DIAZABICYCLOOCTANE DERIVATIVES USEFUL AS MATRIX METALLOPROTEINASE INHIBITORS

Provided herein are compounds that are MMP inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in treating a disease, disorder or condition selected from cardiovascular disorders, lung disorders, renal disorders, hepatic disorders, and scleroderma pigmentosum. (Formula I)

BACKGROUND

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

Cardiac damage, valvular heart disease such as aortic stenosis, vascular hypertension, and aging are the major factors leading to pressure overload of the pump function of the heart. Hypertrophy of the left ventricle of the heart is a normal response of the heart to such pressure overload. Hypertrophy enables cardiomyocytes to generate the additional force required to compensate for the increased pressure load and maintain necessary pump function. At least 10% of the population in industrialized societies have severe hypertension, which leads not only to left ventricular hypertrophy and secondary heart failure, but also myocardial infarctions and lethal arrhythmias (1). Aging is another common cause of pressure overload of the pump, leading to diastolic dysfunction and concentric remodeling in the left ventricle, though in many cases systolic function is unaffected until late-life senescence (2). The initially appropriate and compensatory left ventricular remodeling may progress to the point of pathophysiology, however, as ischemic and otherwise damaged cardiomyocytes degenerate, fibrosis begins and progresses, and chambers dilate, causing a progressive decline in cardiac pump function (3-9).

The maladaptive remodeling process leading to heart failure can be conceptually divided into hypertrophic changes of cardiomyocytes, and alterations to the normal patterning of the extracellular matrix (ECM) network. Changes in both systolic and diastolic function can be attributed back these two categories (10). The cardiac ECM provides structural support for the myocardium, and generates cytokines, growth factors, and modulatory proteins that modify myocardial function (11). The appearance of adverse ECM remodeling represents a significant etiologic milestone in the progression to frank heart failure. Normal basement membrane fibronectin, laminin, and collagens bind cardiomyocytes to the interstitial ECM and promote transmembrane signaling through integrin receptors (12), with collagen fibers architecturally organizing myocytes and muscle fibers to permit optimal force generation and transmission. However, when collagen fibrils and struts are lost, cardiomyocyte contraction slippage, chamber dilation, and worsening contractile dysfunction may occur (13). As well, with increasing disease promotion through worsening of the factors described above, fibrillar collagens accumulate in the left ventricular myocardium, causing increased myocardial stiffness (2, 14, 15).

The extracellular matrix of the heart, like skeletal bone and other structural components of the body, undergoes a continuous process of synthesis, degradation, and resynthesis to maintain appropriate structure and strength. Though this healthy remodeling of the cardiac ECM requires healthy proteolysis, proteolysis also is involved in adverse remodeling as part of disease processed including progressive heart failure. Of note, increased activation and expression of matrix metalloproteinases (MMPs), Zn-dependent proteases, are associated with heart failure and thus implicated in the remodeling process of progressive pump failure (16-18). There are 25 members of the mammalian MMP superfamily, including stromelysins, gelatinases, collagenases, matrilysins, membrane-type MMPs, and other MMPs (19). Their various actions are endogenously regulated by tissue inhibitors of metalloproteinases (TIMPs: TIMP1-4), which noncovalently bind with generally low selectivity to form 1:1 complexes with both active and pro-form MMPs. Each myocardial ECM protein serves as a substrate for at least one cardiac MMP (20), which also inactivate and activate ECM-derived cytokines and growth factors (21, 22).

Involvement of MMPs with pathological remodeling of myocardium leading to and worsening heart failure has been characterized in both plasma and left ventricle of animal disease models and humans (8, 16-18, 23-46). While the majority of substrates of MMPs are accessible from extracellular space, more recently an intracellular role in regulation of calcium handling important for excitation-contraction coupling and direct effects on sarcomeric function have been reported for MMPs (47-53). In humans, elevated MMP2 and MMP9 are strongly associated with diastolic dysfunction or heart failure in a number of studies (54-61).

Evidence that MMPs are not simply associated, but cause, pathological left ventricular and overall cardiac remodeling leading to reduced pump function and disease have been generated through both genetic and pharmacological interventions. Nonselective pharmacologic inhibition of MMPs has been demonstrated to significantly reduce pathological remodeling associated with various disease triggers in animal models (28, 40, 62-69). Data showing that selective MMP inhibition, in particular sparing MMP1 action, provides benefit for cardiac remodeling has been generated for MMP-1, MMP-2, MMP-9, TIMP 1, and TIMP-3 (70-74). The strongest bodies of evidence generate the therapeutic hypothesis that selective inhibition of at least MMP-2 and MMP-9 promotes less adverse cardiac function after a variety of interventions that cause cardiac pump failure (59, 75, 76).

MMP9 mice are protected from diastolic dysfunction and fibrosis accumulation (77), as well as remodeling after infarction (59)(75). MMP2 expression, as well as MMP9 expression, has been demonstrated to be elevated in pressure overload hypertrophy in both spontaneously hypertensive (66) and in Dahl salt-sensitive hypertensive rats (43). Most convincingly, both transgenically overexpressing MMP2 and transgenically overexpressing MMP9 mice develop pathologically fibrotic myocardium (78, 79), while MMP2 and MMP9 genetically deleted mice are protected structurally and functionally in disease models of heart failure, results that are nicely recapitulated with prototype pharmacological inhibitors blocking MMP2 and/or MMP9 action (80, 81).

