical, corresponds to Write in the correct order;

[0107] Where nitrogen is If the connection point is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH-, or -N(R). 5 )-;

[0108] R 1 It is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 -C1-C6 alkylene-N(R) 6 )2、-C1-C6 alkylene-C(=O)-N(R 6 2. -C1-C6 alkylene-C(=O)-C4-C5 heterocyclic alkyl, -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;

[0109] R 2 It is -C(=O)OH, -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,

[0110] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0111] R 5 It is hydrogen or -C1-C6 alkyl;

[0112] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0113] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0114] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0115] R 8 Selected from hydrogen, -C1-C6 alkyl, and -N(H)C1-C6 alkyl;

[0116] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0117] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they are optionally substituted with a -C1-C6 alkyl group or a -C1-C6 haloalkyl group or a halogen.

[0118] n is 0, 1, or 2;

[0119] p is 0, 1, 2, or 3; and

[0120] q can be 0, 1, 2 or 3.

[0121] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(=O)2-. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(=O)-.

[0122] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (Ia):

[0123]

[0124] in:

[0125] R 1 R 2 R 3 R 4 n, p and q are as defined in equation (I).

[0126] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (Ib):

[0127]

[0128] in:

[0129] R 1 R 2 R 3 R 4 n, p and q are as defined in equation (I).

[0130] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (Ic):

[0131]

[0132] in:

[0133] It is a C2-C9 heterocyclic alkyl group; and R 1 R 2 R 3 R 4 Y, n, p and q are defined as in equation (I).

[0134] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (II):

[0135]

[0136] in:

[0137] R 1 R 3 R 4 X, Y, p and q are defined as in equation (I).

[0138] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (III):

[0139]

[0140] in:

[0141] R 1 R 3 R 4 Y, p, and q are defined as in equation (I).

[0142] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (IIIa):

[0143]

[0144] in:

[0145] R 1 R 3 p is defined as in equation (I).

[0146] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (IIIb):

[0147]

[0148] in:

[0149] R 1 R 3 R 4 p and q are as defined in equation (I).

[0150] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (IIIc):

[0151]

[0152] in:

[0153] R 1 R 3 p is defined as in equation (I).

[0154] In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 -SO2N(R) 6 )2 and optionally halogen-substituted phenyl groups. In some embodiments, the invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein each R 3 The compounds are independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or pharmaceutically acceptable salts or solvates 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 (IIIa) or (IIIb) or (IIIc), or pharmaceutically acceptable salts or solvates 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 (IIIa) or (IIIb) or (IIIc), or pharmaceutically acceptable salts or solvates 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 (IIIb), or their pharmaceutically acceptable salts or solvates, wherein each R 4Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 )2 and optionally halogen-substituted phenyl groups. In some embodiments, the invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIb), or their pharmaceutically acceptable salts or solvates, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIb), or their pharmaceutically acceptable salts or solvates, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIb), or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIb), or pharmaceutically acceptable salts or solvates thereof, wherein q is 2. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIb), or pharmaceutically acceptable salts or solvates thereof, wherein q is 0. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -C(=O)NH(OH). In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic), or their pharmaceutically acceptable salts or solvates, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein R 6 It is hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 92. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein R 9 It is a C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or their pharmaceutically acceptable salts or solvates, wherein R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic), or their pharmaceutically acceptable salts or solvates, wherein n is 1.

[0155] In some embodiments, the present invention provides compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), selected from the following compounds or their pharmaceutically acceptable salts or solvates:

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171] In another aspect, pharmaceutical compositions are disclosed herein that comprise pharmaceutically acceptable diluents, excipients or binders, and compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) or their pharmaceutically acceptable salts or solvates.

[0172] In another aspect, this document discloses a method for treating diseases, disorders, or conditions selected from those in mammals in need, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof:

[0173] Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, impaired cardiac contractility, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-related myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation-induced myocardial fibrosis, chemotherapy-induced cardiomyopathy, vascular sparseness, aortic valve sclerosis, calcific aortic stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy.

[0174] Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudrag syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema,

[0175] Polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary nephropathy, chronic allogeneic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, HIV-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced kidney injury, post-septic tubular injury, acute ischemic kidney injury, contrast agent-induced kidney injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, and tubulointerstitial fibrosis.

[0176] Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, steatosis, 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.

[0177] And pigmented scleroderma.

[0178] By referencing the merging

[0179] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent as each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0180] Unless the context clearly specifies otherwise, nouns without quantifiers as used herein and in the appended claims mean one or more species. Thus, for example, reference to “pharmaceutical” includes a plurality of such pharmaceuticals, and reference to “cell” includes reference to one or more types of cells and their equivalents. When a range is used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), all combinations and sub-combinations of the range and specific embodiments are intended to be included. When referring to a number or numerical range, the term “about / approximately” means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range varies from 1% to 15% of the stated number or numerical range. The term “comprising” (and related terms such as variations thereof or “having” or “including”) is not intended to exclude certain other embodiments described herein (e.g., embodiments of any composition, composition, method, or process, etc.) from being “consistent with” or “substantially composed of” the stated features.

[0181] definition

[0182] As used in the specification and appended claims, unless otherwise stated, the following terms shall have the meanings indicated below.

[0183] The terms used herein may be preceded and / or followed by a single dash "-" or a double dash "=" to indicate the bond order of the bond between the specified 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 the dash, substituents are intended to be read "from left to right". For example, C1-C6 alkoxycarbonyloxy and -OC(O)O-C1-C6 alkyl represent the same functionality; similarly, arylalkyl and -alkylaryl represent the same functionality.

[0184] For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inner cover.

[0185] As used in this article, C1-C x Including C1-C2, C1-C3…C1-C x C1-C x It refers to the number of carbon atoms that constitute the specified part (excluding optional substituents).

[0186] In this document, the terms “hydrogen,” “hydrogen atom,” and the symbol “H” used in the context of substituents in structural formulas (e.g., formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc)) denote hydrogen atoms bonded to the remainder of the molecule or group under discussion. For simplicity, hydrogen atoms bonded to carbon atoms are not shown in the structural formulas; each carbon atom is understood to be associated with enough hydrogen atoms to give the carbon atom four bonds.

[0187] A "saturated" or "fully saturated" compound means that the chemical structure involved does not contain any multiple carbon-carbon bonds. For example, saturated cycloalkyl groups as defined herein include cyclohexyl, cyclopropyl, etc.

[0188] "Unsaturated" or "partially saturated" compounds mean that the chemical structure involved may contain one or more carbon-carbon bonds, but is not aromatic. For example, unsaturated cycloalkyl groups as defined herein include cyclohexenyl, cyclopentenyl, cyclohexadienyl, etc.

[0189] "Amino" refers to the -NH2 group.

[0190] "Cyano" refers to the -CN group.

[0191] "Nitro" refers to the -NO2 group.

[0192] "O-" refers to the -O- group.

[0193] "Oxo" refers to the =O group.

[0194] "Thio" refers to the =S group.

[0195] "Imine" refers to the =NH group.

[0196] "Oxime group" refers to the =N-OH group.

[0197] It should be understood that “substitution” or “substituted” includes the implicit condition that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, which does not spontaneously undergo transformation (e.g., by rearrangement, cleavage, decomposition, cyclization, elimination or other reactions).

[0198] The term "substituted" is also considered to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic aromatic and non-aromatic substituents in organic compounds. Some illustrative substituents include, for example, halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, (cycloalkyl)alkoxy, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, aminosulfonyl, sulfinylamino, ketone, aldehyde, ester, heterocyclic, heterocyclic alkyl, aromatic or heteroaromatic moiety, aminoalkyl, haloalkyl, fluoroalkyl (e.g., trifluoromethyl), haloalkoxy, cyano, or other substituents listed above. For suitable organic compounds, permissible substituents may be one or more, and may be the same or different. For the purposes of this specification, heteroatoms (e.g., nitrogen) may have hydrogen substituents and / or any permitted substituents of the organic compounds described herein that satisfy the valence of the heteroatoms. This invention is not intended to be limited in any way to permitted substituents of organic compounds.

[0199] "alkyl" or "alkylene" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, and having one to fifteen carbon atoms (e.g., -C1-C). 15 Alkyl groups. In some embodiments, the alkyl group comprises one to thirteen carbon atoms (e.g., -C1-C1). 13Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., -C1-C8 alkyl). In other embodiments, the alkyl group comprises one to six carbon atoms (e.g., -C1-C6 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., -C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., -C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., -C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., -C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., -C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., -C5-C6 alkyl). 15 Alkyl group. In some embodiments, the alkyl group comprises five to eight carbon atoms (e.g., -C5-C8 alkyl). In some embodiments, the alkyl group comprises two to five carbon atoms (e.g., -C2-C5 alkyl). In some embodiments, the alkyl group comprises three to five carbon atoms (e.g., -C3-C5 alkyl). In some embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and 2,2-dimethylpropyl (neopentyl). The alkyl group is connected to the rest of the molecule by a single bond. The alkylene group is a digroup and is connected to both parts of the molecule by two single bonds, for example, in the case of methylene (-CH2-) or ethylene (-CH2CH2- or -CH(-CH3)-). Unless otherwise specified in the specification, the alkyl group may optionally be substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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 ORa (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0200] "Alkoxy" refers to a group bonded by an oxygen atom of the formula -O-alkyl, wherein the alkyl is an alkyl chain as defined above.

[0201] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In some embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, the alkenyl group may optionally be substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR 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 (where t is 1 or 2) and -S(O) t N(R a)2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0202] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In some embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group has two to four carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specified in the specification, the alkynyl group may optionally be substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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 (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0203] "Aryl" refers to a group derived from aromatic monocyclic or polycyclic hydrocarbon ring systems by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and six to eighteen carbon atoms, wherein at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups originate include, but are not limited to, cyclic systems such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene, corresponding to phenyl, fluorene, indane, tetrahydronaphthalene, and naphthyl, respectively, which can be further substituted. Unless otherwise specified in the specification, the term "aryl" or the prefix "ar-" (e.g., "aryl group") means an aryl group optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylyynyl, 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 Independently, each R is a hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halogen groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl group. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain. In particular, the phenyl group may optionally be substituted by one to five substituents independently selected from the above-mentioned substituents. For example, halogen-substituted phenyl groups represent 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4,6-trifluorophenyl, 3-chloro-4-fluorophenyl, etc., but also 3-methyl-4-fluorophenyl and 3,5-dimethyl-4-bromophenyl.

[0204] "Aryloxy group" refers to a group bonded by an oxygen atom of the formula -O-aryl, wherein the aryl group is as defined above.

[0205] "Aryl group" refers to the formula -R c -aryl groups, where R c It is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

[0206] "Aryloxy group" refers to a group bonded by an oxygen atom of the formula -O-aryl group, wherein the aryl group is as defined above.

[0207] "Aryl" refers to the formula -R d -aryl groups, where R d It is an alkenyl chain as defined above. The aryl portion of the aryl group is optionally substituted as described above for the aryl group. The alkenyl chain portion of the aryl group is optionally substituted as defined above for the alkenyl group.

