Diazabicyclooctane derivatives useful as matrix metalloproteinase inhibitors

Abstract

This specification provides compounds that are MMP inhibitors, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in the treatment of a disease, disorder or condition selected from cardiovascular disease, pulmonary disease, renal disease, hepatic disease, and pigmented scleroderma. [Formula 1] JPEG2025512125000354.jpg62170

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from Polish Patent Application No. P.440789 (filed March 29, 2022) and U.S. Provisional Patent Application No. 63 / 324,713 (filed March 29, 2022), the contents of which are incorporated herein by reference. [Background technology]

[0002] Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide (The Global Burden of Disease: 2004 Update. In: World Health Organization; 2004). Despite progress in treating risk factors (Circulation. 2017;135(10):e146), by 2030, nearly half of the US population will suffer from CVD.

[0003] Cardiac injury, valvular heart disease such as aortic stenosis, vascular hypertension, and aging are major factors leading to pressure overload of the cardiac pumping function. Left ventricular hypertrophy is the heart's normal response to such pressure overload. Hypertrophy allows cardiomyocytes to generate the additional force required to compensate for the increased pressure overload and maintain essential pumping function. At least 10% of the population in developed countries suffers from severe hypertension, which can lead not only to left ventricular hypertrophy and secondary heart failure, but also to myocardial infarction and fatal arrhythmias (1). Aging is another common cause of pumping pressure overload, leading to left ventricular diastolic dysfunction and concentric remodeling, although systolic function is often unaffected until later in life (2). Initially, appropriate compensatory left ventricular remodeling may progress to a pathophysiological stage. However, as cardiomyocytes degenerate due to ischemia or other injuries, fibrosis progresses, the ventricles dilate, and the cardiac pumping function gradually declines (3-9).

[0004] The maladaptive remodeling process leading to heart failure can be conceptually divided into cardiomyocyte hypertrophy and alterations in the normal patterning of the extracellular matrix (ECM) network. Alterations in both systolic and diastolic function can result from these two categories (10). The cardiac ECM provides structural support to the myocardium and produces cytokines, growth factors, and regulatory proteins that alter myocardial function (11). The emergence of adverse ECM remodeling represents a critical pathogenetic milestone in the overt progression to heart failure. Normal basement membranes, fibronectin, laminin, and collagen, connect cardiomyocytes to the interstitial ECM and facilitate transmembrane signaling via integrin receptors (12), and collagen fibers structurally organize myocytes and myofibers, allowing optimal force generation and transmission. However, loss of collagen fibrils and struts can result in myocardial contractile slippage, ventricular dilatation, and exacerbated systolic dysfunction (13). Furthermore, as the disease progresses due to the worsening of the above factors, fibrous collagen accumulates in the left ventricular myocardium, leading to increased myocardial stiffness ( 2 , 14 , 15 ).

[0005] The cardiac extracellular matrix, like skeletal bone and other structural components of the body, undergoes continuous synthesis, degradation, and resynthesis to maintain its inherent structure and strength. Normal proteolysis is necessary for this healthy remodeling of the cardiac ECM, but proteolysis is also involved in adverse remodeling as part of disease progression, including progressive heart failure. Notably, increased activation and expression of zinc-dependent proteases, matrix metalloproteinases (MMPs), are associated with heart failure and contribute to the remodeling of progressive pump failure (16-18). The mammalian MMP superfamily comprises 25 members, including stromelysins, gelatinases, collagenases, matrilysins, membrane-type MMPs, and other MMPs (19). Their activity is endogenously regulated by tissue inhibitors of metalloproteinases (TIMPs: TIMPs 1-4), which generally bind noncovalently with active and pro-forms of MMPs to form 1:1 complexes with low selectivity. Myocardial ECM proteins serve as substrates for at least one cardiac MMP (20), which in turn inactivate and activate ECM-derived cytokines and growth factors (21, 22).

[0006] The involvement of MMPs in pathological myocardial remodeling, which leads to or exacerbates heart failure, has been characterized in both plasma and left ventricle of disease models and humans (8, 16-18, 23-26). While the majority of MMP substrates are accessible extracellularly, recent studies have demonstrated their intracellular role in regulating calcium handling, which is important for excitation-contraction coupling, and their direct effects on sarcomere function (47-53). In humans, elevated levels of MMP2 and MMP9 have been strongly associated with diastolic dysfunction or heart failure in numerous studies (54-61).

[0007] Evidence from both genetic and pharmacological interventions is emerging that MMPs are not only associated with, but also contribute to pathological left ventricular and global cardiac remodeling, leading to impaired pump function and disease. Nonselective pharmacological inhibition of MMPs has been demonstrated in animal models to significantly reduce the pathological remodeling associated with various disease processes (28, 40, 62-69). Data suggest that selective inhibition of MMPs, particularly preserving the activity of MMP1, is beneficial for cardiac remodeling. These data include MMP1, MMP2, MMP9, TIMP1, and TIMP3 (70-74). The strongest evidence raises the therapeutic hypothesis that selective inhibition of at least MMP2 and MMP9 may mitigate adverse cardiac effects following various interventions that result in cardiac pump failure (59, 75, 76).

[0008] MMP9 mice are protected from diastolic dysfunction and fibrosis accumulation (77) and post-infarction remodeling (59, 75). Expression of MMP2 and MMP9 has been shown to be elevated during pressure-overload-induced hypertrophy in both spontaneously hypertensive rats (66) and Dahl salt-sensitive hypertensive rats (43). Most convincingly, mice transgenic for MMP2 overexpression and mice transgenic for MMP9 overexpression exhibit pathologically fibrotic myocardium (78, 79), whereas mice genetically deficient in MMP2 and MMP9 are structurally and functionally protected in disease models of heart failure, a finding successfully recapitulated by prototypic pharmacological inhibitors of MMP2 and / or MMP9 (80, 81).

[0009] TACE / ADAM17 (tumor necrosis factor-α-converting enzyme; a disintegrin and metalloproteinase 17) is a soluble or membrane-bound metalloproteinase primarily involved in the activation of proTNFα, but also targets proteins such as fractalkine, amyloid precursor protein, and CD40. ADAM17 / TACE is involved in cancer, vascular disorders, and inflammatory diseases such as rheumatoid arthritis and focal ischemic injury. The catalytic domain of ADAM17 / TACE can cleave proTNFα and is used to screen inhibitors.

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[0011] There is a strong need for the development of therapies specifically targeted at the underlying cause of heart failure (HF), which is the impairment of the heart's pumping function. However, current standard treatments for HF and other CVDs do not correct the underlying defect that causes loss of pumping function—the loss of functioning cardiomyocytes. Rather, existing pharmacological therapies target peripheral aspects of the cardiovascular system, such as targeting blood pressure to reduce preload and afterload, reducing blood volume (aldosterone antagonists, diuretics), or lowering lipids that contribute to vascular disease.

[0012] Selective inhibition of matrix metalloproteinases provides a valuable therapeutic option for treating a variety of disorders associated with abnormal activity of matrix metalloproteinases, including, but not limited to, cardiovascular disease, pulmonary disease, renal disease, liver disease, and pigmented scleroderma.

[0013] Cardiovascular diseases of interest include, inter alia, cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, cardiac systolic dysfunction, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19 myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, pathological remodeling of the myocardium, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, and right ventricular hypertrophy.

[0014] The lung diseases of concern include idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD) and emphysema.

[0015] Eligible renal diseases include polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, chronic allograft nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, post-sepsis tubular injury, acute ischemic renal injury, contrast-induced renal injury, acute tubular injury after ischemia-reperfusion, end-stage renal disease, and tubulointerstitial fibrosis.

[0016] Target liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia-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

[0017] This disclosure provides, for example, compounds and compositions that are MMP inhibitors, their pharmaceutical uses, 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 to inhibit MMPs in warm-blooded animals, such as humans, for the treatment of heart failure and other CVDs, and / or the use of the disclosed compounds in the manufacture of such pharmaceuticals.

[0018] In one aspect, the present invention provides a compound of formula (I):

[0019] [ka]

[0020] (In the formula, [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; X is -C(=O)- or -S(=O)-; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)-, -C(=O)NH- or -N(R 5 )-and; where Y is the asymmetric case. [ka] are expressed in the order of; Nitrogen is bonded to Y [ka] When Y is the point of attachment in 5 )-rather than; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to C6 alkylene-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 -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, [ka] Each R 3and each R 4 are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, -C1-C6 haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 or a pharmaceutically acceptable salt or solvate thereof.

[0021] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is phenyl. In some aspects, the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, where Y is -O-. In some aspects, the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, where X is -S(=O)2-. In some aspects, the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, where X is -C(=O).

[0022] In some embodiments, the present invention provides a compound of formula (Ia):

[0023] [ka]

[0024] (In the formula, R 1 , R 2 , R 3 , R 4 , n, p and q are as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0025] In some embodiments, the present invention provides a compound of formula (Ib):

[0026] [ka]

[0027] (In the formula, R 1 , R 2 , R 3 , R 4 , n, p and q are as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0028] In some embodiments, the present invention provides a compound of formula (Ic):

[0029] [ka]

[0030] (In the formula, [ka] is a C2-C9 heterocycloalkyl; R 1 , R 2 , R 3 , R 4 , Y, n, p and q are as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0031] In some embodiments, the present invention provides a compound of formula (II):

[0032] [ka]

[0033] (In the formula, [ka] R 1 , R 3 , R 4 , X, Y, p and q are as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0034] In some embodiments, the present invention provides a compound of formula (III):

[0035] [ka]

[0036] (In the formula, [ka] R 1 , R 3 , R 4 , Y, p and q are as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0037] In some embodiments, the present invention provides a compound of formula (IIIa):

[0038] [ka]

[0039] (In the formula, [ka] R 1 , R 3 and p is as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0040] In some embodiments, the present invention provides a compound of formula (IIIb):

[0041] [ka]

[0042] (In the formula, [ka] R 1 , R 3 , R 4 , p and q are as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0043] In some embodiments, the present invention provides a compound of formula (IIIc):

[0044] [ka]

[0045] (In the formula, [ka] R 1 , R 3 and p is as defined in formula (I). The present invention provides a compound of formula (I) having the structure:

[0046] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically 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 , -SO2N(R 6In some embodiments, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from the group consisting of phenyl, optionally substituted with halogen, and phenyl. 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently selected from halogen and -C1-C6 alkyl. In some embodiments, the present invention provides a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, the present invention provides a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb) or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb) or Formula (IIIc), 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 , -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), (II), (III) or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from the group consisting of phenyl, ... 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and -C1-C6 alkyl. In some aspects, the invention provides a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some aspects, the invention provides a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), or Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), or Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib) or Formula (Ic), wherein R is —C(═O)NH(OH), or a pharmaceutically acceptable salt or solvate thereof. 1 -C(=O)OR 6In some aspects, the present invention provides a compound of formula (I), formula (Ia), formula (Ib) or formula (Ic), wherein R 6 is hydrogen, -C1-C6 alkyl, -C1-C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb) or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb) or Formula (IIIc), wherein R 9 In some embodiments, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is -C1-C6 alkyl. In some aspects, the present invention provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0047] In some aspects, the present invention provides a compound comprising:

[0048] [Table A-1]

[0049] [Table A-2]

[0050]

Table A-3

[0051]

Table A-4

[0052]

Table A-5

[0053]

Table A-6

[0054]

Table A-7

[0055]

Table A-8

[0056]

Table A-9

[0057]

Table A-10

[0058]

Table A-11

[0059]

Table A-12

[0060] [Table A-13]

[0061] [Table A-14]

[0062] or a pharmaceutically acceptable salt or solvate thereof.

[0063] In another aspect, this specification discloses a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or binder and a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof.

[0064] In another aspect, this specification provides a method for treating cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVI, or other conditions comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof. D-19 myocarditis, COVID-19 myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, myocardial pathological remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, chronic allograft nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, postsepsis renal tubular damage Disclosed are methods for treating a disease, disorder, or condition selected from: kidney injury, acute ischemic kidney injury, contrast-induced kidney injury, acute tubular damage after ischemia-reperfusion, end-stage renal disease, tubulointerstitial fibrosis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia-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.

[0065] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0066] Detailed Description of the Invention In this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, "an agent" includes plural agents, and "the cell" includes one or more cells (or cells) and their equivalents. When a range is expressed for a physical property, such as molecular weight, or a chemical property, such as a chemical formula, it is intended to include all combinations and subcombinations of the range and specific embodiments therein. The term "about" in connection with a numerical value or range means that the numerical value or range is approximate within experimental variation (or statistical experimental error), and that the numerical value or range may vary from 1% to 15% of the numerical value or range. The term "comprising" (and related terms such as "having") is not intended to exclude other specific embodiments, such as embodiments of the materials, compositions, methods, or manufacturing processes described herein that may "consist of" or "consist essentially of" the described feature.

[0067] definition In this specification and claims, unless specified to the contrary, the following terms shall have the meanings indicated below.

[0068] Terms used in the specification may be preceded or followed by a single dash "-" or a double dash "=" to indicate the bond order of the bond between the substituent and its parent moiety, with a single dash indicating a single bond and a double dash indicating a double bond. In the absence of a single or double dash, it is understood that the bond between the substituent and its parent moiety is a single bond; further, substituents are intended to be read "left to right" unless the dash indicates otherwise. For example, C1-C6 alkoxycarbonyloxy and -OC(O)O-C1-C6 alkyl are the same functional group; similarly, arylalkyl and -alkylaryl are the same functional group.