TACE/ADAM17 (Tumor necrosis factor-α-converting enzyme; A Disintegrin And Metalloproteinase 17) is a soluble or membrane-bound metalloproteinase primarily responsible for activation of proTNF-α, while also targeting proteins such as fractalkine, amyloid precursor proteins, 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 is able to cleave proTNF-α and is used in inhibitor screening.

REFERENCES

There is a strong need to develop therapeutic treatment options directed specifically at reversing the underlying cause of heart failure (HF), which is an impaired pumping function of the heart. However, current standard of care for HF and other CVD does not correct the underlying defect causing loss of pump function, which is loss of functioning heart muscle cells, or cardiomyocytes. Instead, existing pharmacotherapies target non-cardiac, peripheral characteristics of the cardiovascular system, including reducing pre-load and after-load by targeting blood pressure, reducing blood volume (aldosterone antagonists, diuretics), or lowering lipids contributing to vascular disease.

Selective inhibition of matrix metalloproteinases provides a valuable therapeutic treatment option for treating various disorders related to abnormal activity of matrix metalloproteinases, including, but not limited to cardiovascular disorders, lung disorders, renal disorders, hepatic disorders, and also scleroderma pigmentosum.

The lung disorders in question comprise idiopathic pulmonary fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Hermansky-Pudlak syndrome (HPS), chronic obstructive pulmonary disease (COPD), and emphysema.

BRIEF SUMMARY OF THE INVENTION

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

In one aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —O—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —S(═O)2—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(═O)—.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ib):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIb):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIc):

In some embodiments, the invention provides a compound of Formula (I) or (Ia) or (lb) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) that is selected from the following compounds:

Ex.
Structure
Name

or is a pharmaceutically acceptable salt or solvate thereof.

In another aspect disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or binder, and a compound of Formula (I) or (1a) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof.

In another aspect disclosed herein is a method for treating a disease, disorder or condition selected from:

INCORPORATION BY REFERENCE

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that which in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of” or “consist essentially of” the described features.

Definitions

The terms used herein may be preceded and/or followed by a single dash “—”, or a double dash “═”, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “from left to right,” unless a dash indicates otherwise. For example, C1-C6alkoxycarbonyloxy and —OC(O)O—C1-C6alkyl indicate the same functionality; similarly arylalkyl and -alkylaryl indicate the same functionality.

For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th ed., 1986-87, inside cover.

As used herein, C1-Cx includes C1-C2, C1-C3 . . . C1-Cx. C1-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

The terms “hydrogen”, “hydrogen atom”, and symbol “H”, as used herein in the context of substituents to structural formulas, such as Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), denote a hydrogen atom attached to the remaining part of the molecule or group in question. For the sake of simplicity, hydrogen atoms attached to carbon atoms are not shown in the structural formulas; each carbon atom is understood to be associated with enough hydrogen atoms to give the carbon atom four bonds.

A “saturated” or “fully saturated” compound means that the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.

An “unsaturated” or “partially saturated” compound means that the referenced chemical structure may contains on or more multiple carbon-carbon bonds, but is not aromatic. For example, an unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

“Amino” refers to the —NH2 radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO2 radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

For purposes of this specification, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

“Alkyl” or “alkylene” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., —C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., —C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., —C1-C8 alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., —C1-C6 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., —C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., —C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., —C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., —C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., —C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., —C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., —C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., —C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., —C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and 2,2-dimethylpropyl (neopentyl). The alkyl is attached to the rest of the molecule by a single bond. The alkylene is a diradical and is attached to two parts of the molecule by two single bonds, such as in the case of methylene (—CH2—) or ethylene (—CH2CH2— or —CH(—CH3)—). Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —ORa, —SRa, —OC(O)Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORf, —OC(O)—NRaRf, —N(Ra)C(O)Rf, —N(Ra)S(O)tRf (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tRf (where t is 1 or 2) and —S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of the formula —O-alkyl, where alkyl is an alkyl chain as defined above.

“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 two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, 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 stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Rf, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O) ORf, —OC(O)—NRaRf, —N(Ra)C(O)Rf, —N(Ra)S(O)tRf (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tRf (where t is 1 or 2) and —S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

“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, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —ORa, —SRa, —OC(O)Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORf, —OC(O)—NRaRf, —N(Ra)C(O)Rf, —N(Ra)S(O)tRf (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tRf (where t is 1 or 2) and —S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring systems from which aryl groups are derived, include, but are not limited to, cyclic systems such as benzene, fluorene, indane, indene, tetralin and naphthalene, corresponding respectively to phenyl, fluorenyl, indanyl, tetralinyl, and naphthalenyl radicals, that can be further substituted. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O) ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain. In particular, phenyl can be optionally substituted by one to five substituents independently selected from the above-mentioned substituents. For example, phenyl substituted with halogen represents 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4,6-trifluorophenyl, 3-chloro-4-fluorophenyl, etc., but also 3-methyl-4-fluorophenyl, and 3,5-dimethyl-4-bromophenyl.

“Aryloxy” refers to a radical bonded through an oxygen atom of the formula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —Rd-aryl where Rd is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Aralkyloxy” refers to a radical bonded through an oxygen atom of the formula —O— aralkyl, where aralkyl is as defined above.

“Aralkenyl” refers to a radical of the formula —Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyls are saturated, (i.e., containing single C—C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.) Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., —C3-C8 cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., —C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., —C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., —C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., —C3-C4 cycloalkyl). A partially unsaturated cycloalkyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., 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 specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,

heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.