[0208] "Arotyne group" refers to the formula -R e -aryl groups, where R e It is an alkynyl chain as defined above. The aryl portion of the aryl group is optionally substituted as described above for the aryl group. The alkynyl chain portion of the aryl group is optionally substituted as defined above for the alkynyl chain.

[0209] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems having three to fifteen carbon atoms. In some embodiments, the cycloalkyl group contains three to ten carbon atoms. In other embodiments, the cycloalkyl group contains five to seven carbon atoms. The cycloalkyl group is connected to the rest of the molecule by a single bond. The cycloalkyl group is saturated (i.e., containing only a single C-C bond) or partially unsaturated (i.e., containing one or more double or triple bonds). Some examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group contains three to eight carbon atoms (e.g., -C3-C8 cycloalkyl). In other embodiments, the cycloalkyl group contains three to seven carbon atoms (e.g., -C3-C7 cycloalkyl). In still other embodiments, the cycloalkyl group contains three to six carbon atoms (e.g., -C3-C6 cycloalkyl). In some embodiments, the cycloalkyl group comprises three to five carbon atoms (e.g., -C3-C5 cycloalkyl). In other embodiments, the cycloalkyl group comprises three to four carbon atoms (e.g., -C3-C4 cycloalkyl). Partially unsaturated cycloalkyl groups are also referred to as "cycloalkenyl". Some examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specified in the specification, the term "cycloalkyl" means cycloalkyl, including those optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, 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(Ra )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 Independently, each R is a hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halogenated groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl group. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0210] "Halogen" or "halogenated" refers to a bromine, chlorine, fluorine, or iodine substituent.

[0211] "Halogenated alkyl" means an alkyl group as defined above that is substituted with one or more halogenated groups as defined above. Some examples of halogenated alkyl groups include chloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, and 1-bromo-2-chloro-3-fluoropropyl.

[0212] "Fluoroalkyl" means an alkyl group as defined above that is substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of a fluoroalkyl group is optionally substituted as defined above for the alkyl group.

[0213] "Haloalkoxy" refers to an alkoxy group as defined above that is substituted with one or more halogenated groups as defined above.

[0214] "Heterocyclic alkyl" refers to a stable 3- to 18-membered non-aromatic ring system group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. "C2-C9 heterocyclic alkyl" refers to a heterocyclic alkyl group as defined above, containing two to nine carbon atoms and one to four heteroatoms. "C4-C5 heterocyclic alkyl" refers to a heterocyclic alkyl group as defined above, containing four to five carbon atoms and one to three heteroatoms. Unless otherwise specified in the specification, heterocyclic alkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused ring, spirocyclic, or bridged ring systems. The heteroatoms in the heterocyclic alkyl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclic alkyl is partially or fully saturated. In some embodiments, the heterocyclic alkyl is connected to the remainder of the molecule by any atom of the ring. Examples of such heterocyclic alkyl groups include, but are not limited to: dioxolanyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, and isothiazolyl. Zolpidemyl, morpholinyl (especially morpholin-4-yl), octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidyl, 2-oxopiperylalkyl Azolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the term "heterocyclic alkyl" means a heterocyclic alkyl group, as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocyclic alkyl, 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(Ra )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 Independently, each R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0215] "Heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring system, containing one to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. "C2-C9 heteroaryl" refers to a group derived from a 3- to 10-membered aromatic ring system, containing two to nine carbon atoms and one to four heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryls used herein are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to Hückel's theory. Exemplary heteroaryls include pyridyl, quinolinyl, ... azole and benzo[] Azolium group (i.e., benzo[d]) (Azolyl). Heteroaryl groups include fused-ring or bridged-ring systems. The heteroatom in the heteroaryl group is optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl group is connected to the rest of the molecule by any atom on the ring. Unless otherwise specified in the specification, the term "heteroaryl" means a heteroaryl group as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, halogenated, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, arylenyl, aryynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -ORa -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 Independently, each R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0216] "N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the connection point between the heteroaryl group and the rest of the molecule is through a nitrogen atom in the heteroaryl group. The N-heteroaryl group is optionally substituted as described above for heteroaryl groups.

[0217] "C-heteroaryl" refers to the heteroaryl group as defined above, wherein the connection point between the heteroaryl group and the rest of the molecule is through a carbon atom in the heteroaryl group. The C-heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0218] "Heteroaryloxy group" refers to a group bonded by an oxygen atom of the formula -O-heteroaryl, wherein the heteroaryl group is as defined above.

[0219] "Heteroarylalkyl" refers to the formula -R c - A heteroaryl group, wherein R c It is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heteroaryl alkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroaryl alkyl group is optionally substituted as defined above for the heteroaryl group.

[0220] "Heteroarylalkoxy" refers to the compound with the formula -OR c - A heteroaryl group bonded to an oxygen atom, wherein R c It is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0221] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers defined in absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, all stereoisomers of the compounds disclosed herein are intended to be considered in this disclosure. When the compounds described herein contain an alkene double bond, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans) unless otherwise stated. Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer of the alkene double bond (e.g., cis or trans). The term "positional isomer" refers to a structural isomer surrounding a central ring, such as ortho-, meta-, and para-isomers surrounding a benzene ring.

[0222] A "tautomer" is a molecule in which it is possible for a proton to transfer from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds described herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibria include:

[0223]

[0224] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0225] The term "prodrug" refers to compounds that are metabolized into pharmacologically active drugs after administration (RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chp. 8). Prodrugs can be used to improve how compounds are absorbed, distributed, metabolized, and excreted.

[0226] The term "medicinal salt" encompasses both acid and base addition salts. The term "medicinal salt" for any of the compounds described herein is intended to cover any and all pharmaceutically suitable salt forms. Preferred pharmaceutical salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0227] "Medicinal acid addition salts" refer to salts that retain the bioavailability and properties of a free base, are not biologically or otherwise undesirable, and are formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. Salts formed from organic acids are also included, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, 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, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, caprylate succinate, sebacic acid, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids, such as arginine salts, gluconates, and galacturons, are also considered (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt.

[0228] "Pharmaceutical-grade base addition salts" refer to those salts that retain the bioavailability and properties of free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutical-grade base addition salts are formed using metals or amines, such as alkali metals 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, and aluminum salts. 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, ethylenediphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., ibid.

[0229] IC 50 "" refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of such a response in a determination that measures the maximum response.

[0230] As used herein, “object” means a warm-blooded animal, such as a mammal, preferably a human or human child, that suffers from or may suffer from one or more of the diseases and disorders described herein.

[0231] The term "mammal" refers to humans, non-human primates, dogs, cats, cattle, sheep, pigs, rats, or other veterinary or laboratory mammals. Those skilled in the art recognize that a treatment that reduces the pathological severity of one mammal presupposes an effect of that treatment on another mammal.

[0232] "Effective amount" means any amount sufficient to achieve the desired biological effect. Combining the teachings provided herein, effective preventative or therapeutic regimens can be designed that do not cause significant unwanted toxicity and are also effective for treating a specific subject by selecting from a variety of active compounds and weighting factors such as potency, relative bioavailability, patient weight, sex, age, medical history, severity of adverse side effects, and preferred mode of administration. The effective amount for any particular application can vary depending on factors such as the disease or condition being treated, the specific compound of the invention being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a specific compound and / or other therapeutic agent of the invention without excessive experimentation. Generally, the maximum dose is preferred, i.e., the highest safe dose based on some medical judgment. Multiple doses per day may be considered to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient's peak drug level or sustained plasma levels. "Dose" and "dosage" are used interchangeably herein.

[0233] The terms “treatment” and its variations, or “relief” or “improvement”, as used herein are interchangeable. These terms refer to methods for achieving beneficial or desired outcomes, including, but not limited to, therapeutic and / or preventative benefits. “Therapeutic benefit” means the eradication or improvement of the underlying disorder being treated. Furthermore, a therapeutic benefit is achieved in the case of eradication or improvement of one or more physical symptoms associated with the underlying disorder, such that improvement is observed in the patient, even though the patient still suffers from the underlying disorder. For preventative benefits, the composition is administered to a patient at risk of developing a specific disease, or to a patient reporting one or more physical symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0234] compound

[0235] The compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) described herein are MMP inhibitors. In some embodiments, the compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) described herein, and compositions comprising these compounds, may be used to treat cardiovascular diseases, disorders, or conditions, particularly heart failure.

[0236] In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof:

[0237]

[0238] in:

[0239] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0240] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0241] X is -C(=O)- or -S(=O)2-;

[0242] Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R) 5 )-;

[0243] Where Y, if asymmetrical, corresponds to Write in the correct order;

[0244] Where nitrogen is If the connection point is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH-, or -N(R). 5 )-;

[0245] R 1 It is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 -C1-C6 alkylene-N(R) 6 )2、-C1-C6 alkylene-C(=O)-N(R 6 2. -C1-C6 alkylene-C(=O)-C4-C5 heterocyclic alkyl, -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;

[0246] R 2 It is -C(=O)OH, -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,

[0247] Each R 3 and each R 4Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0248] R 5 It is hydrogen or -C1-C6 alkyl;

[0249] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0250] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0251] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0252] R 8 Selected from hydrogen, -C1-C6 alkyl, and -N(H)C1-C6 alkyl;

[0253] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0254] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they are optionally substituted with a -C1-C6 alkyl group or a -C1-C6 haloalkyl group or a halogen.

[0255] n is 0, 1, or 2;

[0256] p is 0, 1, 2, or 3; and

[0257] q can be 0, 1, 2 or 3.

[0258] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (I), and some embodiments are pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0259] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (I), and some embodiments are pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0260] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl and It is phenyl.

[0261] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(=O)-. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(=O)2-.

[0262] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2O-. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH2-. 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 5In 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 It is a -C1-C6 alkyl group.

[0263] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0264] In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In another embodiment, R 3 It is a phenyl group optionally substituted with a halogen. In some embodiments, the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2. In some implementations, -N(R 6 )2 represents a C3-C5 heterocyclic alkyl group, for example, 4-morpholino.

[0265] In some embodiments, the present invention provides a compound of formula (I) 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 a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0266] In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6)2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4 It is methyl. In another embodiment, R 4 It is a phenyl group optionally substituted with a halogen. In some embodiments, the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl group. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -SO2N(R) 6 )2. In some implementations, -N(R 6 )2 represents a C3-C5 heterocyclic alkyl group, for example, 4-morpholino.

[0267] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 -C(=O)OR 6 -C(=O)N(R) 6 )2、-S(=O)2R 7 or -S(=O)2N(R) 62. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -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 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from 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 Yes-S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0268] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It 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, In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -C(=O)NH(OH). In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R2 It is -CH(OH)N (=O). In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -C(=O)CF3. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(NH2)C(=O)OH. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes

[0269] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0270] In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof:

[0271]

[0272] in:

[0273] R 1 It is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 -C1-C6 alkylene-N(R) 6 )2、-C1-C6 alkylene-C(=O)-N(R 62. -C1-C6 alkylene-C(=O)-C4-C5 heterocyclic alkyl, -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;

[0274] R 2 It 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,

[0275] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0276] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0277] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0278] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9)2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0279] R 8 Selected from hydrogen, -C1-C6 alkyl, and -N(H)C1-C6 alkyl;

[0280] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0281] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they are optionally substituted with a -C1-C6 alkyl group or a -C1-C6 haloalkyl group or a halogen.