[0069] In the present invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, back cover of Handbook of Chemistry and Physics, 67th ed., 1986-87.

[0070] In this specification, C1 to C x are C1~C2, C1~C3...C1~C x Includes C1~C x refers to the number of carbon atoms that make up the specified moiety (excluding substituents).

[0071] The terms "hydrogen," "hydrogen atom," and the symbol "H," as used herein as substituents in structural formulae such as Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), refer to a hydrogen atom that is bonded to the remainder of the molecule or substituent in question. For simplicity, hydrogen atoms bonded to carbon atoms are not shown in the structural formulae. It is understood that each carbon atom is bonded to the number of hydrogen atoms such that the carbon atom has four bonds.

[0072] A "saturated" or "fully saturated" compound means that the chemical structure does not contain any carbon-carbon double or triple bonds. For example, saturated cycloalkyl groups, as defined herein, include cyclohexyl, cyclopropyl, and the like.

[0073] "Unsaturated" or "partially saturated" means that the chemical structure contains one or more carbon-carbon double or triple bonds, but is not aromatic. For example, unsaturated cycloalkyl groups, as defined herein, include cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

[0074] "Amino" refers to the -NH2 radical.

[0075] "Cyano" refers to the -CN radical.

[0076] "Nitro" refers to the -NO2 radical.

[0077] "Oxa" refers to the -O- radical.

[0078] "Oxa" refers to the =O radical.

[0079] "Thioxo" refers to the =S radical.

[0080] "Imino" refers to the =NH radical.

[0081] "Oxime" refers to the =N-OH radical.

[0082] It is understood that "substituted" or "substituted" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, as well as the implicit proviso that the substitution results in a stable compound that is not spontaneously altered by, for example, rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0083] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Representative substituents include, for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, (cycloalkyl)alkoxyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, aminosulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, heterocyclylalkyl, aromatic or heteroaromatic moiety, aminoalkyl, haloalkyl, fluoroalkyl (such as trifluoromethyl), haloalkoxyl, cyano, or other substituents described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this specification, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0084] "Alkyl" or "alkylene" means an alkyl group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, and having 1 to 15 carbon atoms (e.g., -C1 to -C 15 alkyl) refers to a straight or branched hydrocarbon chain radical having 1 to 13 carbon atoms (e.g., -C1 to -C6). 13In certain embodiments, the alkyl has 1 to 8 carbon atoms (e.g., —C1-C8 alkyl). In other embodiments, the alkyl has 1 to 6 carbon atoms (e.g., —C1-C6 alkyl). In other embodiments, the alkyl has 1 to 5 carbon atoms (e.g., —C1-C5 alkyl). In other embodiments, the alkyl has 1 to 4 carbon atoms (e.g., —C1-C4 alkyl). In other embodiments, the alkyl has 1 to 3 carbon atoms (e.g., —C1-C3 alkyl). In other embodiments, the alkyl has 1 to 2 carbon atoms (e.g., —C1-C2 alkyl). In other embodiments, the alkyl has 1 carbon atom (e.g., —C1 alkyl). In other embodiments, the alkyl has 5 to 15 carbon atoms (e.g., —C5-C6 alkyl). 15 In other embodiments, the alkyl has 5 to 8 carbon atoms (e.g., —C5-C8 alkyl). In other embodiments, the alkyl has 2 to 5 carbon atoms (e.g., —C2-C5 alkyl). In other embodiments, the alkyl has 3 to 5 carbon atoms (e.g., —C3-C5 alkyl). In other 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 is attached to the rest of the molecule by a single bond. An alkylene is a diradical, attached to two parts of the molecule by two single bonds, such as in methylene (—CH2—) or ethylene (—CH2CH2— or —CH(—CH3)—). Unless stated otherwise in the specification, alkyl groups may contain one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f, -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f , -S(O) t OR a , -S(O) t R f and -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f are optionally substituted with alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl).

[0085] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as previously defined.

[0086] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkenyl has from 2 to 8 carbon atoms. In other embodiments, alkenyl has from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise stated in the specification, an alkenyl group may contain one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilanyl, -OR, or the like. a , -SR a , -OC(O)-R f , -N(R a )2, -C(O)R a , -C(O)ORa , -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 , -S(O) t OR a , -S(O) t R f and -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f are optionally substituted with alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl).

[0087] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkynyl has from 2 to 8 carbon atoms. In other embodiments, alkynyl has from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise stated in the specification, an alkynyl group may contain one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilanyl, -OR, or the like. 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 , -S(O) t OR a , -S(O) t R f and -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f are optionally substituted with alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl).

[0088] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen atoms and 6 to 18 carbon atoms, and at least one ring of the ring system is fully unsaturated, i.e., contains a delocalized (4n+2) π-electron system according to cyclic Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, ring systems such as benzene, fluorene, indane, indene, tetralin, and naphthalene, which correspond to phenyl, fluorenyl, indanyl, tetralinyl, and naphthalene radicals, respectively, and which can be further substituted. Unless otherwise explained in the specification, the term "aryl" or the prefix "ar" (e.g., "aralkyl") refers to any of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -Rb -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a , -R b -S(O) t OR a , -R b -S(O) t R a and -R b -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl; and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R cis a straight or branched alkylene or alkenylene chain). In particular, phenyl may be substituted with 1 to 5 substituents independently selected from the substituents described above. For example, phenyl substituted with halogen includes 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4,6-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-methyl-4-fluorophenyl, and 3,5-dimethyl-4-bromophenyl.

[0089] "Aryloxy" refers to a radical attached through an oxygen atom of the formula -O-aryl, where aryl is as previously defined.

[0090] "Aralkyl" is a group of the formula -R c -refers to the aryl radical, R c is an alkylene chain as previously defined, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical may be optionally substituted as previously described for an alkylene chain. The aryl part of the aralkyl radical may be optionally substituted as previously described for an aryl group.

[0091] "Aralkyloxy" refers to a radical attached through an oxygen atom of the formula -O-aralkyl, where aralkyl is as previously defined.

[0092] "Aralkenyl" refers to a group of the formula -R d -refers to the aryl radical, R d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical may be optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical may be optionally substituted as defined above for an alkenylene group.

[0093] "Aralkynyl" refers to a group of the formula -Re -refers to the aryl radical, R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0094] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems having from 3 to 15 carbon atoms. In certain embodiments, cycloalkyls have from 3 to 10 carbon atoms. In other embodiments, cycloalkyls have from 5 to 7 carbon atoms. A cycloalkyl is attached to the remainder of the molecule by a single bond. A cycloalkyl is saturated (i.e., contains only one C-C bond) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl has from 3 to 8 carbon atoms (e.g., -C3-C8 cycloalkyl). In other embodiments, a cycloalkyl has from 3 to 7 carbon atoms (e.g., -C3-C7 cycloalkyl). In other embodiments, a cycloalkyl has from 3 to 6 carbon atoms (e.g., -C3-C6 cycloalkyl). In another embodiment, cycloalkyl has 3 to 5 carbon atoms (e.g., —C3-C5 cycloalkyl). In another embodiment, cycloalkyl has 3 to 4 carbon atoms (e.g., —C3-C4 cycloalkyl). Partially unsaturated cycloalkyls are also referred to as “cycloalkenyls.” Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated in the specification, the term “cycloalkyl” includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b -OR a , -R b -OC(O)-R a , -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 , -R b -S(O) t OR a , -R b -S(O) t R a and -R b -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl; and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain).

[0095] "Halo" or "halogen" refers to a bromine, chlorine, fluorine, or iodine substituent.

[0096] "Haloalkyl" refers to an alkyl radical as defined above that is substituted with one or more halo radicals as defined above. Examples of haloalkyl include chloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, and 1-bromo-2-chloro-3-fluoropropyl.

[0097] "Fluoroalkyl" refers to an alkyl radical as defined above that is substituted with one or more fluoro radicals as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0098] "Haloalkoxy" refers to an alkoxy radical as defined above that is substituted by one or more halo radicals as defined above.

[0099] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring system radical having 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. "C2-C9 heterocycloalkyl" refers to a heterocycloalkyl radical as defined above having 2 to 9 carbon atoms and 1 to 4 heteroatoms. "C4-C5 heterocycloalkyl" refers to a heterocycloalkyl radical as defined above having 4 to 5 carbon atoms and 1 to 3 heteroatoms. Unless otherwise stated in the specification, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused, spiro, or bridged ring systems. The heteroatoms in a heterocycloalkyl radical may be oxidized. One or more nitrogen atoms, if present, may be quaternized. The heterocycloalkyl radical may be partially or fully saturated. In some embodiments, a heterocycloalkyl is attached to the remainder of the molecule through a ring atom. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl (especially morpholin-4-yl), octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless explained otherwise in the specification, the term “heterocycloalkyl” includes any of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b -OR a , -R b -OC(O)-R a , -R b-OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a , -R b -S(O) t OR a , -R b -S(O) t R a and -R b -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain).

[0100] "Heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring system having 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. "C2-C9 heteroaryl" refers to a radical derived from a 3- to 10-membered aromatic ring system having 2 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring of the ring system is fully unsaturated, i.e., contains a delocalized (4n+2) π-electron system according to the cyclic Hückel theory. Heteroaryl radicals are exemplified by pyridinyl, quinolinyl, oxazolyl, and benzoxazolyl (i.e., benzo[d]oxazolyl). Heteroaryl includes fused or bridged ring systems. The heteroatoms in a heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, may be quaternized. A heteroaryl is attached to the remainder of the molecule through an atom of the ring. Unless explained otherwise in the specification, the term "heteroaryl" includes any of alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b-N(R a )C(O)R a , -R b -N(R a )S(O) t R a , -R b -S(O) t OR a , -R b -S(O) t R a and -R b -S(O) t N(R a )2 (where t is 1 or 2, and each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is meant to include heteroaryl radicals as previously defined, optionally substituted by one or more substituents selected from: a straight or branched alkylene or alkenylene chain;

[0101] "N-heteroaryl" refers to a heteroaryl radical as defined above having at least one nitrogen, where the point of attachment of the heteroaryl radical to the rest of the molecule is through the nitrogen atom of the heteroaryl radical. The N-heteroaryl radical may be optionally substituted as previously described for heteroaryl radicals.

[0102] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom of the heteroaryl radical. The C-heteroaryl radical may be optionally substituted as previously described for heteroaryl radicals.

[0103] "Heteroaryloxy" refers to a radical attached through an oxygen atom of the formula -O-heteroaryl, where heteroaryl is as previously defined.

[0104] "Heteroarylalkyl" refers to a group of the formula -R c - refers to the heteroaryl radical, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkyl radical at said nitrogen atom. The alkylene chain of the heteroarylalkyl radical may be optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group.

[0105] "Heteroarylalkoxy" refers to a group of the formula -OR c - refers to a radical attached through an oxygen atom of a heteroaryl, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkyl radical at said nitrogen atom. The alkylene chain of the heteroarylalkoxy radical may be optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical may be optionally substituted as defined above for a heteroaryl group.

[0106] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomers of the compounds disclosed herein are intended to be contemplated. When a compound described herein contains an alkene double bond, the disclosure is intended to include both the E and Z geometric isomers (e.g., cis or trans) unless otherwise specified. Similarly, all isomers, racemic and optically pure forms, and all tautomers are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers about a benzene ring.

[0107] "Tautomer" refers to a molecule capable of migrating a proton from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of the tautomers exists. The exact ratio of the tautomers depends on several factors, including the physical state, temperature, solvent, and pH. Examples of tautomeric equilibrium include:

[0108] [ka] Includes:

[0109] "Optional" or "optionally" means that the modifying event or circumstance may or may not occur, including cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted aryl" or "optionally substituted aryl" means that the aryl radical may or may not be substituted, and includes both substituted and unsubstituted aryl radicals.

[0110] The term "prodrug" includes 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 may be used to improve absorption, distribution, metabolism, or excretion of a compound.

[0111] "Pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts of the compounds described herein are intended to encompass all pharmaceutically suitable salts. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0112] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like, which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable. Also included are salts formed with organic acids, such as fatty acid mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, representative salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base with a sufficient amount of the desired acid to produce the salt.

[0113] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some aspects, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0114] "I C 50 " refers to the amount, concentration or dose of a particular test compound that inhibits 50% of the maximal response in an assay.

[0115] As used herein, "subject" refers to a warm-blooded animal, such as a mammal, preferably a human or human child, that is suffering from or may be suffering from one or more of the diseases and disorders described herein.

[0116] The term "mammal" refers to a human, non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art will recognize that a treatment that reduces the severity of a disease in one species of mammal is predictive of the effectiveness of that treatment in another species of mammal.

[0117] An "effective amount" refers to an amount sufficient to achieve a desired biological effect. In combination with the teachings provided herein, various weighting factors, such as potency, relative bioavailability, patient weight, sex, age, medical history, severity of side effects, and preferred mode of administration, as well as the selection from among various active compounds, can be used to develop an effective prophylactic or therapeutic regimen that is effective in treating a particular subject without causing substantial undesirable toxicity. The effective amount for a particular application will vary depending on factors such as the disease or condition being treated, the compound of the present invention being administered, the size of the subject, or the severity of the disease or condition. Those of ordinary skill in the art can empirically determine effective amounts of the compounds of the present invention and / or other therapeutic agents without undue experimentation. Generally, it is preferable to use a maximum dose, i.e., the highest safe dose according to medical judgment. Multiple daily administrations are contemplated to achieve adequate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring peak or sustained plasma levels of the drug in the patient. "Administration" and "dosage" are used interchangeably herein.