“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by 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.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring system radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. “C2-C9heterocycloalkyl” refers to a heterocycloalkyl radical as defined above that comprises from two to nine carbon atoms and from one to four heteroatoms. “C4-C5heterocycloalkyl” refers to a heterocycloalkyl radical as defined above that comprises from four to five carbon atoms and from one to three heteroatoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl (in particular, 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-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocycloalkyl” is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,

“Heteroaryl” refers to a radical derived from a 5- to 18-membered aromatic ring system that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. “C2-C9 heteroaryl” refers to a radical derived from a 3- to 10-membered aromatic ring system that comprises two to nine carbon atoms and from one to 4 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the 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 heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.

“N-Heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“C-Heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of the formula —O— heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)—. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

The term “prodrugs” includes compounds that, after administration, are metabolized into a pharmacologically active drug (R. B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp. 8). A prodrug may be used to improve how a compound is absorbed, distributed, metabolized, and excreted.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“IC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

As used herein, “subject” refers to a warm blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and disorders described herein.

The term “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

An “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, sex, age, medical history, severity of adverse side-effects and preferred mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and/or other therapeutic agent without necessitating undue experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient's peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

Compounds

The compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) described herein are MMP inhibitors. In some embodiments, the compounds of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc) described herein, and compositions comprising these compounds, are useful for treating a cardiovascular disease, disorder or condition, in particular heart failure.

In some embodiments, the invention provides a compound of Formula (I):

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl and {circle around (B)} is phenyl.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(═O)—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —S(═O)2—.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —O—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —CH2O—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —OCH2—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)— and R5 is —C1-C6alkyl.

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

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In a further embodiment, R3 is phenyl optionally substituted with halogen. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2. In some embodiments, —N(R6)2 represents C3-C5heterocycloalkyl, e.g., 4-morpholinyl.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In a further embodiment, R4 is phenyl optionally substituted with halogen. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2. In some embodiments, —N(R6)2 represents C3-C5heterocycloalkyl, e.g., 4-morpholinyl.

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH), —CH2N(OH)C(═O)R8, —CH(OH)N(═O), —C(═O)CF3, —CH2NHS(═O)2R8, —CH(NH2)C(═O)OH,

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH). In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2N(OH)C(═O)R8. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(OH)N(═O). In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)CF3. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2NHS(═O)2R8. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(NH2)C(═O)OH. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

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

In some embodiments, the invention provides a compound of Formula (Ia):

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

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

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

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH), —CH2N(OH)C(═O)R8, —CH(OH)N(═O), —C(═O)CF3, —CH2NHS(═O)2R8, —CH(NH2)C(═O)OH,

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH). In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2N(OH)C(═O)R8. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(OH)N(═O). In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)CF3. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2NHS(═O)2R8. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(NH2)C(═O)OH. In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

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

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (Ib):

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

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

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

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH), —CH2N(OH)C(═O)R8, —CH(OH)N(═O), —C(═O)CF3, —CH2NHS(═O)2R8, —CH(NH2)C(═O)OH,

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH). In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2N(OH)C(═O)R8. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(OH)N(═O). In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)CF3. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2NHS(═O)2R8. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(NH2)C(═O)OH. In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

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

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (Ic):

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

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

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

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

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH), —CH2N(OH)C(═O)R8, —CH(OH)N(═O), —C(═O)CF3, —CH2NHS(═O)2R8, —CH(NH2)C(═O)OH,

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)NH(OH). In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2N(OH)C(═O)R8. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(OH)N(═O). In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —C(═O)CF3. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH2NHS(═O)2R8. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is —CH(NH2)C(═O)OH. In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

In some embodiments, the invention provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is

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

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (II):

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is phenyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl and {circle around (B)} is phenyl.

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(═O)—. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —S(═O)2—.

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —O—. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —CH2O—. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —OCH2—. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)—. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)— and R5 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5) and R5 is methyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5) and R5 is ethyl.

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

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

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

In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (III):

In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is phenyl. In some embodiments, the invention provides a compound of Formula (IT), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (B)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl and {circle around (B)} is phenyl.

In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —O—. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —CH2O—. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —OCH2—. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)—. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)— and R5 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5) and R5 is methyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5) and R5 is ethyl.

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

In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

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

In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and -C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (IIIa):

In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C2-C9heteroaryl.

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

In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (IIIb):

In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C2-C9heteroaryl.

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

In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

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

In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is halogen. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6alkyl. In a further embodiment, R4 is methyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C1-C6haloalkyl. In a further embodiment, R4 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is —SO2N(R6)2.

In some embodiments, the invention provides a compound of Formula (I), having the structure of Formula (IIIc):

In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is phenyl. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C3-C10cycloalkyl or C2-C9heteroaryl. In some embodiments, the invention provides a compound of Formula some embodiments is a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein {circle around (A)} is C2-C9heteroaryl.

In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —O—. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —CH2O—. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —OCH2—. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)—. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(H)—. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5)— and R5 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5) and R5 is methyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —N(R5) and R5 is ethyl.

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

In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, —N(R6)2, —CN, —C(═O)OR6, —C(═O)N(R6)2, —SO2R7, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, —C1-C6alkyl, —C1-C6haloalkyl, —OR6, and —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen and —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is halogen. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6alkyl. In a further embodiment, R3 is methyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C1-C6haloalkyl. In a further embodiment, R3 is trifluoromethyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from —OR6, —N(R6)2, —C(═O)OR6, —C(═O)N(R6)2, and —SO2N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6. In a further embodiment, R6 is hydrogen or methyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —OR6 and each R6 is —C1-C6alkyl. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)OR6. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —C(═O)N(R6)2. In some embodiments, the invention provides a compound of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is —SO2N(R6)2.