[0282] n is 0, 1, or 2;

[0283] p is 0, 1, 2, or 3; and

[0284] q can be 0, 1, 2 or 3.

[0285] In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0286] In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R3 It is a halogen. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0287] In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0288] In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4 It is methyl. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 62. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -SO2N(R) 6 )2.

[0289] In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 7or -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -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 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from 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 Yes-S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0290] In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It 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, In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -C(=O)NH(OH). In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(OH)N (=O). In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -C(=O)CF3. In some embodiments, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(NH2)C(=O)OH. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes

[0291] In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0292] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (Ib):

[0293]

[0294] in:

[0295] R 1 It is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 -C1-C6 alkylene-N(R) 6 )2、-C1-C6 alkylene-C(=O)-N(R 6 2. -C1-C6 alkylene-C(=O)-C4-C5 heterocyclic alkyl, -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;

[0296] R 2 It 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,

[0297] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0298] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9)2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0299] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0300] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0301] R 8 Selected from hydrogen, -C1-C6 alkyl, and -N(H)C1-C6 alkyl;

[0302] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0303] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they are optionally substituted with a -C1-C6 alkyl group or a -C1-C6 haloalkyl group or a halogen.

[0304] n is 0, 1, or 2;

[0305] p is 0, 1, 2, or 3; and

[0306] q can be 0, 1, 2 or 3.

[0307] In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0308] In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 62. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0309] In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0310] In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4 It is methyl. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 62. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -SO2N(R) 6 )2.

[0311] In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 6 -C1-C6 alkylene-N(R) 6 )2、-C(=O)R 7 -C(=O)OR6 -C(=O)N(R) 6 )2、-S(=O)2R 7 or -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 R 6It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0312] In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It 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, In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -C(=O)NH(OH). In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(OH)N (=O). In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -C(=O)CF3. In some embodiments, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(NH2)C(=O)OH. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes

[0313] In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0314] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (Ic):

[0315]

[0316] in:

[0317] It is a C2-C9 heterocyclic alkyl group.

[0318] Y is a direct bond, -O-, -CH2-, or -C(=O)-;

[0319] Where nitrogen is If the connection point is used to connect Y, then Y cannot be -O-;

[0320] R 1 It is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 -C1-C6 alkylene-N(R) 6 )2、-C1-C6 alkylene-C(=O)-N(R 6 2. -C1-C6 alkylene-C(=O)-C4-C5 heterocyclic alkyl, -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;

[0321] R 2 It 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,

[0322] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -OR 6 -N(R) 6 )2、-CN、-C(=O)R 7 -C(=O)OR 6 -C(=O)N(R) 6 )2、-NR 6C(=O)R 7 -NR 6 SO2R 7 -SO2R 7 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0323] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0324] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0325] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0326] R 8 Selected from hydrogen, -C1-C6 alkyl, and -N(H)C1-C6 alkyl;

[0327] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0328] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they are optionally substituted with a -C1-C6 alkyl group or a -C1-C6 haloalkyl group or a halogen.

[0329] n is 0, 1, or 2;

[0330] p is 0, 1, 2, or 3; and

[0331] q can be 0, 1, 2 or 3.

[0332] 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-.

[0333] In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0334] In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 62. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0335] In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0336] In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4 It is methyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4It is -SO2N(R) 6 )2.

[0337] In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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 R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein R1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0338] In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It 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, In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -C(=O)NH(OH). In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2N(OH)C(=O)R 8 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(OH)N (=O). In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -C(=O)CF3. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is -CH2NHS(=O)2R 8 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH(NH2)C(=O)OH. In some embodiments, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes

[0339] In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0340] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (II):

[0341]

[0342] in:

[0343] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0344] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0345] X is -C(=O)- or -S(=O)2-;

[0346] Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R) 5 )-;

[0347] Where Y, if asymmetrical, corresponds to Write in the correct order;

[0348] Where nitrogen is If the connection point is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH-, or -N(R). 5 )-;

[0349] R 1 It 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;

[0350] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0351] R 5 It is hydrogen or -C1-C6 alkyl;

[0352] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0353] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0354] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R)9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0355] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0356] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they are optionally substituted with a -C1-C6 alkyl group or a -C1-C6 haloalkyl group or a halogen.

[0357] p is 0, 1, 2, or 3; and

[0358] q can be 0, 1, 2 or 3.

[0359] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (II), and in some embodiments, compounds of formula (II) or their pharmaceutically acceptable salts or solvates, wherein... It is a C2-C9 heteroaryl group.

[0360] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0361] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl and It is phenyl.

[0362] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(=O)-. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(=O)2-.

[0363] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2O-. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH2-. 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 In 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 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 ), and R 5 It is methyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 ), and R 5 It is an ethyl group.

[0364] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0365] In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0366] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0367] In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4 It is methyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 62. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -SO2N(R) 6 )2.

[0368] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 7or -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0369] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (III):

[0370]

[0371] in:

[0372] It is phenyl, C3-C10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0373] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0374] Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R) 5 )-;

[0375] Where Y, if asymmetrical, corresponds to Write in the correct order;

[0376] Where nitrogen is If the connection point is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH-, or -N(R). 5 )-;

[0377] R 1 It 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;

[0378] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0379] R5 It is hydrogen or -C1-C6 alkyl;

[0380] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0381] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0382] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0383] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0384] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they may be optionally substituted with a -C1-C6 alkyl group, a halo-C1-C6 alkyl group, or a halogen.

[0385] p is 0, 1, 2, or 3; and

[0386] q can be 0, 1, 2 or 3.

[0387] In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (III), and in some embodiments, compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0388] In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein... It is C3-C 10Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0389] In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein is Phenyl and It is a phenyl group.

[0390] In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2O-. In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH2-. 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 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 5 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 ), and R 5 It is methyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 ), and R 5 It is an ethyl group.

[0391] In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0392] In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6)2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 62. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0393] In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0394] In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4It is methyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -SO2N(R) 6 )2.

[0395] In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -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. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6It is ethyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)R 7 .

[0396] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (IIIa):

[0397]

[0398] in:

[0399] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0400] R 1 It 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;

[0401] Each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0402] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9-C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0403] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0404] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0405] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0406] Each occurrence of the C2-C9 heterocyclic alkyl and C2-C9 heteroaryl groups may optionally be replaced by a -C1-C6 alkyl, a halo-C1-C6 alkyl, or a halogen; and

[0407] p is 0, 1, 2 or 3.

[0408] In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (IIIa), and some embodiments are pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0409] In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0410] In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6)2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 62. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0411] In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -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. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9 It is methyl. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R)9 2. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0412] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (IIIb):

[0413]

[0414] in:

[0415] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl;

[0416] R 1 It 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)2R7 、or -S(=O)2N(R 6 )2;

[0417] Each R 3 and each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 )2 or phenyl groups optionally substituted with halogens;

[0418] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0419] Or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0420] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl and -C1-C6 alkylene-C2-C9 heteroaryl;

[0421] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0422] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they may be optionally substituted with a -C1-C6 alkyl group, a halo-C1-C6 alkyl group, or a halogen.

[0423] p is 0, 1, 2, or 3; and

[0424] q can be 0, 1, 2 or 3.

[0425] In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (IIIb), and in some embodiments, compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0426] In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0427] In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3It is methyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl group. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0428] In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0429] In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a halogen. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a C1-C6 alkyl group. In another embodiment, R 4 It is methyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is a -C1-C6 haloalkyl. In another embodiment, R 4 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 Yes - OR6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein each R 4 It is -SO2N(R) 6 )2.

[0430] In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 -C(=O)OR 6 -C(=O)N(R) 6 )2、-S(=O)2R7 or -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In yet another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9It is methyl. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2 and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -C(=O)R 7 .

[0431] In some embodiments, the present invention provides compounds of formula (I) having a structure of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof:

[0432]

[0433] in:

[0434] It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; R 1 It 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;

[0435] Each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, -C1-C6 alkylene groups, and -OR groups. 6 C1-C6 haloalkoxy groups, -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 -SO2N(R) 6 2. Or optionally, a phenyl group substituted with a halogen;

[0436] Each R 6 Independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2 and -C1-C6 alkylene-C2-C9 heterocyclic alkyl;

[0437] or -N(R) 6 )2 represents a C3-C5 heterocyclic alkyl group;

[0438] Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 -C1-C6 alkylene-N(R) 9 )2, -C2-C9 heterocyclic alkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocyclic alkyl, and -C1-C6 alkylene-C2-C9 heteroaryl;

[0439] Each R 9 Independently selected from hydrogen and -C1-C6 alkyl groups;

[0440] Each time a C2-C9 heterocyclic alkyl group and a C2-C9 heteroaryl group appear, they may be optionally substituted with a -C1-C6 alkyl group, a halogenated -C1-C6 alkyl group, or a halogen; and

[0441] p is 0, 1, 2 or 3.

[0442] In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein It is phenyl. In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein... It is C3-C 10 Cycloalkyl or C2-C9 heteroaryl. In some embodiments, the present invention provides compounds of formula (IIIc). Some embodiments are compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein... It is a C2-C9 heteroaryl group.

[0443] In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2O-. In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH2-. In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(H)-. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R)-. 5 )-and R 5 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 And R 5 It is methyl. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 And R 5 It is an ethyl group.

[0444] In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0445] In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 -N(R) 6 )2、-CN、-C(=O)OR 6 -C(=O)N(R) 6 )2、-SO2R 7 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups, and -OR groups. 6 and -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from halogens and -C1-C6 alkyl groups. In some embodiments, the invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a halogen. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a C1-C6 alkyl group. In another embodiment, R 3 It is methyl. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is a -C1-C6 haloalkyl group. In another embodiment, R 3 It is trifluoromethyl. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Independently selected from -OR 6 -N(R) 6 2. -C(=O)OR 6 -C(=O)N(R) 6 )2 and -SO2N(R 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR 6 In another implementation, R 6 It is hydrogen or methyl. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 Yes - OR6 And each R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 It is -SO2N(R) 6 )2.

[0446] In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It 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 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)R 7 -C(=O)OR 6 -C(=O)N(R) 6 )2、-S(=O)2R7 or -S(=O)2N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , or -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkyl group. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 6 It is methyl, ethyl, n-propyl, isobutyl, or tert-butyl. In another embodiment, R 6 It is methyl. In yet another embodiment, R 6 It is ethyl. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 R 6 It is a -C1-C6 alkylene-OR 9 And R 9 It is a C1-C6 alkyl group. In another embodiment, R 6 It is ethylene-OR 9 In another implementation, R 6 It is methylene-OR 9 In another implementation, R 9 Selected from methyl, ethyl, n-propyl, or tert-butyl. In one embodiment, R... 9It is methyl. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)OR 6 And R 6 It is a -C1-C6 alkylene-N(R) 9 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkyl groups. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)N(R) 6 )2, and each R 6 Independently selected from hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 Yes-S(=O)2R 7 In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -S(=O)2N(R) 6 2. In some embodiments, the present invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 It is -C(=O)R 7 .