[0118] As used herein, the terms "treatment," "alleviation," and "amelioration" are used interchangeably. These terms refer to an approach to achieving a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, even though the patient still suffers from the underlying disease, resulting in improvement in the patient. For prophylactic benefit, the composition is administered to a patient at risk of developing a particular disease or to a patient who reports one or more physiological symptoms of a disease, even though the patient has not been diagnosed with the disease.

[0119] compound The compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc) described herein are MMP inhibitors. In some aspects, the compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc) described herein and compositions comprising them are useful for treating cardiovascular diseases, disorders, or conditions, particularly heart failure.

[0120] In some embodiments, the present invention provides a compound of formula (I):

[0121] [ka]

[0122] (In the formula, [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; [ka] is phenyl, C3-C 10cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; X is -C(=O)- or -S(=O)-; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)-, -C(=O)NH- or -N(R 5 )-and; where Y is the asymmetric case. [ka] are expressed in the order of; Nitrogen is bonded to Y [ka] When Y is the point of attachment in 5 )-rather than; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to 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 -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, [ka] Each R 3 and each R 4are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, -C1-C6 haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 or a pharmaceutically acceptable salt or solvate thereof.

[0123] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0124] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0125] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] is phenyl, [ka] is phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0126] In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein X is -C(=O)-. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein X is -S(=O)-.

[0127] In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -O-. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -CHO-. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -OCH-. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 )- or a pharmaceutically acceptable salt or solvate thereof. In some aspects, the invention provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(H)-. In some aspects, the invention provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 )-R 5 is -C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0128] In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0129] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically 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 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I) wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In another embodiment, R 3 is phenyl optionally substituted with halogen. In some embodiments, the present invention provides 3In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 -OR 6 In some embodiments, the present invention provides a compound of formula (I), wherein each R 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In another aspect, the present invention provides a compound of formula (I), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 )2. In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 In some embodiments, the compound of formula (I) is —N(R )2, or a pharmaceutically acceptable salt or solvate thereof. 6 )2 represents a C3-C5 heterocycloalkyl, such as 4-morpholinyl.

[0130] In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein q is 0. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein q is 2.

[0131] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I) wherein each R is selected from the group consisting of: 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl. In another embodiment, R 4 is phenyl optionally substituted with halogen. In some embodiments, the present invention provides 4In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (I), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 )2. In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (I), wherein each R 4 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 In some embodiments, the compound of formula (I) is —N(R )2, or a pharmaceutically acceptable salt or solvate thereof.6 )2 represents a C3-C5 heterocycloalkyl, such as 4-morpholinyl.

[0132] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (I) wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (I) wherein R 1 -C(=O)OR 6 With R 6 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (I) wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9 In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R9 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (I) selected from R 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (I) wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (I), wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0133] In some aspects, the present invention provides a method for producing a medicament comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some aspects, the present invention provides a compound of formula (I) wherein R 2 In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some aspects, the present invention provides a compound of formula (I) wherein R 2 In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some aspects, the present invention provides a compound of formula (I) wherein R 2 In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (I) wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (I) wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (I) wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (I) wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0134] In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein n is 1. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein n is 2. In some aspects, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein n is 0.

[0135] In some embodiments, the present invention provides a compound of formula (Ia):

[0136] [ka]

[0137] (In the formula, R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to 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)2R7 or -S(=O)2N(R 6 )2; R 2 is -C(=O)NH(OH), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] Each R 3 and each R 4 are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9)2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, -C1-C6 haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 or a pharmaceutically acceptable salt or solvate thereof.

[0138] In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0139] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another aspect, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another aspect, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6 In another aspect, the present invention provides a compound of formula (Ia), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ia), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein q is 0. In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein q is 2.

[0141] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6In some embodiments, the present invention provides a compound of formula (Ia), wherein each R is selected from the group consisting of: 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another aspect, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl. In some embodiments, the present invention provides 4 In another aspect, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (Ia), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ia), wherein each R 4 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0142] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 So, R 6 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9In another aspect, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (Ia) selected from: 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (Ia), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ia), wherein R 1 -C(=O)R 7or a pharmaceutically acceptable salt or solvate thereof.

[0143] In some aspects, the present invention provides a method for producing a medicament comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 In some aspects, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 In some aspects, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 In some aspects, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ia), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0144] In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein n is 1. In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein n is 2. In some aspects, the present invention provides compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein n is 0.

[0145] In some embodiments, the present invention provides a compound of formula (Ib):

[0146] [ka]

[0147] (In the formula, R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to 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), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] Each R 3 and each R 4 are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, -C1-C6 haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0148] In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0149] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 , -N(R6 )2, -CN, -C(=O)OR 6 , -C(=O)N(R 6 )2, -SO2R 7 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib) wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6In another aspect, the present invention provides a compound of formula (Ib), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ib), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0150] In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein q is 0. In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein q is 2.

[0151] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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, -SO2R7 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ib) wherein each R is selected from the group consisting of: 4 is independently selected from halogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl. In some embodiments, the present invention provides 4 In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (Ib), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR6 At each R 6 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ib), wherein each R 4 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 With R 6 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-OR 9In some aspects, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9 In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (Ib) selected from: 1 is -S(=O)2R 7In some aspects, the present invention provides a compound of formula (Ib), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ib), wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0153] In some aspects, the present invention provides a method for producing a medicament comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some aspects, the present invention provides a compound of formula (Ib), wherein R 2 In some aspects, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some aspects, the present invention provides a compound of formula (Ib), wherein R 2 In some aspects, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some aspects, the present invention provides a compound of formula (Ib), wherein R 2In some aspects, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ib), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0154] In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein n is 1. In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein n is 2. In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein n is 0.

[0155] In some embodiments, the present invention provides a compound of formula (Ic):

[0156] [ka]

[0157] (In the formula, [ka] is a C2-C9 heterocycloalkyl; Y is a direct bond, —O—, —CH—, or —C(═O)—; Here, nitrogen is bonded to Y. [ka] when Y is not -O-; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to 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), -CHN(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] Each R 3 and each R 4are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; R 8 is selected from hydrogen, —C1-C6 alkyl, and —N(H)C1-C6 alkyl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, -C1-C6 haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0158] In some aspects, the present invention provides compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof, wherein Y is a direct bond. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -O-. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -CH2-.

[0159] In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0160] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein each R is selected from the group consisting of: 3is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another embodiment, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another embodiment, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6 In another aspect, the present invention provides a compound of formula (Ic), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6In some embodiments, the present invention provides a compound of formula (Ic), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0161] In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein q is 0. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein q is 2.

[0162] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein each R is selected from the group consisting of: 4is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another embodiment, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl. In some embodiments, the present invention provides 4 In another embodiment, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (Ic), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6In some embodiments, the present invention provides a compound of formula (Ic), wherein each R 4 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0163] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 So, R 6 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9In another embodiment, the present invention provides a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some embodiments, the present invention provides a compound of formula (Ic) selected from the group consisting of R 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (Ic), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (Ic), wherein R 1 -C(=O)R 7or a pharmaceutically acceptable salt or solvate thereof.

[0164] In some aspects, the present invention provides a method for producing a medicament comprising: 2 is -C(=O)NH(OH), -CH2N(OH)C(=O)R 8 , -CH(OH)N(=O), -C(=O)CF3, -CH2NHS(=O)2R 8 , -CH(NH2)C(=O)OH, [ka] In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 In some aspects, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2N(OH)C(=O)R 8 In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 In some aspects, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH2NHS(=O)2R 8 In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 In some aspects, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] In some aspects, the present invention provides a compound of formula (Ic), wherein R 2 but [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0165] In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein n is 1. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein n is 2. In some aspects, the present invention provides compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof, wherein n is 0.

[0166] In some embodiments, the present invention provides a compound of formula (II):

[0167] [ka]

[0168] (In the formula, [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; X is -C(=O)- or -S(=O)-; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)-, -C(=O)NH- or -N(R 5 )-and; where Y is the asymmetric case. [ka] are expressed in the order of; Nitrogen is bonded to Y [ka] When Y is the point of attachment in 5 )-rather than; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to 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 4are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, -C1-C6 haloalkyl or halogen; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0169] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0170] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] But C3~C 10 In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0171] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] is phenyl, [ka] is phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0172] In some aspects, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein X is -C(=O)-. In some aspects, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein X is -S(=O)-.

[0173] In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CHO-. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH-. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 )- or a pharmaceutically acceptable salt or solvate thereof. In some aspects, the invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(H)-. In some aspects, the invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 )-, R 5 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) and R 5In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) and R 5 is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

[0174] In some aspects, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0175] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II) wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6 In another aspect, the present invention provides a compound of formula (II) wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 )2. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (II), wherein each R 3 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6)2 or a pharmaceutically acceptable salt or solvate thereof.

[0176] In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0177] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (II) wherein each R is selected from the group consisting of: 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4is methyl. In some embodiments, the present invention provides 4 In another aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (II) wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 )2. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (II), wherein each R 4 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0178] In some aspects, the present invention provides a method for producing a medicament comprising:1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (II) wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (II) wherein R 1 -C(=O)OR 6 With R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (II) wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9 In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1-C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (II) selected from the group consisting of R 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (II) wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0179] In some embodiments, the present invention provides a compound of formula (III):

[0180] [ka]

[0181] (In the formula, [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; [ka] is phenyl, C3-C 10 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl; Y is a direct bond, -O-, -CHO-, -OCH-, -CH-, -C(=O)-, -C(=O)NH- or -N(R 5 )-and; where Y is the asymmetric case. [ka] are expressed in the order of; Nitrogen is bonded to Y [ka] When Y is the point of attachment in 5 )-rather than; R 1 is hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 )2; Each R 3 and each R 4 are 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 SO2R 7, -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; R 5 is hydrogen or -C1-C6 alkyl; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0182] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0183] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0184] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] is phenyl [ka] is phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0185] In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CHO-. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH-. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 )- or a pharmaceutically acceptable salt or solvate thereof. In some aspects, the invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(H)-. In some aspects, the invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 )-R 5 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) with R 5 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R 5 ) with R 5 is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

[0186] In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0187] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 3are 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 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III) wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from:3 -OR 6 In another aspect, the present invention provides a compound of formula (III), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 )2. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (III), wherein each R 3 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0188] In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0189] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (III) wherein each R is selected from the group consisting of: 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl. In some embodiments, the present invention provides 4 In another aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (III), wherein R 6is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 )2. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (III), wherein each R 4 -C(=O)N(R 6 )2. In some aspects, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0190] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6)2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (III) wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (III) wherein R 1 -C(=O)OR 6 So, R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (III) wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9 In another aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (III) selected from the group consisting of R 1 is -S(=O)2R7 In some aspects, the present invention provides a compound of formula (III) wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0191] In some embodiments, the present invention provides a compound of formula (IIIa):

[0192] [ka]

[0193] (In the formula, [ka] 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 to 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 are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; p is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0194] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0195] In some aspects, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (IIIa) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0196] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (IIIa), wherein each R is selected from the group consisting of: 3is independently selected from halogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another aspect, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another aspect, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6 In another aspect, the present invention provides a compound of formula (IIIa), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6In some aspects, the present invention provides a compound of formula (IIIa), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0197] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)OR 6 With R 6 In some embodiments, the present invention provides a compound of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9In another aspect, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (IIIa) selected from the group consisting of R 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (IIIa), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIa), wherein R 1-C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0198] In some embodiments, the present invention provides a compound of formula (IIIb):

[0199] [ka]

[0200] (In the formula, [ka] 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 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 )2; Each R 3 and each R 4 are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6) 2 or phenyl optionally substituted with halogen; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0201] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0202] In some aspects, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein p is 0. In some aspects, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. In some aspects, the present invention provides compounds of formula (IIIb) or pharmaceutically acceptable salts or solvates thereof, wherein p is 2.

[0203] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another aspect, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another aspect, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6 In another aspect, the present invention provides a compound of formula (IIIb), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIb), wherein each R 3 -C(=O)N(R 6In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0204] In some aspects, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some aspects, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some aspects, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0205] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein each R is selected from the group consisting of: 4 is independently selected from halogen and —C1-C6 alkyl. In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4In some embodiments, the present invention provides a compound of formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 In another aspect, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl. In some embodiments, the present invention provides 4 In another aspect, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 In some embodiments, the present invention provides a method for preparing a compound in which each R 4 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 4 -OR 6 In another aspect, the present invention provides a compound of formula (IIIb), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 4 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIb), wherein each R 4 -C(=O)N(R 6In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0206] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)OR 6In some aspects, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)OR 6 With R 6 In some embodiments, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another embodiment, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R 6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9 In another aspect, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (IIIb) selected from the group consisting of R 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (IIIb), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIb), wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0207] In some embodiments, the present invention provides a compound of formula (IIIc):

[0208] [ka]

[0209] (In the formula, [ka] 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 to 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 are 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 SO2R 7 , -SO2R 7 , -SO2N(R 6 ) 2 or phenyl optionally substituted with halogen; Each R 6 are independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2 and -C1-C6 alkylene-C2-C9 heterocycloalkyl; -N(R 6 )2 is a C3-C5 heterocycloalkyl; Each R 7 are independently -C1-C6 alkyl, -C1-C6 alkylene-OR 9 , -C1 to C6 alkylene-N(R 9 )2, selected from -C2-C9 heterocycloalkyl, -C2-C9 heteroaryl, -C1-C6 alkylene-C2-C9 heterocycloalkyl, and -C1-C6 alkylene-C2-C9 heteroaryl; Each R 9 is independently selected from hydrogen and -C1-C6 alkyl; C2-C9 heterocycloalkyl and C2-C9 heteroaryl may be substituted with -C1-C6 alkyl, halo-C1-C6 alkyl or halogen; p is 0, 1, 2 or 3 The present invention provides a compound of formula (I) having the structure:

[0210] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] C3~C 10 In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a C2-C9 heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

[0211] In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CHO-. In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -OCH-. In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R 5 )- or a pharmaceutically acceptable salt or solvate thereof. In some aspects, the invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(H)-. In some aspects, the invention provides compounds of formula (IIIc) or pharmaceutically acceptable salts or solvates thereof, wherein Y is -N(R 5 )-R 5 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 ) with R 5 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 ) with R 5 is ethyl, or a pharmaceutically acceptable salt or solvate thereof.