In some embodiments described herein, the disclosed compound is a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), selected from the following compounds:

Ex
Structure
Name

or is a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, a disclosed compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein, such as a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), described herein.

Preparation of the Compounds

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

Specific and analogous reactants are also identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Further Forms of Compounds Disclosed Herein

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

Labeled Compounds

In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases 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 those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H, 3H, 13C, 14C, 15N, 16O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, esters, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i. e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof is prepared by any suitable method.

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 diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

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

In some embodiments, the compounds described herein are formulated as agents which are converted in vivo to active forms in order to alter the biodistribution or the pharmacokinetics for a particular agent. For example, a carboxylic acid group can be esterified, e.g., with a methyl group or an ethyl group 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 the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate agent which subsequently decomposes to yield the active agent. The prodrug moieties may be metabolized in vivo by esterases or by other mechanisms to carboxylic acids. Alternatively, other functional groups may be modified into a prodrug form. For instance, an amine group may be converted into a carbamate or amide which would be cleavable in vivo.

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

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

Pharmaceutical Compositions

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

Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

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

Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I) or (Ta) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

In some embodiments, a compound of Formula (I) or (Ia) or (Ib) or (Ic), described herein is administered to subjects in a biologically compatible form suitable for topical administration to treat or prevent dermal diseases, disorders or conditions. By “biologically compatible form suitable for topical administration” is meant a form of the compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), to be administered in which any toxic effects are outweighed by the therapeutic effects of the inhibitor. Administration of a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), as described herein can be in any pharmacological form including a therapeutically effective amount of a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), alone or in combination with a pharmaceutically acceptable carrier.

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

Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer such as DMSO to increase the absorption of the compounds. Patches can include those that control the rate of drug delivery to the skin. Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively. The reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water-resistant backing. Such a design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of skin.

The monolithic design, for example, typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a water-proof backing. This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin. As the drug amount decreases in the patch to below the saturating level, the delivery rate falls.

In one embodiment, the topical composition may, for example, take the form of hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethylene glycol (PEG) as the carrier, like the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, especially a microemulsion based on water-in-oil or oil-in-water, optionally with added liposomes. Suitable permeation accelerators (entraining agents) include sulfoxide derivatives such as dimethylsulfoxide (DMSO) or decylmethylsulfoxide (decyl-MSO) and transcutol (diethyleneglycolmonoethylether) or cyclodextrin; as well as pyrrolidones, for example 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or the biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3-diphenylurea; terpenes, for example D-limonene, menthone, α-terpineol, carvol, limonene oxide, or 1,8-cineol.

Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals. In general, such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

In some embodiments for preparing solid compositions such as tablets, the principal 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 a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragées, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

The dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

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

Methods

In some embodiments disclosed herein is a method for treating a disease, disorder or condition selected from:

and scleroderma pigmentosum,

in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia) or (Ib) or (Ic) or (II) or (III) or (IIIa) or (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof.

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

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

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

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

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

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

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

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

Pharmaceutical Combinations

Also contemplated herein are combination therapies, for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.

Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Substantially simultaneous administration is also accomplished by administering to the subject a new chemical entity that is comprised of disclosed compound bound through chemical bond or linker to one or more additional active agents. Sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

In some embodiments, disclosed herein is a method of treating a disease, disorder or condition selected from:

Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

The components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously.

Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, that are administered either simultaneously or sequentially.

EXAMPLES

The present invention is further illustrated by the following examples, which in no way should be construed as limiting the scope of the claims provided herein.

List of Abbreviations

As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

If not otherwise defined, purity of a solid substance is expressed as a ratio of the weight of the component in question to the total weight, multiplied by 100 (weight %); purity of a liquid is expressed as a ratio of the volume of the component in question to the total volume, multiplied by 100 (volume %); concentration of a solution is expressed as a ratio of the weight of the solute (in grams) to the total volume (in mL) of the solution, multiplied by 100(% w/v). Yield of a reaction is expressed as a ratio of the weight of the product in question to the theoretical yield of this product, multiplied by 100(%). Composition of a mixed solvent is expressed as a proportion of volume parts of the component solvents (e.g., 80:20 or 3:2:1).

GENERAL REMARKS

Analytical Methods

Proton (1H) and carbon (13C) NMR spectra were recorded on a Bruker Ascend-400 spectrometer operating at 400 MHz for proton and 100 MHz for carbon using CDCl3, DMSO-d6, CD3CN or D2O as solvents. Chemical shifts are expressed as parts per million (6, ppm) and coupling constants (J) are reported in Hertz. For proton spectra, the solvent peak was used as the reference peak. LCMS was performed on Shimadzu LCMS-2020 or Agilent 6420 Triple Quad LC/MS or Agilent Infinity Lab LC/MSD XT using PDA detector under the conditions of electrospray ionization (ESI) in both positive and negative mode. HPLC was performed on Shimadzu LC-2010 and Agilent 1290 Infinity II using PDA detector. Preparative HPLC was performed on Shimadzu semi preparative or Agilent 1260 Infinity II using PDA detector. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted.

The operating conditions of chromatographic and mass-spectral analyses are summarized in Tables 1-3 below.

LCMS conditions

Method
Conditions

Preparative HPLC conditions

Method
Conditions

HPLC conditions

Method
Conditions

Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized.

Compounds according to the present invention may be prepared using the synthetic transformations illustrated in Synthetic Schemes 1 to 10 below. Starting materials are commercially available, may be prepared by the procedures described herein, by literature procedures, or by procedures that would be well known to one skilled in the art of organic chemistry.