[0447] In some embodiments described herein, the disclosed compounds are compounds selected from those of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or pharmaceutically acceptable salts or solvates thereof:

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] In some embodiments, the disclosed compound used by one or more of the foregoing methods is one of the genera, subgenera or specific compounds described herein, such as compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) described herein.

[0464] Preparation of compounds

[0465] The compounds used in the methods described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to the procedures disclosed herein or by known organic synthesis techniques.

[0466] Detailed descriptions of the synthesis of reactants used to prepare the compounds described herein or to provide reference to articles describing such preparations are provided in suitable reference books and papers, including, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SRSandler et al., "Organic Functional Group Preparations", 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WABenjamin, Inc., Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992.

[0467] Detailed descriptions of the synthesis of reactants used to prepare the compounds described herein or other suitable reference books and papers that provide reference to articles describing such preparations 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) "ModemCarbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's1992Guide 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 OrganicChemicals: 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, with over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, with 73 volumes. .

[0468] Specific and similar reactants can also be identified using the index of known chemicals from the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries and can also be identified through online databases (for more details, contact the American Chemical Society, Washington, DC). Known but not commercially available chemicals in the catalogue are optionally prepared by custom chemical synthesis companies, many of which offer custom synthesis services to standard chemical suppliers (e.g., those listed above). One of the references for the preparation and selection of pharmaceutical salts of the compounds described herein is P.Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0469] Other forms of the compounds disclosed in this article

[0470] Isomers

[0471] Furthermore, in some embodiments, the compounds described herein are present as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis / syn / entgegen(E)) and trans (trans / anti / zusammen(Z)) isomers, and corresponding mixtures thereof. In some cases, the compounds are present as tautomers. The compounds described herein include all possible tautomers of the formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center is present in an R configuration or an S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, and corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or tautomerization can be used for the applications described herein. In some embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form diastereomeric compound pairs, separating the diastereomeric compounds, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes (e.g., crystalline diastereomeric salts) are preferred. In some embodiments, the diastereomeric compounds have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomeric compounds are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are subsequently recovered by any practical method that does not cause racemization.

[0472] Labeled compounds

[0473] In some embodiments, the compounds described herein are present in their 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 a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Some examples of isotopes of the compounds incorporated herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 14 C l5N、 16 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl. The pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives of the compounds described herein and other isotopes comprising the aforementioned isotopes and / or other atoms are within the scope of this invention. Certain isotopically labeled compounds, for example, those incorporating radioactive isotopes, are also included. 3 H and 14 Those with C can be used for drug and / or matrix tissue distribution determination. Tritiumization, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavy isotopes such as deuterium (i.e.,...) are also used. 2 H) Substitution produces certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. In some embodiments, the isotopically labeled compound, its pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative is prepared by any suitable method.

[0474] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0475] Medicinal salt

[0476] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0477] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final separation and purification of the compounds of the invention, or by reacting the purified free form of the compound alone with a suitable acid or base and separating the resulting salt.

[0478] prodrug

[0479] In some embodiments, the compounds described herein are formulated to be converted in vivo into their active form to alter the biodistribution or pharmacokinetics of a particular agent. For example, the carboxylic acid group can be esterified, for example, with methyl or ethyl groups to produce an ester. When the ester is applied to a target, it is enzymatically or non-enzymatically, reductively, oxidatively, or hydrolyzed to expose an anionic group. The anionic group can be partially esterified (e.g., with an acyloxymethyl ester), which is then cleaved to expose an intermediate, which is subsequently degraded to produce the active agent. The prodrug moiety can be metabolized in vivo by esterases or other mechanisms to a carboxylic acid. Alternatively, other functional groups can be modified into the prodrug form. For example, the amino group can be converted into a cleavable carbamate or amide in vivo.

[0480] solvates

[0481] In some embodiments, the compounds described herein are present as solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention also provides a method for treating a disease by administering such solvates as a pharmaceutical composition.

[0482] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholic product is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydration of the compounds described herein can be conveniently prepared by recrystallization from a mixture of water and an organic solvent, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein exist in both solvated and non-solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0483] Pharmaceutical Composition

[0484] In some embodiments, the compounds described herein are administered as pure chemical substances. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or pharmaceutically acceptable carrier (also referred to herein as a pharmaceutically suitable (or pharmaceutically acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), said carrier being based on the chosen route of administration and, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21). st The standard pharmaceutical practices described in Ed. Mack Pub. Co., Easton, PA (2005) were selected.

[0485] Therefore, pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt described herein, and one or more pharmaceutically acceptable carriers are provided herein. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is harmless to the recipient (i.e., the object) of the composition.

[0486] 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 (IIIa) or (IIIb) or (IIIc) or a pharmaceutically acceptable salt thereof.

[0487] Another embodiment provides a pharmaceutical composition which is substantially composed of a pharmaceutically acceptable carrier and a compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) or a pharmaceutically acceptable salt thereof.

[0488] In some embodiments, the compound as described herein is substantially pure because it contains 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 byproducts generated in one or more steps of, for example, synthetic methods.

[0489] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0490] Exemplary pharmaceutical compositions are used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more disclosed compounds as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for topical, enteral, or parenteral application. In some embodiments, the active ingredient is mixed, for example, with a commonly used, non-toxic, pharmaceutically acceptable carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The amount of the active target compound included in the pharmaceutical composition is sufficient to produce the desired effect on the course or condition of a disease.

[0491] In some embodiments, the compounds of formula (I) or (Ia) or (Ib) or (Ic) described herein are administered to a subject in a biocompatible form suitable for surface application to treat or prevent skin diseases, disorders, or conditions. “Biocompatible form suitable for surface application” means the form of the compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) to be administered, wherein the therapeutic effect of the inhibitor outweighs any toxic effects. As described herein, the administration of the compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) can be any pharmacological form, alone or in combination with a pharmaceutically acceptable carrier, including therapeutically effective amounts of the compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc).

[0492] Topical application of compounds of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) can be in the form of aerosols, semi-solid pharmaceutical compositions, powders, or solutions. The term "semi-solid composition" means an ointment, cream, lotion, gel, or other pharmaceutical composition with substantially similar consistency suitable for application to the skin. Some examples of semi-solid compositions are given in Chapter 17 of *The Theory and Practice of Industrial Pharmacy*, by Lea and Febiger (1970), Lachman, Lieberman, and Kanig, and Chapter 67 of *Remington's Pharmaceutical Sciences*, 15th edition (1975), Mack Publishing Company.

[0493] Dermal or skin patches are another method of transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches may include absorption enhancers, such as DMSO, to improve compound absorption. Patches may include those that control the rate of drug delivery to the skin. Patches can provide various drug delivery systems, including reservoir systems or monolithic systems. For example, a reservoir design may have four layers: an adhesive layer in direct contact with the skin, a control membrane to control drug molecule diffusion, a drug molecule reservoir, and a water-resistant backing. Such a design delivers a uniform amount of drug over a specific time period, and the delivery rate must be less than the saturation limit of different skin types. For example, a monolithic design typically has only three layers: an adhesive layer, a polymer matrix containing the complex, and a water-resistant backing. This design provides the skin with a saturated amount of drug. Therefore, delivery is controlled by the skin. As the amount of drug in the patch decreases below the saturation level, the delivery rate decreases.

[0494] In one embodiment, the topical composition may take, for example, the form of a hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, particularly based on a water-in-oil or oil-in-water microemulsion, optionally with the addition of liposomes. Suitable penetration enhancers (carriers) include sulfoxide derivatives, such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO) and carbitol (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 its fatty acid esters; urea derivatives, such as dodecylurea, 1,3-bisdodecylurea and 1,3-diphenylurea; and terpenes, such as D-limonene, menthone, α-terpineol, carvol, limonene oxide or 1,8-cineole.

[0495] Ointments, pastes, creams, and gels may also contain excipients such as starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any known method conventionally used for the preparation of aerosol pharmaceuticals. Typically, such methods involve pressurization or providing a device for pressurizing the solution container, usually utilizing an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0496] In some embodiments for preparing solid compositions (e.g., tablets), the major active ingredient is mixed with a pharmaceutical carrier (e.g., a conventional tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformed composition comprising a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When these preformed compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily further divided into equivalent unit dosage forms, such as tablets, pills, and capsules.

[0497] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the composition of the present invention is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) a filler or extender, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) a binder, such as carboxymethyl cellulose, hydroxyl group monophosphate ... The composition comprises: (1) propyl methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (2) humectants, such as glycerin; (3) disintegrants, such as crospovidone, crospovidone sodium carboxymethyl cellulose, sodium glycolate starch, agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; (4) solution retardants, such as paraffin; (5) absorption enhancers, such as quaternary ammonium compounds; (6) humectants, such as docusate sodium, cetyl alcohol, and glyceryl monostearate; (7) absorbents, such as kaolin and bentonite clay; (8) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and (9) colorants. In the case of capsules, tablets, and pills, in some embodiments, the composition comprises a buffer. In some embodiments, similar types of solid compositions are also used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol, etc.

[0498] In some embodiments, tablets are formed by compression or molding, optionally with one or more excipients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. In some embodiments, molded tablets are prepared by molding a mixture of the compositions of the invention moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, are scored or prepared to have a coating and shell, such as enteric coating and other coatings.

[0499] Compositions for inhalation or inhalation 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 addition to the compositions of the present invention, in some embodiments, the liquid dosage form comprises an inert diluent, such as water or other solvents, a solubilizer, and an emulsifier, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0500] In some embodiments, in addition to the compositions of the present invention, the suspension also includes suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth gum, and mixtures thereof.

[0501] In some embodiments, in addition to the compositions of the present invention, the powders and sprays also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, the sprays also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0502] The compositions and compounds disclosed herein can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In some embodiments, sonic aerosols are used because they minimize the degree of shear exposure of the reagents, which leads to degradation of the compounds contained in the compositions of the invention. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions of the invention together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular compositions of the invention, but typically include nonionic surfactants (Tween, Pluronic, 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 typically prepared from isotonic solutions.

[0503] Pharmaceutical compositions suitable for parenteral administration comprise the compositions of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders, which are reconstituted into sterile injectable solutions or dispersions only prior to use. In some embodiments, they contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0504] Examples of suitable aqueous and non-aqueous carriers for pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate and cyclodextrin). Appropriate flowability is maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0505] The dosage of compositions containing at least one of the compounds described herein varies depending on the patient's (e.g., person's) condition, i.e., stage of disease, general health condition, age, and other factors.

[0506] The pharmaceutical composition is administered in a manner suitable for the treatment (or prevention) of the disease. The appropriate dosage and suitable duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dosage and treatment regimen provides an amount of composition sufficient to provide therapeutic and / or preventative benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free survival and / or overall survival, or reduction in symptom severity). The optimal dosage is typically determined using experimental models and / or clinical trials. In some embodiments, the optimal dosage depends on the patient's weight, body mass, or blood volume.

[0507] The oral dose is usually from about 1.0 mg to about 1000 mg, once to four times or more daily.