[0212] In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some aspects, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0213] In some aspects, the present invention provides a method for treating a pulmonary arthritis (PTA) comprising administering to a patient a therapeutically effective amount of ... PTA. 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 In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 are independently selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OR 6 and -C(=O)OR 6 In some embodiments, the present invention provides a compound of formula (IIIc) wherein each R is selected from the group consisting of: 3 is independently selected from halogen and —C1-C6 alkyl. In some aspects, the present invention provides a compound represented by formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 In another aspect, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is methyl. In some embodiments, the present invention provides 3 In another aspect, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 In some embodiments, the present invention provides a method for preparing a compound in which each R 3 but independently, -OR 6 , -N(R 6 )2, -C(=O)OR 6 , -C(=O)N(R 6 )2 and -SO2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from: 3 -OR 6In another aspect, the present invention provides a compound of formula (IIIc), wherein R 6 is hydrogen or methyl. In some embodiments, the present invention provides 3 -OR 6 At each R 6 In some embodiments, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIc), wherein each R 3 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -SO2N(R 6 )2 or a pharmaceutically acceptable salt or solvate thereof.

[0214] In some aspects, the present invention provides a method for producing a medicament comprising: 1 is -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6 )2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C1~C6 alkyl, -C1~C6 alkylene-OR 6 , -C1 to C6 alkylene-N(R 6)2, -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)R 7 , -C(=O)OR 6 , -C(=O)N(R 6 )2, -S(=O)2R 7 or -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkyl, -C1~C6 alkylene-OR 9 or -C1-C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)OR 6 In some aspects, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)OR 6 With R 6 In some embodiments, the present invention provides a compound of formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 In another aspect, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, n-propyl, isobutyl, or t-butyl. 6 is methyl. In yet another embodiment, R6 In some embodiments, the present invention provides a method for preparing a compound having R 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-OR 9 In some aspects, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)OR 6 So, R 6 -C1~C6 alkylene-OR 9 So, R 9 In another aspect, the present invention provides a compound of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is ethylene-OR 9 In another embodiment, R 6 is methylene-OR 9 In another embodiment, R 9 is selected from methyl, ethyl, n-propyl, or t-butyl. 9 is methyl. In some embodiments, the present invention provides 1 -C(=O)OR 6 With R 6 -C1~C6 alkylene-N(R 9 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)N(R 6 )2, each R 6 is independently selected from hydrogen and —C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 1 -C(=O)N(R 6 )2, each R 6 are independently hydrogen and -C1-C6 alkylene-OR 9In some aspects, the present invention provides a compound of formula (IIIc) selected from the group consisting of R 1 is -S(=O)2R 7 In some aspects, the present invention provides a compound of formula (IIIc), wherein R 1 is -S(=O)2N(R 6 In some embodiments, the present invention provides a compound of formula (IIIc), wherein R 1 -C(=O)R 7 or a pharmaceutically acceptable salt or solvate thereof.

[0215] In some embodiments described herein, the disclosed compounds are

[0216] [Table B-1]

[0217] [Table B-2]

[0218] [Table B-3]

[0219] [Table B-4]

[0220] [Table B-5]

[0221] [Table B-6]

[0222] [Table B-7]

[0223] [Table B-8]

[0224] [Table B-9]

[0225] [Table B-10]

[0226] [Table B-11]

[0227] [Table B-12]

[0228] [Table B-13]

[0229] [Table B-14]

[0230] or a pharmaceutically acceptable salt or solvate thereof.

[0231] In certain embodiments, the disclosed compounds utilized by one or more of the foregoing methods are either general compounds, semi-generic compounds, or specific compounds described herein, such as compounds represented by Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc) as described herein.

[0232] Compound production The compounds used in the methods described herein are prepared by procedures disclosed herein or by known organic synthesis techniques, starting from commercially available chemicals and / or compounds described in the chemical literature.

[0233] Suitable references and articles detailing the synthesis of reactants useful in preparing the compounds described herein, or review articles providing references to literature describing the preparation, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif., 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992. Other suitable references and articles detailing the synthesis of reactants useful in preparing the compounds described herein, or review articles providing references to literature describing the 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) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1;Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[0234] Specific reactants and similar reactants can also be found in the index of known chemicals compiled by the Chemical Abstract Service of the American Chemical Society, which is available in many public and university libraries and online databases (contact the American Chemical Society for details). Known but uncataloged chemicals can be prepared by custom chemical synthesis companies as needed, and many of the standard chemical suppliers (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0235] Alternative forms of the compounds disclosed herein Isomers Additionally, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center may be in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In another embodiment of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers obtained in a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optical resolution reagent to form a pair of diastereomers, and then separating the diastereomers to recover the optically pure enantiomer. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by exploiting these dissimilarities. In some embodiments, the separation is achieved by chiral chromatography or, preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is recovered, along with the resolving reagent, by any practical means that does not subsequently result in racemization.

[0236] labeled compound In some embodiments, the compounds described herein exist in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to the compounds recited herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, respectively, 2 H, 3 H, 13 C. 14 C. l5 N, 16 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Included within the scope of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, that contain the aforementioned isotopes and / or other isotopes of atoms, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H and carbon 14, i.e. 14 C isotopes are particularly preferred because they are easy to produce and detect. 2 Substitution with heavy isotopes such as H may confer therapeutic advantages resulting from increased metabolic stability, e.g., increased in vivo half-life or reduced dosage. In some embodiments, isotopically labeled compounds, pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof are prepared by suitable methods.

[0237] In some aspects, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0238] pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0239] In some aspects, the compounds described herein possess acidic or basic groups and therefore react with either inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some aspects, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound in its free form with the appropriate acid or base and isolating the formed salt.

[0240] Prodrug In some aspects, the compounds described herein are formulated as drugs that are converted to active forms in vivo to alter the biodistribution or pharmacokinetics of certain drugs. For example, a carboxylic acid group can be esterified with a methyl or ethyl group, etc., to yield an ester. When the ester is administered to a subject, the ester is cleaved enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal an anionic group. The anionic group can be esterified with a moiety (e.g., an acyloxymethyl ester) that is cleaved to reveal an intermediate, which subsequently decomposes to the active agent. Prodrug moieties may be metabolized in vivo by esterases or other mechanisms to carboxylic acids. Alternatively, other functional groups may be modified into prodrug forms. For example, an amine group may be converted to a carbamate or amide that is cleaved in vivo.

[0241] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0242] Solvates have stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the methods described herein. By way of example, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein exist in both unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0243] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are administered as pure chemicals according to the chosen route of administration and the dosage form used, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 2011). st The pharmaceutical composition is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected in accordance with standard pharmaceutical practice as described in (Ed. Mack Pub. Co., Easton, PA (2005)).

[0244] Thus, provided herein are pharmaceutical compositions containing at least one compound or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0245] In one aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound represented by Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), or a pharmaceutically acceptable salt thereof.

[0246] In another aspect, there is provided a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb) or Formula (IIIc), or a pharmaceutically acceptable salt thereof.

[0247] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products, e.g., produced in one or more steps of the synthetic method.

[0248] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal or intravenous) or aerosol administration.

[0249] Representative pharmaceutical compositions are used in the form of, for example, solid, semi-solid, or liquid pharmaceutical preparations, comprising one or more of the disclosed compounds as an active ingredient in a mixture with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. In some embodiments, the active ingredient is combined with a typically non-toxic pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other dosage forms suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of the disease.

[0250] In some embodiments, the compounds of Formula (I), Formula (Ia), Formula (Ib), or Formula (Ic) described herein are administered to a subject in a biologically compatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. By "biologically compatible form suitable for topical administration" is meant a form of the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc) administered in which the therapeutic effects of the inhibitor outweigh the toxic effects. The administration of the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (III), formula (IIIa), formula (IIIb) or formula (IIIc) described herein can be in any pharmacological form, including a therapeutically effective amount of a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (III), formula (IIIa), formula (IIIb) or formula (IIIc), alone or in combination with a pharmaceutically acceptable carrier.

[0251] Topical administration of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc) can be provided in the form of an aerosol, semi-solid pharmaceutical composition, powder, or liquid. The term "semi-solid composition" refers to an ointment, cream, salve, gel, or other pharmaceutical composition of substantially similar viscosity suitable for application to the skin. Examples of semi-solid compositions are described in Chapter 17 of *The Theory and Practice of Industrial Pharmacy*, Lachman, Lieberman, and Kanig, published by Lea and Febiger (1970), and Chapter 67 of *Remington's Pharmaceutical Sciences*, 15th Edition (1975) published by Mack Publishing Company.

[0252] Skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can contain absorption enhancers, such as DMSO, to increase absorption of the compound. Patches can also include those that control the rate of drug delivery to the skin. Patches can have a variety of administration systems, including reservoir-type or monolithic-type. Reservoir-type designs can have, for example, four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of drug molecules, a reservoir of drug molecules, and a water-resistant backing. Such designs deliver a uniform amount of drug over a period of time, and the delivery rate must be below the saturation limit of various types of skin. For example, monolithic-type designs typically have only three layers: an adhesive layer, a compound-containing polymer matrix, and a water-resistant backing. This design delivers a saturating amount of drug to the skin. Thus, delivery is controlled by the skin. As the amount of drug in the patch decreases below the saturation level, the delivery rate decreases.

[0253] In certain embodiments, for example, the topical composition can take the form of a polyacrylic acid or polyacrylamide-based hydrogel; a polyethylene glycol (PEG)-based ointment, such as the standard ointment DAB8 (50% PEG 300, 50% PEG 1500); or an emulsion, particularly a water-in-oil or oil-in-water microemulsion, optionally with the addition of liposomes. Suitable penetration enhancers (entraining agents) include sulfoxide derivatives such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO) with transcutol (diethylene glycol monoethyl ether) or cyclodextrins; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and their fatty acid esters; urea derivatives such as dodecyl urea, 1,3-didodecyl urea and 1,3-diphenyl urea; and terpenes such as D-limonene, menthone, α-terpineol, carbol, limonene oxide or 1,8-cineole.

[0254] Ointments, pastes, creams, and gels can also contain excipients such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by known means routinely used to prepare aerosol formulations. Generally, such methods involve pressurizing, or providing a means to pressurize, a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0255] In some embodiments for preparing solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of the disclosed compounds or their non-toxic pharmaceutically acceptable salts. When these preformulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition may be readily separated into unit dosage forms (e.g., tablets, pills, capsules) of equal efficacy.

[0256] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules), the compositions of the present invention may be administered in the form of one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) dissolution enhancers, such as hydroxybenzoates, ... For example, the composition may be mixed with any of the following: (8) a wetting agent such as docusate sodium, cetyl alcohol, and glycerin monostearate; (9) an absorbent such as kaolin or bentonite clay; (10) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (11) a coloring agent. For capsules, tablets, and pills, the composition may also contain a buffering agent. In some embodiments, solid compositions of a similar type are also used as fillers for soft and hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0257] In some embodiments, tablets are prepared by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin, hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. In some embodiments, molded tablets are prepared by molding in a suitable machine a mixture of the composition of the present invention moistened with an inert liquid diluent. In some embodiments, tablets and other solid dosage forms such as dragees, capsules, pills, and granules are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0258] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid formulations for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, liquid formulations contain, in addition to the compositions of the present invention, inert diluents such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0259] In some embodiments, the suspension comprises, in addition to the composition of the present invention, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol / sorbitan ester, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and tragacanth, and mixtures thereof.

[0260] In some embodiments, powders and sprays contain, in addition to a composition of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane or propane.

[0261] Alternatively, the compositions and compounds disclosed herein may be administered by aerosol. This can be accomplished by preparing aqueous aerosols, liposomal formulations, or solid particles containing the compounds. In some embodiments, non-aqueous (e.g., fluorocarbon propellant) suspensions are used. In some embodiments, ultrasonic nebulizers are used to minimize exposure of the agent to shear, which can lead to degradation of the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions of the present invention with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition of the present invention, but typically include non-ionic 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 generally prepared from isotonic solutions.

[0262] Pharmaceutical compositions suitable for parenteral administration include compositions of the invention in combination with one or more pharmaceutically acceptable isotonic sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders to be reconstituted into sterile injectable solutions or dispersions immediately before use, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes that render the formulation / preparation isotonic with the blood of the recipient, or suspending or thickening agents.

[0263] Examples of suitable aqueous and non-aqueous carriers for use in pharmaceutical compositions include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in dispersions, and by the use of surfactants.