Exemplary synthetic methodologies for making compounds according to this disclosure are provided below.

In Step 1 of the General Synthetic Scheme 1, various sulfonyl chlorides (1B) react with the secondary amine (1A) to afford Formula 1C. Formula 1C undergoes deprotection to afford Formula 1D. Further Formula 1D is reacted with methoxyethyl chloroformate to afford Formula 1E. Further Formula 1E was treated with inorganic base in water and THF to afford Formula 1F, which on further coupling with protected hydroxylamine under usual amide conditions yielded Formula 1G. Finally, Formula 1G undergoes deprotection in presence of suitable acids such as TFA, 1N HCl etc. in suitable solvents such as DCM, 1,4-dioxane, and MeOH to provide Formula 1.

To a stirred solution of (1S,2S,5R)-8-tert-butyl 2-ethyl 3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (300 mg, 1.05 mmol) in acetone (6 mL) under nitrogen atmosphere at 0-10° C., was added K2CO3 (580 mg, 4.2 mmol) 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. Then, water (0.05 mL) was 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 obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 15-20% EtOAc in hexane) to afford (1S,2S,5R)-8-tert-butyl 2-ethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3, 8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (330 mg, 0.61 mmol, 58% yield) as a colorless sticky gum. MS (ESI): m/z 480.0 [M-t-Bu+H]+.

To a stirred solution of (1S,2S,5R)-8-tert-butyl 2-ethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (0.33 g, 0.61 mmol) in DCM (4 mL) at 0-5° C., was added trifluoroacetic acid (0.5 mL, 6.1 mmol) dropwise and stirred at room temperature for 16 h while being monitored by TLC. The reaction mixture was evaporated to dryness, the residue was diluted with ethyl acetate (40 mL) and washed with saturated NaHCO3 solution (2×15 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain (1S,2S,5R)-ethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (270 mg, 0.62 mmol, quantitative) as a colorless sticky gum. This was used as such for the next step without further purification. MS (ESI): m/z 436.0 [M+H]+.

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

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

To a stirred solution of (1S,2S,5R)-2-ethyl 8-(2-methoxyethyl) 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (330 mg, 0.61 mmol) in 1:1:1 mixture of THF:EtOH:H2O (30 mL) at 0° C., was added NaOH (122 mg, 3.0 mmol) in one portion. The reaction mixture was stirred at RT for 16 h while being monitored by TLC. The volatiles were evaporated under reduced pressure, the residue was diluted with water (5 mL) and cooled to 0-10° C. The reaction mixture pH was adjusted to ˜4-5 with 10% aqueous citric acid and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (15 mL), separated, dried over Na2SO4, filtered and concentrated under reduced pressure to afford (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. This was used as such for the next step without further purification. MS (ESI): m/z 510.0 [M+H]+.

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., was added HATU (223 mg, 0.58 mmol) and DIPEA (0.44 mL, 2.4 mmol). The reaction mixture was stirred for 30 min at the same temperature and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (69 mg, 0.63 mmol) was added. The reaction mixture was allowed to warm to RT over a period of 30 min and stirred for 6 h while being monitored by TLC. The reaction mixture was quenched with ice cold water (15 mL) at 0° C. and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (15 mL), separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (1S,2R,5R)-2-methoxyethyl 3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.33 mmol, 67% yield) as a colorless liquid. This was used as such for the next step without further purification. MS (ESI): m/z 606.9 [M−H]−.

Similarly, below examples were prepared by following the same or analogous process as described in Example 1.

Ex.
Structure
Name
Analytical data

Synthesis of ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate fumarate salt

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (250 mg, 0.87 mmol) in THF (5 mL) under nitrogen at 0-10° C. was added DIPEA (0.45 mL, 2.6 mmol) 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 layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude compound. The crude product was purified by silica gel column chromatography (60-120 mesh, 15-40% EtOAc in hexanes) to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (240 mg, 0.45 mmol, 52% yield) as a yellow gum. MS (ESI): m/z 526.2 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 498.2 [M+H]+.

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. was added BOP—Cl (191 mg, 0.75 mmol) and DIPEA (0.16 mL, 0.9 mmol). 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 allowed to warm to RT over a period of 30 min and stirred for 16 h while being monitored by TLC. 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 layer was washed with brine (20 ML), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-methoxyethyl (1S,2R,5R)-3-((6-(cyclohexyloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.30 mmol) as a yellow gum. This was used as such for the next step without further purification. MS (ESI): m/z 595.3 [M−H]−.

Similarly, below examples were prepared by following the same or analogous process as described in Example 10.

Ex.
Structure
Name
Analytical data

To a stirred solution of (1S,2S,5R)-8-tert-butyl 2-ethyl 3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (200 mg, 0.70 mmol) in DCM (5 mL) under nitrogen atmosphere at 0-10° C., was added Et3N (0.2 mL, 1.40 mmol) 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 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 layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 20% EtOAc in hexanes) to afford 8-(tert-butyl) 2-ethyl (1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (200 mg, 0.45 mmol, 64% yield) as an off-white solid. MS (ESI): m/z 444.4 [M+H]+.

To a stirred solution of 8-(tert-butyl) 2-ethyl (1S,2S,5R)-3-((5-fluoropyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (200 mg, 0.45 mmol) in DMF (3 mL), was added Cs2CO3 (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 while monitored by TLC. The reaction mixture was cooled to room temperature, quenched with ice cold water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, 10% EtOAc in hexanes) to afford 8-(tert-butyl) 2-ethyl (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (170 mg, 0.31 mmol, 68% yield) as a colorless liquid. MS (ESI): m/z 536.2 [M+H]+.