[0508] method

[0509] In some embodiments, methods are disclosed herein for treating diseases, disorders, or conditions selected from the following in mammals in need: cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, impaired cardiac contractility, age-related cardiac hypertrophy, inflammation, and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-related myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling following myocardial injury, radiation myocarditis, radiation-induced myocardial fibrosis, chemotherapeutic cardiomyopathy, vascular sparseness, aortic valve sclerosis, calcific aortic stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, and right ventricular hypertrophy.

[0510] Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudrag syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary nephropathy, and chronic allogeneic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, and post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced kidney injury, post-septic tubular injury, acute ischemic kidney injury, contrast agent-induced kidney injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, and tubulointerstitial fibrosis.

[0511] Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, steatosis, 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.

[0512] And pigmented scleroderma, which includes administering to mammals in need a therapeutically effective amount of a compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) or its pharmaceutically acceptable salt or solvate.

[0513] In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (Ia) or its pharmaceutically acceptable salt or solvate.

[0514] In some embodiments, methods for treating cardiovascular diseases, disorders, or conditions in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (Ib) or its pharmaceutically acceptable salt or solvate.

[0515] In some embodiments, methods for treating cardiovascular diseases, disorders, or conditions in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (Ic) or its pharmaceutically acceptable salt or solvate.

[0516] In some embodiments, methods for treating cardiovascular diseases, disorders, or conditions in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof.

[0517] In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof.

[0518] In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof.

[0519] In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof.

[0520] In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed herein, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof.

[0521] Pharmaceutical Composition

[0522] This article also considers combination therapy, such as the co-administration of a disclosed compound and an additional active agent as part of a specific treatment regimen designed to provide a beneficial effect through the synergistic effect of these therapeutic agents. The beneficial effect of this combination includes, but is not limited to, the pharmacokinetic or pharmacodynamic synergistic effect resulting from the combination of therapeutic agents. The combined administration of these therapeutic agents is typically carried out over a defined time period (usually weeks, months, or years, depending on the chosen combination). Combination therapy is intended to include the sequential administration of multiple therapeutic agents, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0523] Substantial simultaneous administration can be achieved, for example, by administering a single formulation or composition (e.g., tablets or capsules in a fixed proportion of each therapeutic agent, or multiple, single formulations of each therapeutic agent (e.g., capsules)) to the subject. Substantial simultaneous administration can also be achieved by administering a novel chemical entity to the subject, the novel chemical entity being composed of a disclosed compound bound to one or more additional active agents by chemical bonds or connectors. The sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered via the same or different routes. For example, the first therapeutic agent in a selected combination may be administered intravenously, while the other therapeutic agents in the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered intravenously.

[0524] In some embodiments, methods are disclosed herein for treating diseases, disorders, or conditions selected from the following in mammals in need: cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, impaired cardiac contractility, age-related cardiac hypertrophy, inflammation, and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-related myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological myocardial remodeling, ECM remodeling following myocardial injury, radiation myocarditis, radiation-induced myocardial fibrosis, chemotherapeutic cardiomyopathy, vascular sparseness, aortic valve sclerosis, calcific aortic stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, and right ventricular hypertrophy.

[0525] Idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudrag syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary nephropathy, and chronic allogeneic transplant nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, and post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced kidney injury, post-septic tubular injury, acute ischemic kidney injury, contrast agent-induced kidney injury, acute tubular injury after ischemia and reperfusion, end-stage renal disease, and tubulointerstitial fibrosis.

[0526] Alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, steatosis, 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.

[0527] And pigmented scleroderma, the method comprising administering to a mammal in need a therapeutically effective amount of a compound of formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) or a pharmaceutically acceptable salt or solvate thereof, the method further comprising administering to the mammal one or more additional agents. In some embodiments, a method for treating cardiovascular disease, disorder or condition in a mammal in need is disclosed, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (I), further comprising administering to the mammal one or more additional agents. In some embodiments, a method for treating cardiovascular disease, disorder or condition in a mammal in need is disclosed, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (Ia), further comprising administering to the mammal one or more additional agents. In some embodiments, a method for treating cardiovascular disease, disorder or condition in a mammal in need is disclosed, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (Ib), further comprising administering to the mammal one or more additional agents. In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed, comprising administering a therapeutically effective amount of a compound of formula (Ic) to the mammal in need, and further comprising administering one or more additional agents to the mammal. In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed, comprising administering a therapeutically effective amount of a compound of formula (II) to the mammal in need, and further comprising administering one or more additional agents to the mammal. In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed, comprising administering a therapeutically effective amount of a compound of formula (III) to the mammal in need, and further comprising administering one or more additional agents to the mammal. In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed, comprising administering a therapeutically effective amount of a compound of formula (IIIa) to the mammal in need, and further comprising administering one or more additional agents to the mammal. In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed, comprising administering a therapeutically effective amount of a compound of formula (IIIb) to the mammal in need, and further comprising administering one or more additional agents to the mammal. In some embodiments, methods for treating cardiovascular disease, disorder, or condition in mammals in need are disclosed, comprising administering a therapeutically effective amount of a compound of formula (IIIc) to the mammal in need, and further comprising administering one or more additional agents to the mammal.

[0528] Combination therapy also includes the additional administration of the therapeutic agents described above in combination with other bioactive ingredients and non-pharmacological treatments. When combination therapy also includes non-pharmacological treatments, these treatments can be administered at any appropriate time, provided that the combination of therapeutic agents and the synergistic effect of the non-pharmacological treatments achieve a beneficial effect. For example, in appropriate circumstances, when non-pharmacological treatments are temporarily discontinued from the administration of the therapeutic agents, beneficial effects may still be achieved for several days or even weeks.

[0529] The components of this combination are administered to the patient simultaneously or sequentially. It should be understood that these components are contained in the same pharmaceutically acceptable carrier and therefore can be administered simultaneously. Alternatively, the active ingredient is contained in a separate drug carrier, such as a conventional oral dosage form for simultaneous or sequential administration.

[0530] Example

[0531] The present invention is further illustrated by the following embodiments, which should not be construed as limiting the scope of the claims provided herein.

[0532] List of abbreviations

[0533] As used above, and throughout the description of this invention, unless otherwise stated, the following abbreviations shall be understood to have the following meanings:

[0534]

[0535]

[0536]

[0537] Unless otherwise defined, the purity of a solid substance is expressed as the ratio of the weight of the component under discussion to the total weight multiplied by 100 (wt%). The purity of a liquid is expressed as the ratio of the volume of the component under discussion to the total volume multiplied by 100 (volume%). The concentration of a solution is expressed as the ratio of 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 reaction is expressed as the ratio of the weight of the product under discussion to the theoretical yield of that product multiplied by 100 (%). The composition of a mixed solvent is expressed as the volume ratio of the component solvents (e.g., 80:20 or 3:2:1).

[0538] General Overview

[0539] Commercially available chemicals are obtained from standard commercial sources, including:

[0540] 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. (Rockville, MD), and WuXi (Shanghai, China).

[0541] Drying solvents such as DCM, diethyl ether, and toluene were purchased from Finar and used as is, while THF was dried with sodium (monitored by colorimetric analysis of benzophenone carbonyl groups) and freshly distilled before use. Liquids and solutions were transferred using syringes or cannulas. All reactions were carried out under a nitrogen / argon atmosphere with magnetic stirring in flame-dried or oven-dried glassware. Merck silica gel 60F was used. 254 All reactions were monitored by thin-layer chromatography (TLC) on pre-coated plates (0.25 mm), using UV light, iodine, potassium permanganate staining, p-anisaldehyde staining, or phosphomolybdic acid staining; GC / FID; LCMS; or 1 Visualization is performed using 1H NMR. Typical laboratory methods include: grinding; silica gel (60 to 120, 100 to 200, or 230 to 400 mesh) chromatography; and combination of rapid normal or reversed-phase chromatography to purify crude compounds.

[0542] Analytical methods

[0543] Protons were recorded on a Bruker Ascend-400 spectrometer using CDCl3, DMSO-d6, CD3CN, or D2O as solvents. 1 H) and carbon ( 13 C) NMR spectroscopy, the spectrometer was operated at 400 MHz for protons and 100 MHz for carbon. Chemical shifts are expressed in parts per million (δ, ppm), and coupling constants (J) are reported in Hertz. For proton spectra, the solvent peak was used as a reference peak. LCMS was performed in both positive and negative modes using a PDA detector on a Shimadzu LCMS-2020, an Agilent 6420 Triple Quad LC / MS, or an Agilent Infinity Lab LC / MSD XT under electrospray ionization (ESI) conditions. HPLC was performed using a PDA detector on a Shimadzu LC-2010 and an Agilent 1290 Infinity II. Preparative HPLC was performed using a PDA detector on a Shimadzu semi-preparative or an Agilent 1260 Infinity II. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise specified.

[0544] The operating conditions for chromatographic and mass spectrometric analyses are summarized in Tables 1 to 3 below.

[0545] Table 1. LCMS Conditions

[0546]

[0547] Table 2: Preparative HPLC conditions

[0548]

[0549]

[0550] Table 3. HPLC conditions

[0551]

[0552]

[0553] Chemical synthesis

[0554] Unless otherwise specified, reagents and solvents obtained from commercial suppliers were used. Anhydrous solvents and dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and not optimized.

[0555] The compounds according to the invention can be prepared using the synthetic transformations illustrated in the following synthetic schemes 1 to 10. The starting materials are commercially available and can be prepared by the operations described herein, by means of literature procedures, or by methods known to those skilled in the art of organic chemistry.

[0556] The following provides exemplary synthetic methods for preparing compounds according to this disclosure.

[0557] In step 1 of general synthetic scheme 1, various sulfonyl chlorides (1B) are reacted with a secondary amine (1A) to give formula 1C. Formula 1C is deprotected to give formula 1D. Formula 1D is further reacted with methoxyethyl chloroformate to give formula 1E. Formula 1E is further treated with an inorganic base in water and THF to give formula 1F, which is further coupled with a protected hydroxylamine under conventional amide conditions to produce formula 1G. Finally, formula 1G is deprotected in a suitable solvent such as DCM, 1,4-dioxane, and MeOH in the presence of a suitable acid such as TFA, 1N HCl, etc., to provide formula 1.

[0558] General Synthesis Scheme 1

[0559]

[0560] Example 1:

[0561] Synthesis of (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[0562]

[0563] Step 1:

[0564] Synthesis of (1S,2S,5R)-8-tert-butyl-2-ethyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0565]

[0566] Under a nitrogen atmosphere, at 0–10 °C, K₂CO₃ (580 mg, 4.2 mmol) was added to a stirred solution of (1S,2S,5R)-8-tert-butyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (300 mg, 1.05 mmol) in acetone (6 mL) and stirred for 20 min. 6-(4-fluorophenoxy)pyridine-3-sulfonyl chloride (450 mg, 1.58 mmol) was dissolved in acetone (4 mL) and added to the reaction mixture at the same temperature. Water (0.05 mL) was then added and the reaction mixture was stirred at room temperature for 16 h, monitored by TLC. The reaction mixture was diluted with water (10 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 obtain the crude product. The crude product was purified by silica gel column chromatography (100 to 200 mesh, 15% to 20% EtOAc in hexane) to give (1S,2S,5R)-8-tert-butyl-2-ethyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (330 mg, 0.61 mmol, 58% yield) as a colorless, viscous gel. MS (ESI): m / z 480.0 [Mt-Bu+H] + .