[0264] The dosage of a composition containing at least one compound described herein will vary depending on the condition of the patient (eg, human), ie, stage of disease, health status, age, and other factors.

[0265] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provides a sufficient amount of the composition to produce a therapeutic and / or prophylactic effect (e.g., improved clinical outcome, such as increased frequency of complete or partial remission, increased disease-free and / or overall survival, reduced severity, etc.). Optimal doses are generally determined in experimental models and / or clinical trials. In some embodiments, optimal doses depend on the patient's body mass, weight, or blood volume.

[0266] Oral doses are typically from about 1.0 mg to about 1000 mg, given one to four or more times per day.

[0267] method In some aspects, this specification provides a method for treating cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, CO2, or other heart diseases, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof. VID-19 myocarditis, COVID-19 myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, myocardial pathological remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS) ), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, chronic allograft nephropathy, focal segmental glomerulosclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, post-sepsis renal tubule injury Disclosed are methods for treating a disease, disorder, or condition selected from: kidney injury, acute ischemic kidney injury, contrast-induced kidney injury, acute tubular injury after ischemia-reperfusion, end-stage renal disease, tubulointerstitial fibrosis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia-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.

[0268] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof.

[0269] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof.

[0270] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by formula (Ic) or a pharmaceutically acceptable salt or solvate thereof.

[0271] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof.

[0272] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by formula (III) or a pharmaceutically acceptable salt or solvate thereof.

[0273] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof.

[0274] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (IIIb) or a pharmaceutically acceptable salt or solvate thereof.

[0275] In some aspects, this specification discloses a method for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof.

[0276] Combination medicines Combination therapy is also contemplated herein, for example, by administering a disclosed compound and another active agent together as part of a specific treatment regimen intended to achieve a beneficial effect from the interaction of these therapeutic agents. Beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions that result from the combination of therapeutic agents. The coadministration of these therapeutic agents generally occurs over a defined period of time (usually weeks, months, or years, depending on the combination). Combination therapy is intended to include the sequential administration of multiple therapeutic agents, i.e., each therapeutic agent is administered at a different time, and the administration of at least two of the therapeutic agents or therapeutic agents substantially simultaneously.

[0277] Substantially simultaneous administration can be achieved, for example, by administering to a subject a single formulation or composition (e.g., a tablet or capsule having a specific ratio of each therapeutic agent) or multiple single formulations (e.g., capsules) of each therapeutic agent. Substantially simultaneous administration can also be achieved by administering to a subject novel chemical entities in which the disclosed compounds are linked to one or more additional active agents via a chemical bond or linker. Sequential or substantially simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct transmucosal absorption. The therapeutic agents can be administered by the same route or by different routes. For example, one therapeutic agent of the combination can be administered by intravenous injection and another therapeutic agent of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection.

[0278] In some aspects, this specification provides a method for treating cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, age-related cardiac hypertrophy, inflammation, or the like, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), or Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, and administering to the mammal one or more additional pharmaceutical agents. and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19 myocarditis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, myocardial pathological remodeling, ECM remodeling after myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy, vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (APS), Acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary kidney disease, chronic 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, postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, sepsis

[0010] Disclosed are methods for treating a disease, disorder, or condition selected from renal tubular injury after ischemia-reperfusion, acute ischemic renal injury, contrast-induced renal injury, acute tubular injury after ischemia-reperfusion, end-stage renal disease, tubulointerstitial fibrosis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, fatty liver, cirrhosis, hepatic ischemia-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.

[0011] Disclosed are methods for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) and administering to the mammal one or more additional pharmaceutical agents.In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (Ia) and administering one or more additional pharmaceutical agents to the mammal. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (Ib) and administering to the mammal one or more additional pharmaceutical agents. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (Ic) and administering to the mammal one or more additional pharmaceutical agents. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (II) and administering to the mammal one or more additional pharmaceutical agents. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (III) and administering one or more additional pharmaceutical agents to the mammal. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (IIIa) and administering to the mammal one or more additional pharmaceutical agents. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (IIIb) and administering to the mammal one or more additional pharmaceutical agents. In some embodiments, methods are disclosed for treating a cardiovascular disease, disorder, or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by Formula (IIIc) and administering to the mammal one or more additional pharmaceutical agents.

[0279] Combination therapy also includes administering the above-mentioned therapeutic agent in further combination with other biologically active ingredients and non-drug therapies. When the combination therapy further includes non-drug therapies, the non-drug treatment is administered at an appropriate time, so long as a beneficial effect is obtained due to the interaction of the combined therapeutic agent and non-drug therapies. For example, where appropriate, the beneficial effect can be achieved even if the non-drug therapies are separated temporarily, perhaps by days or weeks, from the administration of the therapeutic agent.

[0280] The components of the combination are administered to a patient simultaneously or sequentially. It is understood that the components may be present in the same pharmaceutically acceptable carrier and therefore administered simultaneously. Alternatively, the active ingredients may be present separately in pharmaceutical carriers, such as conventional oral dosage formulations, and administered simultaneously or sequentially. [Example]

[0281] This invention is further described in the following examples, which should not be construed as limiting the scope of the claims provided herein.

[0282] List of Abbreviations The following abbreviations, used throughout the description of the invention, unless otherwise indicated, shall be understood to have the following meanings: s singlet d doublet t triplet q quartet m multiplet brs broad singlet dd double doublet td triple doublet dt double triplet ℃ Celsius ACN Acetonitrile Bn Benzyl BOC or Boc tert-butoxycarbonyl (Boc)2O Di-tert-butyl dicarbonate BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride CDI 1,1'-carbonyldiimidazole Cy Cyclohexyl DCE Dichloroethane (ClCH2CH2Cl) DCM dichloromethane, methylene chloride (CH2Cl2) DEAD Diethyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-(N,N-dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide equiv equivalent Et Ethyl EtOH ethanol EA or EtOAc Ethyl acetate g grams h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High-Performance Liquid Chromatography i-PrOAc Isopropyl acetate J NMR coupling constant in hertz (Hz) LAH Lithium Aluminum Hydride LCMS Liquid Chromatography Mass Spectrometry Me methyl MeOH Methanol mL milliliter μL microliter mmol millimolar μmol micromol MS mass spectrometry MTBE Methyl tert-butyl ether NaH Sodium hydride (60% dispersion in mineral oil) NMM N-methylmorpholine NMR nuclear magnetic resonance PDA Photodiode Array Detector Pd / C 10% palladium on activated carbon, 50% wet PMB p-Methoxybenzyl p-TSA p-Toluenesulfonic acid monohydrate RT or rt room temperature TEA or Et3N triethylamine TBAF Tetrabutylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

[0283] Unless otherwise specified, the purity of a solid is expressed as the ratio of the weight of the component to the total weight multiplied by 100 (wt%); the purity of a liquid is expressed as the ratio of the volume of the component to the total volume multiplied by 100 (vol%); the concentration of a solution is expressed as the ratio of the weight of the solute (g) to the total volume (mL) of the solution multiplied by 100 (w / v%). The yield of a reaction is expressed as the ratio of the weight of the product to the theoretical yield of the product multiplied by 100 (%). The composition of a mixed solvent is expressed as the ratio of the volume parts of the component solvents (e.g., 80:20 or 3:2:1).

[0284] General Considerations Commercially available chemicals are from Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc.Chemicals were obtained from standard sources, such as Merck (Rockville, MD) and WuXi (Shanghai, China). Dry solvents, such as DCM, diethyl ether, and toluene, were purchased from Finar and used as received; THF was dried over sodium (monitored by the color of the benzophenone ketyl radical) and distilled before use. Liquids and solutions were handled using syringes or cannulae. All reactions were carried out using flame-dried or oven-dried glassware under a nitrogen / argon atmosphere with magnetic stirring. All reactions were carried out using Merck F. 254 The samples were analyzed by thin-layer chromatography (TLC) on precoated silica gel 60 plates (0.25 mm) and monitored by GC / FID, LCMS, or HPLC using UV light, iodine, potassium permanganate stain, p-anisaldehyde stain, or phosphomolybdic acid stain. 1 Visualized by H NMR. Crude compounds were purified by standard laboratory techniques including trituration, silica gel (60-120, 100-200, or 230-400 mesh) chromatography, and combi flash normal or reverse phase.

[0285] Analysis method proton( 1 H) and carbon ( 13NMR spectra of C) were recorded on a Bruker Ascend-400 spectrometer operating at 400 MHz for proton and 100 MHz for carbon using CDCl3, DMSO-d6, CD3CN, or DO as solvents. Chemical shifts are expressed in parts per million (δ, ppm), and coupling constants (J) are given in hertz. For proton spectra, the solvent peak was used as the reference peak. LCMS was performed on a Shimadzu LCMS-2020, an Agilent 6420 Triple Quad LC / MS, or an Agilent Infinity Lab LC / MSD XT with a PDA detector in both positive and negative electrospray ionization (ESI) modes. HPLC was performed on a Shimadzu LC-2010 and an Agilent 1290 Infinity II with a PDA detector. Preparative HPLC was performed on a Shimadzu semi-preparative or Agilent 1260 Infinity II with a PDA detector. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated.

[0286] The operating conditions for chromatography and mass spectrometry are summarized in Tables 1-3 below.

[0287] [Table 1]

[0288] [Table 2]

[0289] [Table 3]

[0290] chemical synthesis Unless otherwise stated, reagents and solvents were used as received from the supplier. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized.

[0291] The compounds of the present invention can be prepared by the synthetic transformations shown below in Synthetic Schemes 1 to 10. Starting materials are commercially available, can be prepared by procedures described herein, literature procedures, or procedures well known to one skilled in the art of organic chemistry.

[0292] Representative synthetic methods for preparing compounds according to this disclosure are set forth below.

[0293] In step 1 of General Synthesis Scheme 1, a secondary amine (1A) is reacted with various sulfonyl chlorides (1B) to give compounds of formula 1C. Compounds of formula 1C are deprotected to give compounds of formula 1D. Compounds of formula 1D are further reacted with methoxyethyl chloroformate to give compounds of formula 1E. Compounds of formula 1E are further treated with an inorganic base in water and THF to give compounds of formula 1F, which is further coupled with a protected hydroxylamine under standard amide conditions to give compounds of formula 1G. Finally, compounds of formula 1G are deprotected in the presence of a suitable acid, such as TFA or 1N HCl, in a suitable solvent, such as DCM, 1,4-dioxane, and MeOH, to give compounds of formula 1.

[0294] [ka]

[0295] Example 1 Preparation of (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0296] [ka]

[0297] Step 1: Preparation of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester

[0298] [ka]

[0299] To a stirred solution of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester (300 mg, 1.05 mmol) in acetone (6 mL) at 0–10 °C under a nitrogen atmosphere, K2CO3 (580 mg, 4.2 mmol) was added 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 while being 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 give the crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 15-20% EtOAc in hexanes) to give (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester (330 mg, 0.61 mmol, 58% yield) as a colorless sticky gum. MS (ESI): m / z 480.0 [Mt-Bu+H] + .

[0300] Step 2 (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester

[0301] [ka]

[0302] To a stirred solution of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester (0.33 g, 0.61 mmol) in DCM (4 mL) at 0-5 °C, trifluoroacetic acid (0.5 mL, 6.1 mmol) was added dropwise and stirred at room temperature for 16 h with TLC monitoring. The reaction mixture was evaporated to dryness, and the residue was diluted with ethyl acetate (40 mL) and washed with saturated NaHCO solution (2 × 15 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (270 mg, 0.62 mmol, quantitative) as a colorless sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 436.0 [M+H] + .

[0303] Step 3: Preparation of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0304] [ka]

[0305] To a stirred solution of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (270 mg, 0.62 mmol) in DCM (4 mL) at 0-10 °C under a nitrogen atmosphere, DIPEA (0.43 mL, 2.48 mmol) and 2-methoxyethyl chloroformate (0.14 mL, 1.24 mmol) were added. The reaction mixture was stirred at RT for 6 h with TLC monitoring. The reaction mixture was quenched with ice-cold water (5 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with ice-cold water (2 × 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (340 mg, 0.63 mmol, quantitative) as a colorless sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 538.0 [M+H] + .

[0306] Step 4 Preparation 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

[0307] [ka]

[0308] To a stirred solution of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl)ester (330 mg, 0.61 mmol) in a 1:1:1 mixture of THF:EtOH:water (30 mL) at 0 °C, NaOH (122 mg, 3.0 mmol) was added in one portion. The reaction mixture was stirred at RT for 16 h with TLC monitoring. The volatiles were evaporated under reduced pressure, and the residue was diluted with water (5 mL) and cooled to 0–10 °C. The pH of the reaction mixture was adjusted to approximately 4–5 with 10% aqueous citric acid and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (15 mL), separated, dried over NaSO, 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 sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 510.0 [M+H] + .

[0309] Step 5 Preparation of (1S,2R,5R)-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 2-methoxyethyl ester

[0310] [ka]

[0311] 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 0–10 °C, HATU (223 mg, 0.58 mmol) and DIPEA (0.44 mL, 2.4 mmol) were added. 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 RT over 30 min and stirred for 6 h with TLC monitoring. 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 NaSO, filtered, and concentrated under reduced pressure to afford (1S,2R,5R)-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 2-methoxyethyl ester (200 mg, 0.33 mmol, 67% yield) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 606.9 [MH] - .