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

Similar procedure was followed as described for Step 2 of Example 1, to obtain ethyl (1S,2S,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (140 mg, 0.31 mmol, quantitative) as a colorless liquid. MS (ESI): m/z 436.2 [M+H]+.

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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]+.

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 for 30 min at RT. The reaction mixture was cooled to 0-10° C., DIPEA (0.08 mL, 0.47 mmol) was added to it and stirred for 10 min then, 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine hydrochloride (23 mg, 0.204 mmol) was added at the same temperature. The reaction mixture was allowed to warm to RT over a period of 30 min and stirred for 2 h while being monitored by TLC. 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 layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-methoxyethyl (1S,2R,5R)-3-((5-(4-fluorophenoxy)pyridin-2-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.16 mmol, quantitative) as an off-white solid. This was used as such for the next step without further purification. MS (ESI): m/z 609 [M+H]+.

Similarly, below examples were prepared by following the same or analogous process as described in Example 14.

Ex.
Structure
Name
Analytical data

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

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 558.1 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (1S,2R,5R)-3-((6-(4-(difluoromethoxy)phenoxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530 mg, 0.80 mmol) as a brown gum. This was used as such for the next step without further purification. MS (ESI): m/z 657.2 [M+H]+.

Similarly, below examples were prepared by following the same or analogous process as described in Example 24.

Ex.
Structure
Name
Analytical data

To a stirring solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (500 mg, 1.74 mmol) in THF (5 mL) under nitrogen at 0-10° C. was added DIPEA (1.2 mL, 5.2 mmol) 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 at the same temperature. The reaction was allowed to stir 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 layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography (60-120 mesh, 15-25% EtOAc in hexanes) to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((3,4-difluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (360 mg, 0.78 mmol, 44% yield) as a colorless gum. MS (ESI): 463.2 [M+H]+.

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

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 513.2 [M+H]+.

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. was added HATU (233 mg, 0.61 mmol) and DIPEA (0.22 mL, 1.23 mmol), and stirred for 30 min. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (62 mg, 0.53 mmol) was added, warm to RT over a period of 30 min and stirred for 16 h while being monitored by TLC. The reaction was quenched with cold water (10 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-methoxyethyl (1S,2R,5R)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo-[3.2.1]octane-8-carboxylate (210 mg, 0.34 mmol, quantitative) as a colorless oil. This was used as such for the next step without further purification; MS (ESI): m/z 610.2 [M−H]−.

Similar procedure was followed as described for Step 1 of Example 41, to obtain 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((3,4,5-trifluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (400 mg, 0.83 mmol, 48% yield) as a colorless gum. This was used as such for the next step without further purification. MS (ESI): m/z 481.2 [M+H]+.

Similar procedure was followed as described for Step 2 of Example 41, to obtain 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (300 mg, 0.54 mmol, 64% yield) as a colorless liquid. This was used as such for the next step without further purification. MS (ESI): m/z 559.2 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 531.2 [M+H]+.

Similar procedure was followed as described for Step 4 of Example 41, to obtain 2-methoxyethyl (1S,2R,5R)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.32 mmol, quantitative) as colorless liquid. This was used as such for the next step without further purification. MS (ESI): m/z 628.2 [M−H]−.

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

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2R,5R)-3-((6-(4-(methoxymethoxy)phenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (380 mg, 0.65 mmol) in THF (10 mL) at 0-10° C. was added 4M HCl in dioxane (7.6 mL) and stirred at room temperature for 2 h while being monitored by TLC. The volatiles were evaporated to dryness to obtain 2-ethyl 8-(2-methoxyethyl) (1S,2R,5R)-3-((6-(4-hydroxyphenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (340 mg, 0.63 mmol, 97% yield) as a light brown gum. MS (ESI): m/z 536.2 [M+H]+.

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

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 540.2 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (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-carboxylate (160 mg, 0.25 mmol, 92% yield) as a colorless syrup. This was used as such for the next step without further purification. MS (ESI): m/z 639.2 [M+H]+.

To a stirring solution of (1S,2S,5R)-8-tert-butyl 2-ethyl 3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (200 mg, 0.70 mmol) in THF (3 mL) under nitrogen atmosphere at 0-10° C., was added DIPEA (0.4 mL, 2.11 mmol) 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 allowed to stir at 60° C. for 48 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 layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (100-200 mesh, 15-20% EtOAc in hexanes) to afford (1S,2S,5R)-8-tert-butyl 2-ethyl 3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (160 mg, 0.28 mmol, 40% yield) as a colorless sticky gum. MS (ESI): m/z 558.4 [M+H]+.

Similar procedure was followed as described for Step 2 of Example 1, to obtain (1S,2S,5R)-ethyl 3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (150 mg, 0.32 mmol, quantitative) as a colorless liquid. MS (ESI): 458.4 [M+H]+.

Synthesis of (1S,2R,5R)-3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-8-((2-methoxy-ethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

Similar procedure was followed as described for Step 5 of Example 1, to obtain (1S,2R,5R)-2-methoxyethyl 3-((4-(4-chlorophenoxy)piperidin-1-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.11 mmol, quantitative) as a brown sticky gum. MS (ESI): m/z 631.2 [M+H]+.

Similarly, below examples were prepared by following the same or analogous process as described in Example 44.