[0567] Step 2:

[0568] (1S,2S,5R)-ethyl-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ester

[0569]

[0570] Trifluoroacetic acid (0.5 mL, 6.1 mmol) was added to a stirred solution of (1S,2S,5R)-8-tert-butyl-2-ethyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (0.33 g, 0.61 mmol) in DCM (4 mL) at 0 to 5 °C, and the mixture was stirred at room temperature for 16 h while monitoring 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 × 15 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain (1S,2S,5R)-ethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ester (270 mg, 0.62 mmol, quantified) as a colorless, viscous gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 436.0 [M+H] + .

[0571] Step 3:

[0572] Synthesis of (1S,2S,5R)-2-ethyl-8-(2-methoxyethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0573]

[0574] DIPEA (0.43 mL, 2.48 mmol) and 2-methoxyethyl chloroformate (0.14 mL, 1.24 mmol) were added to a stirred solution of (1S,2S,5R)-ethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ester (270 mg, 0.62 mmol) in DCM (4 mL) at 0 to 10 °C under a N2 atmosphere. The reaction mixture was then stirred at room temperature for 6 hours while being monitored by TLC. The reaction mixture was quenched with ice-cold water (5 mL) and extracted into DCM (2 × 20 mL). The combined organic layers were washed with ice-cold water (2 × 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain (1S,2S,5R)-2-ethyl-8-(2-methoxyethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (340 mg, 0.63 mmol, quantified) as a colorless, viscous gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 538.0 [M+H] + .

[0575] Step 4:

[0576] Synthesis of (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0577]

[0578] At 0 °C, a single addition of NaOH (122 mg, 3.0 mmol) was made to a stirred solution of (1S,2S,5R)-2-ethyl-8-(2-methoxyethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (330 mg, 0.61 mmol) in a 1:1:1 mixture of THF:ethanol:H2O (30 mL). The reaction mixture was stirred at room temperature for 16 hours under TLC monitoring. The evaporation was carried out under reduced pressure, and the residue was diluted with water (5 mL) and cooled to 0 to 10 °C. The pH of the reaction mixture was adjusted to approximately 4 to 5 with a 10% aqueous citric acid solution and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (15 mL), separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (270 mg, 0.53 mmol, 86% yield) as a brown, viscous gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 510.0 [M+H] + .

[0579] Step 5:

[0580] Synthesis of (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[0581]

[0582] HATU (223 mg, 0.58 mmol) and DIPEA (0.44 mL, 2.4 mmol) were added to a stirred solution of (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (250 mg, 0.49 mmol) in anhydrous DMF (6 mL) at 0 to 10 °C. The reaction mixture was stirred at the same temperature for 30 min and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (69 mg, 0.63 mmol) was added. The reaction mixture was warmed to room temperature over 30 min and stirred for 6 h while being monitored by TLC. The reaction mixture was quenched with ice-cold water (15 mL) at 0 °C and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (15 mL), separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)-oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (200 mg, 0.33 mmol, 67% yield) as a colorless liquid. This substance was used as is in the next step without further purification. MS (ESI): m / z 606.9 [MH] - .

[0583] Step 6:

[0584] Synthesis of (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 1)

[0585]

[0586] Trifluoroacetic acid (0.24 mL, 3.1 mmol) was added dropwise to a stirred solution of (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (190 mg, 0.31 mmol) in DCM (4 mL) at 0 to 10 °C. The reaction mixture was stirred at room temperature for 16 hours while being monitored by TLC. The evaporator was evaporated, and the residue was diluted with DCM (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 150 mg of crude compound. The crude material was purified by RP prep HPLC (Table 2, Method 2), and the fraction was lyophilized to give (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 1) (45 mg, 0.08 mmol, 14% yield) as a grayish-white solid.

[0587] MS(ESI): m / z5250[M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.64 (brs, 1H), 8.76 (brs, 1H), 8.42 (d, J=2.4Hz, 1H), 8.09 (dd, J=2.8, 8.8Hz, 1H), 7.31-7.27 (m, 4H), 7.18 (d, J=8.8Hz, 1 H), 4.42-4.38(m, 1H), 4.284.20(m, 1H), 4.104.04(m, 2H), 3.903.80(m, 1H ), 3.593.40 (mmm, 4H), 3.23 (s, 3H), 1.93-1.70 (m, 2H), 1.56-1.47 (m, 2H).

[0588] Similarly, the following examples were prepared by following the same or similar methods as described in Example 1.

[0589] Table 4

[0590]

[0591]

[0592]

[0593]

[0594]

[0595] The synthesis of 2-ethyl 2,8-dicarboxylic acid ester (intermediate 2) of 8-(2-methoxyethyl)(1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid is shown below.

[0596] Synthesis Scheme 2

[0597]

[0598] Step 1:

[0599] Synthesis of (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester fumarate

[0600]

[0601] (1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (160 g, 0.81 mol) was dissolved in 2.3 L of a saturated solution of fumaric acid in EtOH (90 g of fumaric acid was dissolved in 2.5 L of EtOH to prepare the saturated solution) and transferred to a 5 L multi-necked round-bottom flask equipped with a mechanical stirrer at room temperature. The reaction mixture was cooled to -10 °C to 0 °C, and a solid precipitate was observed after stirring for 30 min. The mixture was stirred for 24 h and filtered. The resulting pale yellow solid compound was washed with diethyl ether (600 mL) and dried under high vacuum to give (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate ethyl fumarate (60 g, 0.19 mol, 25% in step 2) as a grayish-white solid.

[0602] 1 H NMR (400MHz, CDCl3): δ8.18 (brs, 3H), 7.32 (s, 1H), 6.61 (s, 2H), 4.27 (d, J=4.4Hz, 1H), 4.18-4.11 (m, 2 H), 3.80-3.77 (m, 1H), 3.45-3.43 (m, 1H), 1.86-1.69 (m, 3H), 1.51-1.45 (m, 1H), 1.21 (t, J=7.2Hz, 3H).

[0603] Step 2:

[0604] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0605]

[0606] At 0–10 °C, Et3N (22.2 mL, 159.1 mmol) was added to a stirred solution of (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester fumarate (10 g, 31.8 mmol) in DMF (100 mL) and stirred for 10 min. At 0–10 °C, 2,5-dioxopyrrolidone-1-yl(2-methoxyethyl) carbonate (13.8 g, 63.6 mmol) was added to the reaction mixture, followed by DMAP (0.39 g, 3.18 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h while being monitored by TLC. The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (500 mL). The organic layer was washed with cold water (2 × 100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (7.3 g, 24.3 mmol, 76% yield) as a red syrup. This substance was used as is in the next step without further purification.

[0607] 1 H NMR (400MHz, CDCl3): δ5.87 (brs, 1H), 4.90-4.84 (m, 1H), 4.60-4.51 (m, 2H), 4.35-4.20 (m, 4 H), 3.653.58 (m, 2H), 3.38 (s, 3H), 2.192.07 (m, 3H), 1.721.67 (m, 1H), 1.33 (t, J=7.2Hz, 3H).

[0608] Step 3:

[0609] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (intermediate 2)

[0610]

[0611] BH3 was added to a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (7.3 g, 24.3 mmol) in anhydrous THF (73 mL) at 0–10 °C. DMS (10 M solution, 14.6 mL, 146.0 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 16 hours, monitored by TLC. The reaction was cooled to 0–10 °C, and EtOH (60 mL) was added dropwise. The reaction was stirred at 50 °C for 16 hours and the volatiles were distilled off under reduced pressure to give 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (intermediate 2) (7.0 g, 24.4 mmol) as a colorless, viscous liquid. This substance was used as is in the next step without further purification.

[0612] 1 H NMR (400MHz, CDCl3): δ4.53-4.49(m, 1H), 4.30-4.18(m, 4H), 3.93-3.80(m, 4 H), 3.63-3.59 (m, 2H), 3.38 (s, 3H), 1.31-1.20 (m, 4H), 1.17 (t, J=7.2Hz, 3H)

[0613] General Synthesis Scheme 3

[0614]

[0615] Example 10:

[0616] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0617]

[0618] Step 1:

[0619] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0620]

[0621] DIPEA (0.45 mL, 2.6 mmol) was added to a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (250 mg, 0.87 mmol) in THF (5 mL) at 0–10 °C under nitrogen atmosphere, and the mixture was stirred for 20 min. 6-(cyclohexyloxy)-pyridine-3-sulfonyl chloride (360 mg, 1.31 mmol) was dissolved in THF (5 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at 60 °C for 16 h while monitoring by TLC. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel column chromatography (60 to 120 mesh, 15% to 40% EtOAc in hexane) to give 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (240 mg, 0.45 mmol, 52% yield) as a yellow gel. MS (ESI): m / z 526.2 [M+H] + .

[0622] Step 2:

[0623] Synthesis of (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0624]

[0625] Following a similar procedure to step 4 of Example 1, (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (150 mg, 0.30 mmol, 66% yield) was obtained as a brown gel. This substance was used unchanged in the next step without further purification. MS (ESI): m / z 498.2 [M+H] + .

[0626] Step 3:

[0627] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0628]

[0629] BOP-Cl (191 mg, 0.75 mmol) and DIPEA (0.16 mL, 0.9 mmol) were added to a stirred solution of (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (150 mg, 0.30 mmol) in DCM (3 mL) at 0 to 10 °C. The reaction was stirred for 30 min, and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (46 mg, 0.39 mmol) was added. The reaction mixture was warmed to room temperature over 30 min and stirred for 16 h, monitored by TLC. The reaction was quenched at 0 °C with ice-cold water (20 mL), and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-methoxyethyl(1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (180 mg, 0.30 mmol) as a yellow gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 595.3 [MH] - .

[0630] Step 4:

[0631] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 10)

[0632]

[0633] p-TSA (271 mg, 1.42 mmol) was added to a stirred solution of 2-methoxyethyl(1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (170 mg, 0.28 mmol) in MeOH (4 mL). The reaction was stirred at room temperature for 2 h while being monitored by TLC. The reaction was quenched with saturated aqueous NaHCO3 solution (5 mL) and extracted with DCM (3 × 20 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 prep HPLC (Table 2, Method 3) and the fractions were lyophilized to give 2-methoxyethyl (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 10) as a grayish-white solid (38.4 mg, 0.075 mmol, 26% yield in 2 steps).

[0634] MS(ESI): m / z 513.2[M+H]+ ；1 H NMR (400MHz, DMSO-d6): δ10.64 (brs, 1H), 8.78 (brs, 1H), 8.46 (d, J=2.4Hz, 1H), 7.9 1 (dd, J=2-4, 8.8Hz, 1H), 6.89 (d, J=8.8Hz, 1H), 5.11-5.02 (m, 1H), 4.70-4.35 (m, 1H ), 4.31-4.20(m, 1H), 4.12-3.98(m, 2H), 3.91-3.78(m, 1H), 3.61-3.35(m, 4H), 3.23 (s, 3H), 2.00-1.89 (m, 2H), 1.89-1.75 (m, 2H), 1.75-1.69 (m, 2H), 1.60-1.30 (m, 8H)

[0635] Similarly, the following examples were prepared by following the same or similar methods as described in Example 10.