[0312] Step 6 Preparation of (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 1)

[0313] [ka]

[0314] To a stirred solution of (1S,2R,5R)-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 2-methoxyethyl ester (190 mg, 0.31 mmol) in DCM (4 mL) at 0–10 °C was added trifluoroacetic acid (0.24 mL, 3.1 mmol) dropwise. The reaction mixture was stirred at RT for 16 h with TLC monitoring. The volatiles were evaporated, and the residue was diluted with DCM (40 mL) and washed with saturated NaHCO solution (2 × 10 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 150 mg of crude compound. The crude product was purified by RP preparative HPLC (Table 2, Method 2) and the fractions were lyophilized to give (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 1) (45 mg, 0.08 mmol, 14% yield) as an off-white solid. MS (ESI): m / z 525.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.64 (brs, 1H), 8.76 (brs, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 2.8, 8.8 Hz, 1H), 7.31 - 7.27 (m, 4H), 7.18 (d, J = 8.8 Hz, 1H), 4.42 - 4.38 (m, 1H), 4.28 - 4.20 (m, 1H), 4.10 - 4.04 (m, 2H), 3.90 - 3.80 (m, 1H), 3.59 - 3.40 (m, 4H), 3.23 (s, 3H), 1.93 - 1.70 (m, 2H), 1.56 - 1.47 (m, 2H).

[0315] Similarly, the following examples were prepared in the same or similar manner as Example 1.

[0316] [Table 4-1]

[0317] [Table 4-2]

[0318] [Table 4-3]

[0319] The synthesis of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (Intermediate 2) is shown below.

[0320] [ka]

[0321] Step 1: Preparation of (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester fumarate

[0322] [ka]

[0323] (1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ester (160 g, 0.81 mol) was dissolved in a saturated solution of fumaric acid in 2.3 L of EtOH (90 g of fumaric acid was dissolved in 2.5 L of EtOH to form a saturated solution) and transferred to a 5 L multi-neck round-bottom flask equipped with a mechanical stirrer at room temperature. The reaction mixture was cooled to -10 °C to 0 °C and stirred for 30 min, after which a solid precipitate was observed. The mixture was stirred for 24 h and filtered. The resulting pale yellow solid 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-carboxylic acid ethyl ester fumarate (60 g, 0.19 mol, 25% over two steps) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 8.18 (brs, 3H), 7.32 (s, 1H), 6.61 (s, 2H), 4.27 (d, J = 4.4 Hz, 1H), 4.18 - 4.11 (m, 2H), 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 = 7.2 Hz, 3H).

[0324] Step 2: Preparation of (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0325] [ka]

[0326] 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) at 0-10 °C, EtN (22.2 mL, 159.1 mmol) was added and stirred for 10 min. 2,5-Dioxopyrrolidin-1-yl (2-methoxyethyl) carbonate (13.8 g, 63.6 mmol) was added to the reaction mixture at 0-10 °C, followed by DMAP (0.39 g, 3.18 mmol). The reaction was allowed to warm to RT and stirred for 16 h while being monitored by TLC. The reaction 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 NaSO, filtered, and concentrated under reduced pressure to give (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (7.3 g, 24.3 mmol, 76% yield) as a red syrup, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 5.87 (brs, 1H), 4.90 - 4.84 (m, 1H), 4.60 - 4.51 (m, 2H), 4.35 - 4.20 (m, 4H), 3.65 - 3.58 (m, 2H), 3.38 (s, 3H), 2.19 - 2.07 (m, 3H), 1.72 - 1.67 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H).

[0327] Step 3: Preparation of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (Intermediate 2)

[0328] [ka]

[0329] To a stirred solution of (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (7.3 g, 24.3 mmol) in dry THF (73 mL) at 0-10 °C was added BH3.DMS (10 M solution, 14.6 mL, 146.0 mmol) dropwise. The reaction was allowed to warm slowly to RT and stirred for 16 h while being 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 h and the volatile materials were distilled off under reduced pressure to give (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (Intermediate 2) (7.0 g, 24.4 mmol) as a colorless viscous liquid, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 4.53 - 4.49 (m, 1H), 4.30 - 4.18 (m, 4H), 3.93 - 3.80 (m, 4H), 3.63 - 3.59 (m, 2H), 3.38 (s, 3H), 1.31 - 1.20 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H).

[0330] [ka]

[0331] Example 10 Preparation of (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0332] [ka]

[0333] Step 1: Preparation of (1S,2S,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0334] [ka]

[0335] 3. To a stirred solution of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl)ester (250 mg, 0.87 mmol) in THF (5 mL) at 0–10°C under a nitrogen atmosphere, DIPEA (0.45 mL, 2.6 mmol) was added and 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 being monitored by TLC. The reaction mixture was cooled to RT, 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 compound. The crude product was purified by silica gel column chromatography (60-120 mesh, 15-40% EtOAc in hexanes) to give (1S,2S,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (240 mg, 0.45 mmol, 52% yield) as a yellow gum. MS (ESI): m / z 526.2 [M+H] + .

[0336] Step 2: Preparation 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

[0337] [ka]

[0338] A procedure similar to that of Step 4 of Example 1 afforded (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) as a brown gum, which was used directly in the next step without further purification. MS (ESI): m / z 498.2 [M+H] + .

[0339] Step 3 Preparation of (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 2-methoxyethyl ester

[0340] [ka]

[0341] 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 0–10 °C, BOP-Cl (191 mg, 0.75 mmol) and DIPEA (0.16 mL, 0.9 mmol) were added. 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 RT over 30 min and stirred for 16 h with TLC monitoring. The reaction was quenched with ice-cold water (20 mL) at 0 °C, and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (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 2-methoxyethyl ester (180 mg, 0.30 mmol) as a yellow gum, which was used directly in the next step without further purification. MS (ESI): m / z 595.3 [MH] - .

[0342] Step 4 Preparation of (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 10)

[0343] [ka]

[0344] To a stirred solution of (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 2-methoxyethyl ester (170 mg, 0.28 mmol) in MeOH (4 mL) at 0–10 °C was added p-TSA (271 mg, 1.42 mmol). The reaction was stirred at RT for 2 h while being monitored by TLC. The reaction was quenched with saturated aqueous NaHCO (5 mL) and extracted with DCM (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by RP preparative HPLC (Table 2, Method 2) and the fractions were lyophilized to give (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 10) (38.4 mg, 0.075 mmol, 26% yield over two steps) as an off-white solid. MS (ESI): m / z 513.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.64 (brs, 1H), 8.78 (brs, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 2.4, 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 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).

[0345] Similarly, the following examples were prepared in the same or similar manner as Example 10.

[0346] [Table 5]

[0347] [ka]

[0348] Example 14 Preparation of (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0349] [ka]

[0350] Step 1: Preparation of (1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-(tert-butyl) 2-ethyl ester

[0351] [ka]

[0352] To a stirred solution of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester (200 mg, 0.70 mmol) in DCM (5 mL) at 0–10 °C under a nitrogen atmosphere, EtN (0.2 mL, 1.40 mmol) was added and 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 being monitored 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 NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (100–200 mesh, 20% EtOAc in hexanes) to give (1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-(tert-butyl) 2-ethyl ester (200 mg, 0.45 mmol, 64% yield) as an off-white solid. MS (ESI): m / z 444.4 [M+H] + .

[0353] Step 2: Preparation of (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-(tert-butyl) 2-ethyl ester

[0354] [ka]

[0355] To a stirred solution of (1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-(tert-butyl) 2-ethyl ester (200 mg, 0.45 mmol) in DMF (3 mL) was added CsCO (219 mg, 0.67 mmol), followed by 4-fluorophenol (50 mg, 0.45 mmol) in DMF (1 mL) at RT, and the mixture was stirred at 60 °C for 4 h with TLC monitoring. 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 NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100–200 mesh, 10% EtOAc in hexanes) to give (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-(tert-butyl) 2-ethyl ester (170 mg, 0.31 mmol, 68% yield) as a colorless liquid. MS (ESI): m / z 536.2 [M+H] + .

[0356] Step 3 Preparation of (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester

[0357] [ka]

[0358] The same procedure as in Step 2 of Example 1 was performed to obtain (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, quantitative) as a colorless liquid. MS (ESI): m / z 436.2 [M+H]+ .

[0359] Step 4: Preparation of (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0360] [ka]

[0361] The same procedure as in Step 3 of Example 1 was performed to obtain (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (150 mg, 0.27 mmol, yield 87%) as a colorless liquid. MS (ESI): m / z 538.2 [M+H] + .

[0362] Step 5 Preparation 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

[0363] [ka]

[0364] A procedure similar to that of Step 4 of Example 1 gave (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, quantitative) as a colorless sticky gum. MS (ESI): m / z 510.4 [M+H] + .

[0365] Step 6 Preparation of (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 2-methoxyethyl ester

[0366] [ka]

[0367] 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) was added BOP-Cl (100 mg, 0.39 mmol), and the mixture was stirred at RT for 30 min. The reaction mixture was cooled to 0-10 °C, and DIPEA (0.08 mL, 0.47 mmol) was added thereto and stirred for 10 min. Then, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine hydrochloride (23 mg, 0.204 mmol) was added at the same temperature. The reaction mixture was warmed to RT over 30 min and stirred for 2 h with TLC monitoring. The reaction mixture was quenched with ice-cold water (20 mL) at 0 °C, and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (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 2-methoxyethyl ester (100 mg, 0.16 mmol, quantitative) as an off-white solid, which was used directly in the next step without further purification. MS (ESI): m / z 609 [M+H] + .

[0368] Step 7 Preparation of (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 14)

[0369] [ka]

[0370] Purification by RP preparative HPLC (Table 2, Method 3) using a procedure similar to that of Step 6 of Example 1 afforded (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 14) (10 mg, 0.019 mmol, 11% yield) as an off-white solid. MS (ESI): m / z 525.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.60 (brs, 1H), 8.73 (brs, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 2.8, 8.8 Hz, 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).

[0371] Similarly, the following examples were prepared in the same or similar manner as Example 14.

[0372] [Table 6-1]

[0373] [Table 6-2]

[0374] [Table 6-3]

[0375] [ka]

[0376] Example 24 Preparation of (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0377] [ka]

[0378] Step 1: Preparation of (1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0379] [ka]

[0380] To a stirred solution of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (2 g, 6.98 mmol) in THF (10 mL) at 0–10 °C under a nitrogen atmosphere, DIPEA (3.7 mL, 20.9 mmol) was added and 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 with TLC monitoring. The reaction mixture was cooled to RT, diluted with water (20 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (100-200 mesh, 15-25% EtOAc in hexanes) to give (1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (2.1 g, 4.71 mmol, 67% yield) as a pale yellow gum. MS (ESI): 446.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3): 8.77 - 8.75 (m, 1H), 8.41 - 8.38 (m, 1H), 7.11 (dd, J = 2.4 Hz, 8.4 Hz, 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 = 7.2 Hz, 3H).

[0381] Step 2: Preparation of (1S,2S,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0382] [ka]

[0383] To a stirred solution of 4-(difluoromethoxy)phenol (204 mg, 1.28 mmol) in ACN (5 mL) at 0–10 °C under a nitrogen atmosphere, K2CO3 (530 mg, 3.84 mmol) was added and stirred for 20 min. (1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl)ester (570 mg, 1.28 mmol) was dissolved in ACN (10 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at 50 °C for 4 h with TLC monitoring. 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 (100-200 mesh, 15-30% EtOAc in hexanes) to give (1S,2S,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (450 mg, 0.77 mmol, 60% yield) as a light brown gum. MS (ESI): m / z 586.1 [M+H] + .

[0384] Step 3: Preparation 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

[0385] [ka]

[0386] A procedure similar to that of Step 4 of Example 1 afforded (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) as a light brown gum, which was used directly in the next step without further purification. MS (ESI): m / z 558.1 [M+H] + .

[0387] Step 4 Preparation of (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 2-methoxyethyl ester

[0388] [ka]

[0389] A procedure similar to that of Step 3 of Example 10 afforded (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 2-methoxyethyl ester (530 mg, 0.80 mmol) as a brown gum, which was used directly in the next step without further purification. MS (ESI): m / z 657.2 [M+H] + .

[0390] Step 5 Preparation of (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 24)

[0391] [ka]

[0392] To a stirred solution of (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 2-methoxyethyl ester (530 mg, 0.80 mmol) in MeOH (10 mL) at 0–10 °C, p-TSA (767 mg, 4.03 mmol) was added. The reaction mixture was stirred at RT for 2 h with TLC monitoring. The reaction was quenched with saturated aqueous NaHCO3 (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 give 480 mg of a partially pure product, which was treated with 20% MTBE in i-PrOAc (4.8 mL) and stirred at room temperature for 16 h. The precipitate was filtered, washed with MTBE (2 mL), dissolved in DCM (20 mL), and washed with saturated aqueous NaHCO3 (2 x 5 mL). The organic layer was dried over anhydrous NaSO, filtered, evaporated under reduced pressure, and lyophilized with ACN:HO (1:1, 2 mL) to give (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 24) (130 mg, 0.23 mmol, 26% yield over two steps) as an off-white solid. MS (ESI): m / z 573.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.65 (brs, 1H), 8.77 (brs, 1H), 8.42 (s, 1H), 8.12 (dd, J = 2.4, 8.8 Hz, 1H), 7.30 - 7.26 (m, 4H), 7.25 (t, J = 74.0 Hz, 1H), 7.20 (d, J = 8.8 Hz, 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).

[0393] Similarly, the following examples were prepared in the same or similar manner as Example 24.