Ex.
Structure
Name
Analytical data

Synthesis 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

Synthesis of ethyl (1S,2S,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

To a stirred solution of ethyl (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (200 mg, 0.46 mmol) in DCM (5 mL) at 0-10° C. was added Et3N (0.2 mL, 1.83 mmol) and stirred for 10 min at same temperature. 2-Chloro-N,N-dimethylacetamide (55 mg, 0.46 mmol) was added and the reaction was stirred at RT for 16 h while being monitored by TLC. The reaction was quenched by ice cold water (5 mL) and extracted with DCM (2×20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford ethyl (1S,2S,5R)-8-(2-(dimethylamino)-2-oxoethyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (180 mg, 0.34 mmol, 74% yield) as a light yellow gum. This was used as such for the next step without further purification. MS (ESI): m/z 521.1 [M+H]+.

Synthesis 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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 493.2 [M+H]+.

Synthesis 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

Similar procedure was followed as described for Step 5 of Example 1, to obtain (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 light yellow gum. This was used as such for the next step without further purification. MS (ESI): m/z 592.3 [M+H]+.

Similarly, below example was prepared by following the same or analogous process as described in Example 51.

Ex.
Structure
Name
Analytical data

Synthesis 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

Synthesis of methyl (1S,2S,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

To a solution of methyl (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (150 mg, 0.34 mmol; prepared in analogous fashion as the ethyl ester) in DCM (5 mL) at 0-10° C. was added Et3N (0.14 mL, 1.03 mmol) and stirred for 10 min at same temperature. Acetic anhydride (0.06 mL, 0.68 mmol) was added and the reaction mixture was stirred at RT for 16 h while being monitored by TLC. 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 Na2SO4, filtered and concentrated under reduced pressure to afford methyl (1S,2S,5R)-8-acetyl-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (160 mg, 0.33 mmol, quantitative) as a light yellow syrup. This was used as such for the next step without further purification. MS (ESI): m/z 464.1 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (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. This was used as such for the next step without further purification. MS (ESI): m/z 448.1 [M−H]−.

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

Similar procedure was followed as described for Step 3 of Example 10, to obtain (1S,2R,5R)-8-acetyl-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, 0.18 mmol) as a yellow gum. This was used as such for the next step without further purification. MS (ESI): m/z 547.1 [M−H]−.

Similarly, below examples were prepared by following the same or analogous process as described in Example 53.

Ex.
Structure
Name
Analytical data

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

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (1S,2R,5R)-8-(ethoxycarbonyl)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (100 mg, 0.21 mmol, 79% yield) as a light brown gum. This was used as such for the next step without further purification. MS (ESI): m/z 478.1 [M−H]−.

Synthesis of ethyl (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-carboxylate

Similar procedure was followed as described for Step 3 of Example 10, to obtain ethyl (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-carboxylate (90 mg, 0.15 mmol) as a yellow gum. This was used as such for the next step without further purification. MS (ESI): m/z 577.1 [M−H]−.

Similarly, below examples were prepared by following the same or analogous process as described in Example 65.

Ex.
Structure
Name
Analytical data

Synthesis of (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-N-hydroxy-8-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxamide

Synthesis of methyl (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

To a stirred solution of methyl (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (120 mg, 0.28 mmol) in DCM (5 mL) at 0-10° C. was added Et3N (0.12 mL, 0.85 mmol) and stirred for 10 min. Morpholine-4-carbonyl chloride (0.07 mL, 0.68 mmol) was added and the reaction was stirred at RT for 16 h while being monitored by TLC. The reaction was quenched with ice cold water (5 mL) and extracted with DCM (2×15 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl (1S,2S,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (150 mg, 0.28 mmol, quantitative) as a light yellow syrup. This was used as such for the next step without further purification. MS (ESI): m/z 535.0 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-(morpholine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (140 mg, 0.27 mmol) as a light yellow sticky gum. This was used as such for the next step without further purification. MS (ESI): m/z 521.2 [M+H]+.

Synthesis of (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-(morpholine-4-carbonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)-3,8-diazabicyclo[3.2.1]octane-2-carboxamide

Similar procedure was followed as described for Step 5 of Example 1, to obtain (1S,2R,5R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)sulfonyl)-8-(morpholine-4-carbonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)-3,8-diazabicyclo[3.2.1]octane-2-carboxamide (100 mg, 0.16 mmol) as a yellow color sticky compound. This was used as such for the next step without further purification. MS (ESI): m/z 620.2 [M+H]+.

Similarly, below examples were prepared by following the same or analogous process as described in Example 68.

Ex.
Structure
Name
Analytical data

To a stirring solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1 g, 3.49 mmol) in THF (10 mL) under nitrogen atmosphere at 0-10° C. was added DIPEA (2.5 mL, 13.9 mmol) and stirred for 20 min. 6-((1-(2,2,2-Trifluoroacetyl)piperidin-4-yl)oxy)pyridine-3-sulfonyl chloride (1.95 g, 5.23 mmol) was dissolved in THE (10 mL) and added to the reaction. The reaction was stirred at 60° C. for 16 h while being monitored by TLC. The reaction was cooled to RT, diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((6-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)-3, 8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (2 g, 3.21 mmol, 91% yield) as a light yellow gum. This was used as such for the next step without further purification. MS (ESI): m/z 623.3 [M+H]+.

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((6-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (500 mg, 0.8 mmol) in MeOH (5 mL) at 0-10° C. was added K2CO3 (221 mg, 1.6 mmol) and stirred at room temperature for 1 h. The reaction was monitored by TLC. The volatiles were evaporated to afford semi pure 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((6-(piperidin-4-yloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (420 mg, 0.79 mmol, quantitative) as white gum. This was used for next step without further purification. MS (ESI): m/z 527.3 [M+H]+.