[0636] Table 5

[0637]

[0638]

[0639] General Synthesis Scheme 4

[0640]

[0641] Example 14:

[0642] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0643]

[0644] Step 1:

[0645] Synthesis of 8-(tert-butyl)-2-ethyl(1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0646]

[0647] Et3N (0.2 mL, 1.40 mmol) was added to a stirred solution of (1S,2S,5R)-8-tert-butyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (200 mg, 0.70 mmol) in DCM (5 mL) at 0–10 °C under a nitrogen atmosphere, and the mixture was stirred for 20 min. 5-Fluoropyridine-2-sulfonyl chloride (205 mg, 1.05 mmol) was dissolved in DCM (2 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at room temperature for 16 h while monitoring by TLC. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (100 to 200 mesh, 20% EtOAc in hexane) to give 8-(tert-butyl)-2-ethyl(1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (200 mg, 0.45 mmol, 64% yield) as a grayish-white solid. MS (ESI): m / z 444.4 [M+H] + .

[0648] Step 2:

[0649] Synthesis of 8-(tert-butyl)-2-ethyl(1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0650]

[0651] At room temperature, Cs₂CO₃ (219 mg, 0.67 mmol) was added to a stirred solution of 8-(tert-butyl)-2-ethyl(1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (200 mg, 0.45 mmol) in DMF (3 mL), followed by the addition of 4-fluorophenol (50 mg, 0.45 mmol) in DMF (1 mL). The mixture was stirred at 60 °C for 4 h while being monitored by TLC. The reaction mixture was cooled to room temperature, quenched with ice-cold water (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100 to 200 mesh, 10% EtOAc in hexane) to give 8-(tert-butyl)-2-ethyl(1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (170 mg, 0.31 mmol, 68% yield) as a colorless liquid. MS (ESI): m / z 536.2 [M+H] + .

[0652] Step 3:

[0653] Synthesis of ethyl (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0654]

[0655] Following a similar procedure as described in step 2 of Example 1, (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (140 mg, 0.31 mmol, quantified) was obtained as a colorless liquid. MS (ESI): m / z 436.2 [M+H] + .

[0656] Step 4:

[0657] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0658]

[0659] Following a similar procedure as described in step 3 of Example 1, 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (150 mg, 0.27 mmol, 87% yield) was obtained as a colorless liquid. MS (ESI): m / z 5382 [M+H] + .

[0660] Step 5:

[0661] Synthesis of (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0662]

[0663] Following a similar procedure as described in step 4 of Example 1, (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (150 mg, 0.28 mmol, quantified) was obtained as a colorless, viscous gel. MS (ESI): m / z 510.4 [M+H] + .

[0664] Step 6:

[0665] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0666]

[0667] BOP-Cl (100 mg, 0.39 mmol) was added to a stirred solution of ((1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (80 mg, 0.15 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 to 10 °C. At ℃, DIPEA (0.08 mL, 0.47 mmol) was added to the reaction mixture and stirred for 10 minutes, followed by the addition of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine hydrochloride (23 mg, 0.204 mmol) at the same temperature. The reaction mixture was warmed to room temperature over 30 minutes and stirred for 2 hours, monitored by TLC. At 0℃, the reaction mixture was quenched with ice-cold water (20 mL) and treated with DCM (3 × 20 mL). The aqueous layer was extracted with 20 mL of extract. The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-methoxyethyl(1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.16 mmol, quantified) as a grayish-white solid. This substance was used as is in the next step without further purification. MS (ESI): m / z 609 [M+H] + .

[0668] Step 7:

[0669] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 14)

[0670]

[0671] Purification was performed according to a similar procedure as described in step 6 of Example 1 and by RP prep HPLC (Table 2, Method 3) to obtain 2-methoxyethyl(1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 14) as a grayish-white solid (10 mg, 0.019 mmol, 11% yield).

[0672] MS(ESI): m / z 525.2 [M+H] + ;1 H NMR (400MHz, DMSO-d6): δ10.60 (brs, 1H), 8.73 (brs, 1H), 8.49 (d, J=2.0Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.46 (dd, J=2.8, 8.8Hz.1H), 7.36-7.25 (m, 4H ), 4.48-4.38(m, 1H), 4.30-4.20(m, 1H), 4.12-4.02(m, 2H), 3.80-3.68(m, 1H), 3.54-3.40(m, 4H), 3.23(s, 3H), 1.93-1.68(m, 2H), 1.58-1.30(m, 2H)

[0673] Similarly, the following examples were prepared by following the same or similar methods as described in Example 14.

[0674] Table 6

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] General Synthesis Scheme 5

[0681]

[0682] Example 24:

[0683] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0684]

[0685] Step 1:

[0686] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0687]

[0688] DIPEA (3.7 mL, 20.9 mmol) was added to a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (2 g, 6.98 mmol) in THF (10 mL) at 0–10 °C under nitrogen atmosphere, and the mixture was stirred for 20 min. 6-Fluoropyridine-3-sulfonyl chloride (2 g, 10.4 mmol) was dissolved in THF (10 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at 60 °C for 16 h while being monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were 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 to 200 mesh, 15% to 25% EtOAc in hexane) to give 2-ethyl 8-(2-methoxyethyl)(1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (2.1 g, 4.71 mmol, 67% yield) as a pale yellow gel.

[0689] MS(ESI): 446.1 [M+H] + ; 1 H NMR (400MHz, CDCl3): 8.77-8.75 (m, 1H), 8.41-8.38 (m, 1H), 7.11 (dd, J=2.4Hz, 8.4Hz, 1H), 4.47-4.39 (m, 2H), 4.38-4.29 (m, 1H), 4.28-4.19 (m, 3H), 4.13-4.06 (m, 1H), 3.58-3.56 (m, 2H), 3.38 (s, 3H), 3.21-3.13 (m, 2H), 2.46-2.38 (m, 1H), 2.00-1.98(m, 1H), 1.84-1.71(m, 1H), 1.70-1.62(m, 1H), 1.34(t, J=7.2Hz, 3H).

[0690] Step 2:

[0691] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((6-(4-(difluoromethoxy)-phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0692]

[0693] K₂CO₃ (530 mg, 3.84 mmol) was added to a stirred solution of 4-(difluoromethoxy)phenol (204 mg, 1.28 mmol) in ACN (5 mL) at 0–10 °C under nitrogen atmosphere and stirred for 20 min. 2-Ethyl 8-(2-methoxyethyl)(1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (570 mg, 1.28 mmol) was dissolved in ACN (10 mL) and added to the reaction mixture at the same temperature. The reaction was stirred at 50 °C for 4 h while being monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100 to 200 mesh, 15% to 30% EtOAc in hexane) to give 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (450 mg, 0.77 mmol, 60% yield) as a light brown gel. MS (ESI): m / z 586.1 [M+H] + .

[0694] Step 3:

[0695] Synthesis of (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0696]

[0697] Following a similar procedure as described in step 4 of Example 1, (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (490 mg, 0.88 mmol, 79% yield) was obtained as a light brown gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 558.1 [M+H] + .

[0698] Step 4:

[0699] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0700]

[0701] Following a similar procedure as described in step 3 of Example 10, 2-methoxyethyl(1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (530 mg, 0.80 mmol) was obtained as a brown gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 657.2 [M+H] + .

[0702] Step 5:

[0703] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 24)

[0704]

[0705] p-TSA (767 mg, 4.03 mmol) was added to a stirred solution of 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(difluoromethoxy)-phenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (530 mg, 0.80 mmol) in MeOH (10 mL) at 0 to 10 °C. The reaction mixture was stirred at room temperature for 2 h while being monitored by TLC. The reaction was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to obtain 480 mg of a semipure product. This semipure product was treated with 20% MTBE in i-PrOAC (4.8 mL) and stirred at room temperature for 16 hours. The precipitated solid was filtered, washed with MTBE (2 mL), dissolved in DCM (20 mL), and washed with a saturated NaHCO₃ aqueous solution (2 × 5 mL). The organic layer was dried with anhydrous Na2SO4, filtered, evaporated under reduced pressure, and lyophilized with ACN:H2O (1:1, 2 mL) to give 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(difluoromethoxy)-phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 24) as a grayish-white solid (130 mg, 0.23 mmol, 2-step yield 26%).

[0706] MS(ESI): m / z573.1[M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.65(brs, 1H), 8.77(brs, 1H), 8.42(s, 1H), 8.12(d d, J=2.4, 8.8Hz, 1H), 7.30-7.26 (m, 4H), 7.25 (t, J=74.0Hz, 1H), 7.20 (d, J=8. 8Hz, 1H), 4.70-4.35 (m, 1H), 4.32-4.20 (m, 1H), 4.14-3.99 (m, 2H), 3.95-3.80 (m, 1H), 3.64-3.35 (m, 4H), 3.23 (s, 3H), 2.05-1.71 (m, 2H), 1.70-1.48 (m, 2H).

[0707] Similarly, the following examples were prepared by following the same or similar methods as described in Example 24.

[0708] Table 7

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718] Example 41:

[0719] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0720]

[0721] Step 1:

[0722] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0723]

[0724] DIPEA (1.2 mL, 5.2 mmol) was added to a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (500 mg, 1.74 mmol) in THF (5 mL) at 0–10 °C under nitrogen atmosphere, and the mixture was stirred for 20 min. 3,4-Difluorobenzenesulfonyl chloride (557 mg, 2.61 mmol) was dissolved in THF (5 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at 60 °C for 16 h while being monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (60 to 120 mesh, 15% to 25% EtOAc in hexane) to give 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester as a colorless gel (360 mg, 0.78 mmol, 44% yield). MS (ESI): 463.2 [M+H] + .

[0725] Step 2:

[0726] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0727]

[0728] Under nitrogen atmosphere, at 0–10 °C, K₂CO₃ (322 mg, 2.34 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-4-ol (115 mg, 1.17 mmol) in ACN (4 mL) and stirred for 20 min. 2-Ethyl 8-(2-methoxyethyl)(1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (360 mg, 0.78 mmol) was dissolved in ACN (6 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at 50 °C for 6 h while being monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100 to 200 mesh, 15% to 25% EtOAc in hexane) to give 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester as a colorless liquid (300 mg, 0.55 mmol, 71% yield). MS (ESI): m / z 541.2 [M+H] + .

[0729] Step 3:

[0730] Synthesis of (1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0731]

[0732] Following a similar procedure as described in step 4 of Example 1, (1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (220 mg, 0.43 mmol, 80% yield) was obtained as a colorless gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 513.2 [M+H]+.