[0394] [Table 7-1]

[0395] [Table 7-2]

[0396] [Table 7-3]

[0397] [Table 7-4]

[0398] [Table 7-5]

[0399] [Table 7-6]

[0400] Example 41 Preparation of (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 2-methoxyethyl ester

[0401] [ka]

[0402] Step 1: Preparation of (1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0403] [ka]

[0404] To a stirred solution of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (500 mg, 1.74 mmol) in THF (5 mL) at 0–10 °C under a nitrogen atmosphere, DIPEA (1.2 mL, 5.2 mmol) was added and 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 with TLC monitoring. The reaction mixture was cooled to RT, diluted with water (10 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (60–120 mesh, 15–25% EtOAc in hexanes) to give (1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (360 mg, 0.78 mmol, 44% yield) as a colorless gum. MS (ESI): 463.2 [M+H] + .

[0405] Step 2: Preparation of (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 2-ethyl 8-(2-methoxyethyl) ester

[0406] [ka]

[0407] To a stirred solution of 1-methyl-1H-pyrazol-4-ol (115 mg, 1.17 mmol) in ACN (4 mL) at 0–10 °C under a nitrogen atmosphere, K2CO3 (322 mg, 2.34 mmol) was added and stirred for 20 min. (1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) 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 with TLC monitoring. 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 (100-200 mesh, 10-25% EtOAc in hexanes) to give 2-ethyl 8-(2-methoxyethyl)ethyl (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-dicarboxylate (300 mg, 0.55 mmol, 71% yield) as a colorless liquid. MS (ESI): m / z 541.2 [M+H] + .

[0408] Step 3: Preparation 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

[0409] [ka]

[0410] A procedure similar to that of Step 4 of Example 1 afforded (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) as a colorless gum, which was used directly in the next step without further purification. MS (ESI): m / z 513.2 [M+H] + .

[0411] Step 4 Preparation of (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 2-methoxyethyl ester

[0412] [ka]

[0413] 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 0–10 °C, HATU (233 mg, 0.61 mmol) and DIPEA (0.22 mL, 1.23 mmol) were added and stirred for 30 min. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (62 mg, 0.53 mmol) was added, warmed to RT over 30 min, and stirred for 16 h with TLC monitoring. The reaction was quenched with cold water (10 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (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 2-methoxyethyl ester (210 mg, 0.34 mmol, quantitative) as a colorless oil, which was used directly in the next step without further purification. MS (ESI): m / z 610.2 [M−H] - .

[0414] Step 5 Preparation of (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 2-methoxyethyl ester (Example 41)

[0415] [ka]

[0416] Purification by RP preparative HPLC (Table 2, Method 3) using a procedure similar to Step 5 of Example 24 afforded (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 2-methoxyethyl ester (Example 41) (42 mg, 0.079 mmol, 19% yield over two steps) as an off-white solid. MS (ESI): m / z 528.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.63 (brs, 1H), 8.76 (brs, 1H), 7.89 (s, 1H), 7.67 (d, J = 10.4 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.14 (t, J = 8.4 Hz, 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, 1H), 3.54 - 3.35 (m, 4H), 3.23 (s, 3H), 1.99 - 1.70 (m, 2H), 1.60 - 1.39 (m, 2H).

[0417] Example 42 Preparation of (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 2-methoxyethyl ester

[0418] [ka]

[0419] Step 1: Preparation of (1S,2S,5R)-3-((3,4,5-trifluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0420] [ka]

[0421] A procedure similar to that of Step 1 of Example 41 afforded (1S,2S,5R)-3-((3,4,5-trifluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl)ester (400 mg, 0.83 mmol, 48% yield) as a colorless gum, which was used directly in the next step without further purification. MS (ESI): m / z 481.2 [M+H] + .

[0422] Step 2: Preparation of (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 2-ethyl 8-(2-methoxyethyl) ester

[0423] [ka]

[0424] A procedure similar to that of Step 2 of Example 41 was carried out to give (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 2-ethyl 8-(2-methoxyethyl) ester (300 mg, 0.54 mmol, 64% yield) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 559.2 [M+H]+ .

[0425] Step 3: Preparation 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

[0426] [ka]

[0427] A procedure similar to that of Step 4 of Example 1 afforded (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) as a colorless gum, which was used directly in the next step without further purification. MS (ESI): m / z 531.2 [M+H] + .

[0428] Step 4 Preparation of (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 2-methoxyethyl ester

[0429] [ka]

[0430] A procedure similar to that of Step 4 of Example 41 gave (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 2-methoxyethyl ester (200 mg, 0.32 mmol, quantitative) as a colorless liquid, which was used directly in the next step without further purification. MS (ESI): m / z 628.2 [MH] - .

[0431] Step 5 Preparation 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-carboxylate (Example 42)

[0432] [ka]

[0433] Purification by RP preparative HPLC (Table 2, Method 3) using a procedure similar to Step 5 of Example 24 afforded (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 2-methoxyethyl ester (Example 42) (32 mg, 0.058 mmol, 18% yield over two steps) as an off-white solid. MS (ESI): m / z 546.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 10.65 (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 - 3.99 (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).

[0434] [ka]

[0435] Example 43 Preparation of (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0436] [ka]

[0437] Step 1: Preparation of (1S,2R,5R)-3-((6-(4-(methoxymethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0438] [ka]

[0439] To a stirred solution of (1S,2S,5R)-3-((6-fluoropyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl)ester (400 mg, 0.89 mmol) in ACN (10 mL) at RT was added KCO (372 mg, 2.69 mmol) and 4-(methoxymethoxy)phenol (207 mg, 1.35 mmol) in ACN (5 mL). The reaction was stirred at 50 °C for 6 h with TLC monitoring. The reaction was cooled to RT, 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 NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (100–200 mesh, 20–30% EtOAc in hexanes) to give (1S,2R,5R)-3-((6-(4-(methoxymethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (380 mg, 0.65 mmol, 73% yield) as a light brown syrup. MS (ESI): m / z 580.3 [M+H] + .

[0440] Step 2: Preparation of (1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0441] [ka]

[0442] To a stirred solution of (1S,2R,5R)-3-((6-(4-(methoxymethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (380 mg, 0.65 mmol) in THF (10 mL) at 0-10 °C, 4 M HCl in dioxane (7.6 mL) was added and stirred at room temperature for 2 h with TLC monitoring. Evaporation of volatile materials to dryness afforded (1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (340 mg, 0.63 mmol, 97% yield) as a light brown gum. MS (ESI): m / z 536.2 [M+H] + .

[0443] Step 3: Preparation of (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0444] [ka]

[0445] To a stirred solution of (1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (340 mg, 0.63 mmol) in DMF (5 mL) at 0–10 °C, CsCO (414 mg, 1.27 mmol) was added and stirred for 10 min. Dimethyl 2-((fluoromethyl)(phenyl)-4-sulfanylidene)malonate (259 mg, 0.95 mmol) in DMF (2 mL) was added to the reaction at the same temperature. The reaction was stirred at 60 °C for 16 h with TLC monitoring. The reaction was cooled to RT, 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 give the crude product. The crude product was purified by combi flash reverse-phase purification (10–40% ACN in HO), and the pure fractions were lyophilized to give (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (180 mg, 0.32 mmol, 50% yield) as a light brown syrup. MS (ESI): m / z 568.0 [M+H] + .

[0446] Step 4 Preparation 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

[0447] [ka]

[0448] A procedure similar to that of Step 4 of Example 1 afforded (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) as a brown gum, which was used directly in the next step without further purification. MS (ESI): m / z 540.2 [M+H] + .

[0449] Step 5 Preparation of (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0450] [ka]

[0451] A procedure similar to that of Step 3 of Example 10 afforded (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (160 mg, 0.25 mmol, 92% yield) as a colorless syrup, which was used directly in the next step without further purification. MS (ESI): m / z 639.2 [M+H] + .

[0452] Step 6 Preparation of (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 43)

[0453] [ka]

[0454] Purification by silica gel column chromatography (SiO, 100-200 mesh, 1-3% MeOH in DCM) using a procedure similar to that of Step 4 of Example 10 gave (1S,2R,5R)-3-((6-(4-(fluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 43) (17 mg, 0.03 mmol, 12% yield) as an off-white solid. MS (ESI): m / z 555.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.67 (brs, 1H), 8.78 (brs, 1H), 8.42 (s, 1H), 8.08 (dd, J = 2.4, 8.8 Hz, 1H), 7.24 - 7.15 (m, 5H), 5.88 (d, J = 54.4 Hz, 2H), 4.70 - 4.35 (m, 1H), 4.30 - 4.20 (m, 1H), 4.15 - 3.99 (m, 2H), 3.94 - 3.80 (m, 1H), 3.61 - 3.35 (m, 4H), 3.23 (s, 3H), 2.01 - 1.71 (m, 2H), 1.70 - 1.45 (m, 2H).

[0455] [ka]

[0456] Example 44 Preparation of (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0457] [ka]

[0458] Step 1: Preparation of (1S,2S,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester

[0459] [ka]

[0460] To a stirred solution of (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester (200 mg, 0.70 mmol) in THF (3 mL) at 0–10 °C under a nitrogen atmosphere, DIPEA (0.4 mL, 2.11 mmol) was added and stirred for 20 min. 4-(4-chlorophenoxy)piperidine-1-sulfonyl chloride (309 mg, 1.05 mmol) was dissolved in THF (2 mL) and added to the reaction mixture at the same temperature. The reaction mixture was stirred at 60 °C for 48 h with TLC monitoring. The reaction mixture was cooled to RT, diluted with water (10 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, 15-20% EtOAc in hexanes) to give (1S,2S,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-ethyl ester (160 mg, 0.28 mmol, 40% yield) as a colorless sticky gum. MS (ESI): m / z 558.4 [M+H] + .

[0461] Step 2: Preparation of (1S,2S,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester

[0462] [ka]

[0463] The same procedure as in Step 2 of Example 1 was performed to obtain (1S,2S,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (150 mg, 0.32 mmol, quantitative) as a colorless liquid. MS (ESI): 458.4 [M+H] + .

[0464] Step 3: Preparation of (1S,2S,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester

[0465] [ka]

[0466] A procedure similar to that of Step 3 of Example 1 gave (1S,2S,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid 2-ethyl 8-(2-methoxyethyl) ester (140 mg, 0.25 mmol, 89% yield) as a colorless sticky gum. MS (ESI): 560.4 [M+H] + .

[0467] Step 4 Preparation of (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0468] [ka]

[0469] A procedure similar to that of Step 4 of Example 1 was performed to obtain (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (90 mg, 0.17 mmol, 73% yield) as a brown syrup. MS (ESI): m / z 532.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 12.94 (brs, 1H), 7.34 - 7.30 (m, 2H), 7.03 - 6.99 (m, 2H), 4.62 - 4.50 (m, 2H), 4.33 - 4.27 (m, 1H), 4.26 - 4.17 (m, 1H), 4.16 - 4.03 (m, 2H), 3.60 - 3.47 (m, 4H), 3.26 (s, 3H), 3.25 - 3.15 (m, 1H), 3.12 - 3.04 (m, 2H), 2.01 - 1.80 (m, 5H), 1.76 - 1.60 (m, 4H).

[0470] Step 5 Preparation of (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester

[0471] [ka]

[0472] A procedure similar to that of Step 5 of Example 1 gave (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (70 mg, 0.11 mmol, quantitative) as a brown sticky gum. MS (ESI): m / z 631.2 [M+H] + .

[0473] Step 6 Preparation of (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 44)

[0474] [ka]

[0475] Purification by RP preparative HPLC (Table 2, Method 4) using a procedure similar to Step 6 of Example 1 afforded (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-2-(hydroxycarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 2-methoxyethyl ester (Example 44) (5 mg, 0.009 mmol, 10% yield) as an off-white solid. MS (ESI): m / z 547.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6): δ 10.66 (brs, 1H), 8.84 - 8.80 (m, 1H), 7.33 - 7.30 (m, 2H), 7.02 - 6.99 (m, 2H), 4.60 - 4.47 (m, 2H), 4.31 - 4.26 (m, 2H), 4.24 - 4.07 (m, 2H), 3.92 - 3.78 (m, 2H), 3.53 - 3.43 (m, 3H), 3.25 (s, 3H), 3.17 - 3.14 (m, 1H), 3.03 - 2.98 (m, 2H), 2.01 - 1.84 (m, 4H), 1.69 - 1.60 (m, 4H).

[0476] Similarly, the following examples were prepared in the same or similar manner as Example 44.

[0477] [Table 8-1]

[0478] [Table 8-2]

[0479] [ka]

[0480] Example 51 Preparation of (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-2-carboxamide

[0481] [ka]

[0482] Step 1: Preparation of (1S,2S,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester

[0483] [ka]

[0484] To a stirred solution of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (200 mg, 0.46 mmol) in DCM (5 mL) at 0-10 °C, EtN (0.2 mL, 1.83 mmol) was added and stirred at the same temperature for 10 min. 2-Chloro-N,N-dimethylacetamide (55 mg, 0.46 mmol) was added, and the reaction was stirred at RT for 16 h with TLC monitoring. The reaction was quenched with ice-cold water (5 mL) and extracted with DCM (2 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (1S,2S,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (180 mg, 0.34 mmol, 74% yield) as a pale yellow gum, which was used directly in the next step without further purification. MS (ESI): m / z 521.1 [M+H] + .

[0485] Step 2: Preparation of (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0486] [ka]

[0487] A procedure similar to that of Step 4 of Example 1 afforded (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (90 mg, 0.18 mmol) as a light brown sticky gum, which was used directly in the next step without further purification. MS (ESI): m / z 493.2 [M+H] + .

[0488] Step 3 Preparation of (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)-3,8-diazabicyclo[3.2.1]octane-2-carboxamide

[0489] [ka]

[0490] A procedure similar to that of Step 5 of Example 1 afforded (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)-3,8-diazabicyclo[3.2.1]octane-2-carboxamide (100 mg, 0.17 mmol) as a pale yellow gum, which was used directly in the next step without further purification. MS (ESI): m / z 592.3 [M+H] + .

[0491] Step 4 Preparation of (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-2-carboxamide (Example 51)

[0492] [ka]

[0493] Purification by RP preparative HPLC (Table 2, Method 1) using a procedure similar to Step 6 of Example 1 afforded (1S,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-2-carboxamide (Example 51) (7.5 mg, 0.015 mmol, 8% yield over two steps) as an off-white solid. MS (ESI): m / z 508.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 11.38 (brs, 1H), 8.67 (brs, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 2.4, 8.8 Hz, 1H), 7.31 - 6.95 (m, 6H), 4.20 - 4.19 (m, 1H), 3.59 - 3.50 (m, 1H), 3.41 - 3.35 (m, 1H), 3.26 - 3.15 (m, 2H), 3.09 - 2.95 (m, 2H), 2.92 (m, 3H), 2.82 (m, 3H), 2.02 - 1.70 (m, 2H), 1.60 - 1.40 (m, 2H).

[0494] Similarly, the following examples were prepared in the same or similar manner as Example 51.

[0495] [Table 9]

[0496] Example 53 Preparation of (1S,2R,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-hydroxy-3,8-diazabicyclo[3.2.1]octane-2-carboxamide

[0497] [ka]

[0498] Step 1: Preparation of (1S,2S,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester

[0499] [ka]

[0500] To a solution of (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (150 mg, 0.34 mmol; prepared in a similar manner as the ethyl ester) in DCM (5 mL) at 0–10 °C, EtN (0.14 mL, 1.03 mmol) was added and stirred at the same temperature for 10 min. Acetic anhydride (0.06 mL, 0.68 mmol) was added, and the reaction mixture was stirred at RT for 16 h with TLC monitoring. The reaction was quenched with ice-cold water (5 mL) and extracted with DCM (2 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (1S,2S,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (160 mg, 0.33 mmol, quantitative) as a pale yellow syrup, which was used directly in the next step without further purification. MS (ESI): m / z 464.1 [M+H] + .

[0501] Step 2: Preparation of (1S,2R,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0502] [ka]

[0503] A procedure similar to that of Step 4 of Example 1 afforded (1S,2R,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (110 mg, 0.24 mmol, 77% yield) as a light brown gum, which was used directly in the next step without further purification. MS (ESI): m / z 448.1 [MH] - .

[0504] Step 3 Preparation of (1S,2R,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-((tetrahydro-...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, 【Chemistry 2】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; 【Chemistry 3】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; X is -C(=O)- or -S(=O) ２ - and Y is a direct bond, —O—, —CH ２ O-, -OCH ２ --, --CH ２ -, -C(=O)-, -C(=O)NH- or -N(R ５ )--and Here, in the asymmetric case, Y is 【Chemistry 4】 It is expressed in the order: Nitrogen is bonded to Y. 【Chemistry 5】 When Y is the attachment point in ２ O-, -C(=O)NH- or -N(R ５ )--but not; R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-C ４ ~C ５ Heterocycloalkyl, -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and R ２ は、-C(=O)OH、-C(=O)NH(OH)、-CH ２ N(OH)C(=O)R ８ 、-CH(OH)N(=O)、-C(=O)CF ３ 、-CH ２ NHS(=O) ２ R ８ 、-CH(NH ２ )C(=O)OH、 【Chemistry 6】 Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; R ５ is hydrogen or -C １ -C ６ is alkyl; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; R ８ is hydrogen, -C １ ~C ６ Alkyl and -N(H)C １ ~C ６ alkyl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, -C １ ~C ６ may be substituted with haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt or solvate thereof. 【Request 2】 【Chemical 7】 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein is phenyl. 【Request 3】 【Chemical 8】 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein is phenyl.

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

5. X is -S(=O) ２ 5. The compound according to claim 1, wherein:

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

7. Formula (Ia): 【Chemistry 9】 (In the formula, R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-C ４ ~C ５ Heterocycloalkyl, -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and R ２ は、-C(=O)NH(OH)、-CH ２ N(OH)C(=O)R ８ 、-CH(OH)N(=O)、-C(=O)CF ３ 、-CH ２ NHS(=O) ２ R ８ 、-CH(NH ２ )C(=O)OH、 【Chemistry 10】 Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; R ８ is hydrogen, -C １ ~C ６ Alkyl and -N(H)C １ ~C ６ alkyl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, -C １ ~C ６ may be substituted with haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

8. Formula (Ib): 【Chemistry 11】 (In the formula, R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-C ４ ~C ５ Heterocycloalkyl, -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and R ２ は、-C(=O)NH(OH)、-CH ２ N(OH)C(=O)R ８ 、-CH(OH)N(=O)、-C(=O)CF ３ 、-CH ２ NHS(=O) ２ R ８ 、-CH(NH ２ )C(=O)OH、 【Chemistry 12】 Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; R ８ is hydrogen, -C １ ~C ６ Alkyl and -N(H)C １ ~C ６ alkyl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, -C １ ~C ６ may be substituted with haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3.

6. The compound according to claim 1, 2, 4, or 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

9. Formula (Ic): 【Chemistry 13】 (In the formula, 【Chemistry 14】 is C ２ ~C ９ is heterocycloalkyl; Y is a direct bond, —O—, —CH ２ - or -C(=O)-; Here, nitrogen is bonded to Y. 【Chemistry 15】 When Y is the point of attachment in R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-N(R ６ ) ２ , -C １ ~C ６ Alkylene-C(=O)-C ４ ~C ５ Heterocycloalkyl, -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and R ２ は、-C(=O)NH(OH)、-CH ２ N(OH)C(=O)R ８ 、-CH(OH)N(=O)、-C(=O)CF ３ 、-CH ２ NHS(=O) ２ R ８ 、-CH(NH ２ )C(=O)OH、 【Chemistry 16】 Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; R ８ is hydrogen, -C １ ~C ６ Alkyl and -N(H)C １ ~C ６ alkyl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, -C １ ~C ６ may be substituted with haloalkyl or halogen; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3.

6. The compound according to claim 1, 2, 4, or 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

10. Formula (II): 【Chemistry 17】 (In the formula, 【Chemistry 18】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; 【Chemistry 19】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; X is -C(=O)- or -S(=O) ２ - and Y is a direct bond, —O—, —CH ２ O-, -OCH ２ --, --CH ２ -, -C(=O)-, -C(=O)NH- or -N(R ５ )--and Here, in the asymmetric case, Y is 【Chemistry 20】 It is expressed in the order: Nitrogen is bonded to Y. 【Chemistry 21】 When Y is the attachment point in ２ O-, -C(=O)NH- or -N(R ５ )--but not; R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; R ５ is hydrogen or -C １ ~C ６ is alkyl; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, -C １ ~C ６ may be substituted with haloalkyl or halogen; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

11. Formula (III): 【Chemical 22】 (In the formula, 【Chemistry 23】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; 【Chemistry 24】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; Y is a direct bond, —O—, —CH ２ O-, -OCH ２ --, --CH ２ -, -C(=O)-, -C(=O)NH- or -N(R ５ )--and Here, in the asymmetric case, Y is 【Chemistry 25】 It is expressed in the order: Nitrogen is bonded to Y. 【Chemistry 26】 When Y is the attachment point in ２ O-, -C(=O)NH- or -N(R ５ )--but not; R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; R ５ is hydrogen or -C １ ~C ６ is alkyl; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, halo-C １ ~C ６ may be substituted with alkyl or halogen; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

12. Formula (IIIa): 【Chemical 27】 (In the formula, 【Chemistry 28】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and Each R ３ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, halo-C １ ~C ６ may be substituted with alkyl or halogen; p is 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

13. Formula (IIIb): 【Chemical 29】 (In the formula, 【Chemistry 30】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and Each R ３ And each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, halo-C １ ~C ６ may be substituted with alkyl or halogen; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

14. Formula (IIIc): 【Chemistry 31】 (In the formula, 【Chemistry 32】 is phenyl, C ３ ~C １０ Cycloalkyl, C ２ ~C ９ Heterocycloalkyl or C ２ ~C ９ is heteroaryl; R １ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , -C １ ~C ６ Alkylene-N(R ６ ) ２ , -C(=O)R ７ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -S(=O) ２ R ７ Or -S(=O) ２ N(R ６ ) ２ and Each R ３ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ６ , C １ ~C ６ 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 SO ２ R ７ , -SO ２ R ７ , -SO ２ N(R ６ ) ２ or phenyl optionally substituted with halogen; Each R ６ are independently hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ and -C １ ~C ６ Alkylene-C ２ ~C ９ heterocycloalkyl; -N(R ６ ) ２ is C ３ ~C ５ is heterocycloalkyl; Each R ７ are independently -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ , -C １ ~C ６ Alkylene-N(R ９ ) ２ , -C ２ ~C ９ Heterocycloalkyl, -C ２ ~C ９ Heteroaryl, -C １ ~C ６ Alkylene-C ２ ~C ９ Heterocycloalkyl and -C １ ~C ６ Alkylene-C ２ ~C ９ heteroaryl; Each R ９ are independently hydrogen and -C １ ~C ６ alkyl; C ２ ~C ９ Heterocycloalkyl and C ２ ~C ９ Heteroaryl is -C １ ~C ６ Alkyl, halo-C １ ~C ６ may be substituted with alkyl or halogen; p is 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, which is a compound having a structure represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

15. Each R ３ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -OR ６ , -N(R ６ ) ２ , -CN, -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -SO ２ R ７ and -SO ２ N(R ６ ) ２ 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt or solvate thereof, selected from:

16. Each R ３ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -OR ６ and -C(=O)OR ６ 16. The compound according to any one of claims 1 to 15, selected from:

17. Each R ３ are independently halogen and -C １ ~C ６ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, aryl and alkyl;

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

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

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

21. Each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -OR ６ , -N(R ６ ) ２ , -CN, -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , -SO ２ R ７ and -SO ２ N(R ６ ) ２ 14. The compound according to any one of claims 1 to 11 or 13, or a pharma- ceutically acceptable salt or solvate thereof, selected from:

22. Each R ４ are independently halogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -OR ６ and -C(=O)OR ６ 22. The compound according to any one of claims 1 to 11, 13 or 21, or a pharma- ceutically acceptable salt or solvate thereof, selected from:

23. Each R ４ are independently halogen and -C １ ~C ６ 23. The compound of any one of claims 1 to 11, 13, 21 or 22, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is selected from the group consisting of alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

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

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

26. 14. The compound according to any one of claims 1 to 11 or 13, wherein q is 0, or a pharma- ceutically acceptable salt or solvate thereof.

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

28. R １ -C(=O)OR ６ 28. The compound according to any one of claims 1 to 27, wherein:

29. R ６ is hydrogen, -C １ ~C ６ Alkyl, -C １ ~C ６ Alkylene-OR ９ Or -C １ ~C ６ Alkylene-N(R ９ ) ２ 29. The compound according to any one of claims 1 to 28, which is: or a pharma- ceutically acceptable salt or solvate thereof.

30. R ６ Ga-C １ ~C ６ Alkylene-OR ９ 30. The compound according to any one of claims 1 to 29, wherein:

31. R ９ Ga-C １ ~C ６ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt or solvate thereof, which is alkyl.

32. R ６ Ga-C １ ~C ６ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

33. 10. The compound according to any one of claims 1 to 9, wherein n is 1, or a pharma- ceutically acceptable salt or solvate thereof.

34. The following compounds 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 or a pharma- ceutically acceptable salt or solvate thereof.

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

36. Cardiovascular disease, heart failure, congestive heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, cardiac contractile dysfunction, age-related cardiac hypertrophy, inflammation and fibrosis, viral myocarditis, COVID-19 myocarditis, COVID-19 myocardial fibrosis, pressure overload hypertrophy, myocardial fibrosis, myocardial infarction, myocardial ischemia / reperfusion injury, myocardial pathological remodeling, ECM remodeling following myocardial injury, radiation myocarditis, radiation myocardial fibrosis, chemotherapy cardiomyopathy in a mammal in need thereof , vascular rarefaction, aortic valve sclerosis, calcific aortic valve stenosis, aortic aneurysm, abdominal aortic aneurysm, giant cell arteritis, age-related arterial fibrosis, pulmonary hypertension, right ventricular hypertrophy, idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), emphysema, polycystic kidney disease, membranous nephropathy, diabetic nephropathy, acute kidney injury, glomerulonephritis, hereditary renal disease, chronic transplant nephropathy, focal segmental glomerular Sclerosis, minimal change disease, human immunodeficiency virus-associated nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura, postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, cisplatin-induced renal injury, tubular injury after sepsis, acute ischemic renal injury, contrast-induced renal injury, acute tubular injury after ischemia-reperfusion, end-stage renal disease, tubulointerstitial fibrosis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease 35. A method for treating a disease, disorder or condition selected from hepatitis, fatty liver, cirrhosis, hepatic ischemia-reperfusion injury, viral hepatitis, drug-induced liver injury, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, acute liver failure, biliary atresia and pigmented scleroderma, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmacologic acceptable salt or solvate thereof.

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