[0733] Step 4:

[0734] Synthesis of 2-methoxyethyl(1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)-oxy)phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0735]

[0736] HATU (233 mg, 0.61 mmol) and DIPEA (0.22 mL, 1.23 mmol) were added to a stirred solution of (1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (210 mg, 0.41 mmol) in DMF (4 mL) at 0 to 10 °C, and stirred for 30 min. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (62 mg, 0.53 mmol) was added, and the mixture was warmed to room temperature over 30 min and stirred for 16 h, monitored by TLC. The reaction was quenched with cold water (10 mL), and the aqueous layer was extracted with Et0Ac (2 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-methoxyethyl(1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (210 mg, 0.34 mmol, quantified) as a colorless oil. This substance was used as is in the next step without further purification; MS (ESI): m / z 610.2 [MH].

[0737] Step 5:

[0738] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 41)

[0739]

[0740] Following a similar procedure as described in step 5 of Example 24, and purified by RP prep HPLC (Table 2, Method 3), 2-methoxyethyl(1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 41) as a grayish-white solid (42 mg, 0.079 mmol, 2-step yield 19%).

[0741] MS(ESI): m / z 528.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.63 (brs, 1H), 8.76 (brs, 1H), 7.89 (s, 1H), 7.67 (d, J=10.4Hz, 1H), 7.52-7.48 (m, 2H), 7.14 (t, J=8.4Hz, 1H), 4.70-4.35 ( m, 1H), 4.30-4.19 (m, 1H), 4.11-3.90 (m, 2H), 3.83 (s, 3H), 3.68-3.55 (m, 1 H), 3.54-3.35 (m, 4H), 3.23 (s, 3H), 1.99-1.70 (m, 2H), 1.60-1.39 (m, 2H).

[0742] Example 42:

[0743] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0744]

[0745] Step 1:

[0746] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3,4,5-trifluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0747]

[0748] Following a similar procedure as described in step 1 of Example 41, 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3,4,5-trifluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (400 mg, 0.83 mmol, 48% yield) was obtained as a colorless gel. This substance was used as is in the next step without further purification. MS (ESI): m / z 481.2 [M+H] + .

[0749] Step 2:

[0750] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0751]

[0752] Following a similar procedure as described in step 2 of Example 41, 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (300 mg, 0.54 mmol, 64% yield) was obtained as a colorless liquid. This substance was used as is in the next step without further purification. MS (ESI): m / z 559.2 [M+H] + .

[0753] Step 3:

[0754] Synthesis of (1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0755]

[0756] Following a similar procedure as described in step 4 of Example 1, (1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (180 mg, 0.34 mmol, 65% yield) was obtained as a colorless gel. This substance was used as is in the next step without further purification. MS (ES1): m / z 531.2 [M+H]+.

[0757] Step 4:

[0758] Synthesis of 2-methoxyethyl(1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0759]

[0760] Following a similar procedure as described in step 4 of Example 41, 2-methoxyethyl(1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (200 mg, 0.32 mmol, quantified) was obtained as a colorless liquid. This substance was used as is in the next step without further purification. MS (ESI): m / z 628.2 [MH] - .

[0761] Step 5:

[0762] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 42)

[0763]

[0764] Following a similar procedure as described in step 5 of Example 24, and purified by RP prep HPLC (Table 2, Method 3), 2-methoxyethyl(1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (Example 42) (32 mg, 0.058 mmol, 2-step yield 18%) was obtained as a grayish-white solid. MS(ESI): m / z 546.2[M+H]+; 1H NMR (400MHz, DMSO-d6): δ10.65 (brs, 1H), 8.79 (brs, 1H), 7.69 (s, 1H), 7.66-7.61 (m, 2H), 7.33 (s, 1H), 4.69-4.36 (m, 1H), 4.33-3.9 9 (m, 3H), 3.98-3.80 (m, 1H), 3.74 (s, 3H), 3.69-3.59 (m, 1H), 3.52-3.40 (m, 3H), 3.23 (s, 3H), 1.99-1.72 (m, 2H), 1.70-1.42 (m, 2H).

[0765] Synthesis Scheme 6

[0766]

[0767] Example 43:

[0768] Synthesis of 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0769]

[0770] Step 1:

[0771] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-(methoxymethoxy)-phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0772]

[0773] At room temperature, K₂CO₃ (372 mg, 2.69 mmol) was added to a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (400 mg, 0.89 mmol) in ACN (10 mL), followed by the addition of 4-(methoxymethoxy)phenol (207 mg, 1.35 mmol) in ACN (5 mL). The reaction was stirred at 50 °C for 6 h while being monitored by TLC. The reaction was cooled to room temperature, quenched with ice-cold water (20 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (100 to 200 mesh, 20% to 30% EtOAc in hexane) to give 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-(methoxymethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (380 mg, 0.65 mmol, 73% yield) as a light brown syrup. MS (ESI): m / z 580.3 [M+H] + .

[0774] Step 2:

[0775] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0776]

[0777] At 0 to 10 °C, a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-(methoxymethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (380 mg, 0.65 mmol) in THF (10 mL) was added to 4 M HCl in dioxane (7.6 mL) and stirred at room temperature for 2 h while monitoring by TLC. The volatiles were evaporated to dryness to obtain 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (340 mg, 0.63 mmol, 97% yield) as a light brown gel. MS(ESI): m / z536.2[M+H] + .

[0778] Step 3:

[0779] Synthesis of 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-(fluoromethoxy)-phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester

[0780]

[0781] At 0–10 °C, Cs₂CO₃ (414 mg, 1.27 mmol) was added to a stirred solution of 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (340 mg, 0.63 mmol) in DMF (5 mL) and stirred for 10 min. At the same temperature, dimethyl 2-((fluoromethyl)(phenyl)-14-sulfaneylidene)malonate (259 mg, 0.95 mmol) in DMF (2 mL) was added to the reaction mixture. The reaction was stirred at 60 °C for 16 h while being monitored by TLC. The reaction was cooled to room temperature, quenched with ice-cold water (15 mL), and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combined rapid reverse-phase purification (10% to 40% ACN in H₂O) and the pure fraction was lyophilized to give 2-ethyl-8-(2-methoxyethyl)(1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid ester (180 mg, 0.32 mmol, 50% yield) as a light brown syrup. MS (ESI): m / z 568.0 [M+H] + .

[0782] Step 4:

[0783] Synthesis of (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0784]

[0785] Following a similar procedure as described in step 4 of Example 1, (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (150 mg, 0.27 mmol, 87% yield) was obtained as a brown gel. This substance wa...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: in: It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; X is -C(=O)- or -S(=O)2-; Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R 5 )-; where Y, if asymmetric, corresponds to Write in the order of If nitrogen is If the connection point on the upper side is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH- or -N(R 5 )-; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 、-C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-C(=O)-N(R 6 )2, -C1-C6 alkylene-C(=O)-C4-C5 heterocycloalkyl, -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)OH, -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, Each R 3 and each R 4 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -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 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl or -C1-C6 haloalkyl or halogen; n is 0, 1, or 2; p is 0, 1, 2 or 3; and q is 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein It is phenyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(=O)2-.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(=O)-.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (Ia): in: R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 、-C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-C(=O)-N(R 6 )2, -C1-C6 alkylene-C(=O)-C4-C5 heterocycloalkyl, -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), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, Each R 3 and each R 4 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -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 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl or -C1-C6 haloalkyl or halogen; n is 0, 1, or 2; p is 0, 1, 2 or 3; and q is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

8. The compound according to any one of claims 1, 2, 4 and 5, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (Ib): in: R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 、-C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-C(=O)-N(R 6 )2, -C1-C6 alkylene-C(=O)-C4-C5 heterocycloalkyl, -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), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, Each R 3 and each R 4 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -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 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl or -C1-C6 haloalkyl or halogen; n is 0, 1, or 2; p is 0, 1, 2 or 3; and q is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

9. The compound according to any one of claims 1, 2, 4 and 5, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (Ic): in: is a C2-C9 heterocycloalkyl group; Y is a direct bond, -O-, -CH2- or -C(=O)-; If nitrogen is If the connection point on the right is used to connect to Y, then 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, -C1-C6 alkylene-C(=O)-N(R 6 )2, -C1-C6 alkylene-C(=O)-C4-C5 heterocycloalkyl, -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), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, Each R 3 and each R 4 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -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 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl or -C1-C6 haloalkyl or halogen; n is 0, 1, or 2; p is 0, 1, 2 or 3; and q is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

10. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (II): in: It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; X is -C(=O)- or -S(=O)2-; Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R 5 )-; where Y, if asymmetric, corresponds to Write in the order of If nitrogen is If the connection point on the upper side is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH- or -N(R 5 )-; 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 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl or -C1-C6 haloalkyl or halogen; p is 0, 1, 2 or 3; and q is 0, 1, 2 or 3.

11. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (III): in: It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; Y is a direct bond, -O-, -CH2O-, -OCH2-, -CH2-, -C(=O)-, -C(=O)NH-, or -N(R 5 )-; where Y, if asymmetric, corresponds to Write in the order of If nitrogen is If the connection point on the upper side is used to connect Y, then Y cannot be -O-, -CH2O-, -C(=O)NH- or -N(R 5 )-; 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 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; p is 0, 1, 2 or 3; and q is 0, 1, 2 or 3.

12. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (IIIa): in: It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; 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 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; and p is 0, 1, 2 or 3.

13. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIIb): in: It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; 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 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; p is 0, 1, 2 or 3; and q is 0, 1, 2 or 3.

14. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (IIIc): in: It is phenyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl or C2-C9 heteroaryl; 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 independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , C1-C6 haloalkoxy, -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 S02R 7 、-SO2R 7 、-SO2N(R 6 )2 or phenyl optionally substituted by halogen; Each R 6 independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; or -N(R 6 )2 represents a C3-C5 heterocycloalkyl group; Each R 7 Independently selected from -C1-C6 alkyl, -C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 Independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl are optionally substituted at each occurrence by -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; and p is 0, 1, 2 or 3.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 are independently selected from 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 )2.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 .

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogen and -C1-C6 alkyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

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

21. The compound of any one of claims 1 to 11 or 13, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 are independently selected from 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 )2.

22. The compound of any one of claims 1 to 11 or 13 or 21, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 .

23. A compound as claimed in any one of claims 1 to 11 or 13 or 21 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogen and -C1-C6 alkyl.

24. The compound of any one of claims 1 to 11 or 13 or 21 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

25. The compound of any one of claims 1 to 11 or 13 or 21 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

26. The compound of any one of claims 1 to 11 or 13, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

27. The compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 9, wherein R 2 It is -C(=O)NH(OH).

28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Yes -C(=O)OR 6 .

29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen, -C1-C6 alkyl, -C1-C6 alkylene, -OR 9 or -C1-C6 alkylene-N(R 9 )2.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is -C1-C6 alkylene-OR 9 .

31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It is a -C1-C6 alkyl group.

32. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is a -C1-C6 alkyl group.

33. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

34. The compound of claim 1, which is selected from the following compounds or pharmaceutically acceptable salts or solvates thereof:

35. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or solvate thereof.

36. A method for treating a disease, disorder or condition selected from the following in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt or solvate thereof: Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, impaired cardiac contractility, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19-related 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-induced myocardial fibrosis, chemotherapeutic cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic 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 renal diseases, and chronic allograft nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-related nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein 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, tubulointerstitial fibrosis, Alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, steatosis, 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 scleroderma pigmentosa.

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