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((6-(piperidin-4-yloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (420 mg, 0.79 mmol) in ACN (5 mL) at 0-10° C. was added Et3N (0.46 mL, 3.19 mmol) and ethyl iodide (0.08 mL, 1.04 mmol). The reaction was stirred at RT for 16 h while being monitored by TLC. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((6-((1-ethylpiperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (400 mg, 0.72 mmol, 91% yield) as a light yellow syrup. This was used for next step without further purification. MS (ESI): m/z 555.3 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (1S,2R,5R)-3-((6-((1-ethylpiperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (230 mg, 0.43 mmol, 60% yield) as a brown gum. This was used as such for the next step without further purification. MS (ESI): m/z 527.3 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (1S,2R,5R)-3-((6-((1-ethylpiperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (190 mg, 0.30 mmol) as a light yellow syrup. This was used as such for the next step without further purification. MS (ESI): m/z 626.3 [M+H]+.

Similarly, below example was prepared by following the same or analogous process as described in Example 74.

Ex.
Structure
Name
Analytical data

To a stirring solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (2.97 g, 10.56 mmol) in THF (30 mL) under nitrogen at 0-10° C. was added DIPEA (3.62 mL, 21.12 mmol) and stirred for 20 min. tert-Butyl 4-(chlorosulfonyl)piperazine-1-carboxylate (2.0 g, 7.04 mmol) in THF (20 mL) and added and the reaction mixture was stirred at 60° C. for 48 h while being monitored by TLC. The reaction was cooled to RT, diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 25-30% EtOAc in hexanes) to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (800 mg, 1.49 mmol, 21% yield) as a colorless gum. MS (ESI): m/z 535.3 [M+H]+.

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (800 mg, 1.49 mmol) in DCM (10 mL) at 0-10° C. was added trifluoroacetic acid (1.13 mL, 14.9 mmol) dropwise and stirred at RT for 16 h. The completion of the reaction was monitored by TLC. The volatiles were evaporated under reduced pressure to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-(piperazin-1-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (600 mg, 1.38 mmol, 92% yield) as a colorless gum. This was used as such for the next step without further purification. MS (ESI): m/z 435.2 [M+H]+.

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-(piperazin-1-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (250 mg, 0.57 mmol) in ACN (3 mL) at 0-5° C. was added Et3N (0.4 mL, 2.87 mmol) and 1-chloro-4-(chloromethyl)benzene (0.13 mL, 0.86 mmol). The reaction was stirred at RT for 16 h while being monitored by TLC. The reaction was diluted with ethyl acetate (20 mL), washed with aqueous saturated NaHCO3 solution (2×10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 2-3% MeOH in DCM) to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((4-(4-chlorobenzyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (200 mg, 0.35 mmol, 61% yield) as a colorless gum. MS (ESI): m/z 559.2 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (1S,2R,5R)-3-((4-(4-chlorobenzyl)piperazin-1-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3, 8-diazabicyclo[3.2.1]octane-2-carboxylic acid (150 mg, 0.28 mmol, 83% yield) as a brown gum. This was used as such for the next step without further purification. MS (ESI): m/z 531.2 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (1S,2R,5R)-3-((4-(4-chlorobenzyl)piperazin-1-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.25 mmol, 96% yield) as a colorless gum. This was used as such for the next step without further purification. MS (ESI): m/z 630.2 [M+H]+.

Similarly, below example was prepared by following the same or analogous process as described in Example 76.

Ex.
Structure
Name
Analytical data

To a stirred solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-(piperazin-1-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (250 mg, 0.57 mmol) in ACN (3 mL) at 0-5° C. was added Et3N (0.4 mL, 2.87 mmol) followed by 4-chlorobenzoyl chloride (0.11 mL, 0.86 mmol). The reaction was stirred at RT for 16 h while being monitored by TLC. The reaction was diluted with ethyl acetate (20 mL), washed with water (2×10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 2-3% MeOH in DCM) to afford 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3-((4-(4-chlorobenzoyl)piperazin-1-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (180 mg, 0.31 mmol, 54% yield) as a colorless gum. MS (ESI): m/z 573.1 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (1S,2R,5R)-3-((4-(4-chlorobenzoyl)piperazin-1-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (110 mg, 0.20 mmol, 68% yield) as a brown gum. This was used as such for the next step without further purification. MS (ESI): m/z 545.1 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (1S,2R,5R)-3-((4-(4-chlorobenzoyl)piperazin-1-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.18 mmol, quantitative) as a colorless gum. This was used as such for the next step without further purification. MS (ESI): m/z 642.2 [M−H]−.

To a stirring solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1 g, 3.49 mmol) in THF (5 mL) under nitrogen at 0-10° C. was added DIPEA (1.8 mL, 10.5 mmol) and stirred for 20 min. 4-(Benzyloxy)-3-fluorobenzenesulfonyl chloride (1.57 g, 5.23 mmol) in THF (10 mL) was added and the reaction mixture was stirred at 60° C. for 16 h while being monitored by TLC. The reaction was cooled to RT, diluted with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 25-30% EtOAc in hexanes) to afford 2-ethyl 8-(2-methoxyethyl) (2S,5R)-3-((4-(benzyloxy)-3-fluorophenyl)sulfonyl)-3,8-diazabicyclo[3.2.1]-octane-2,8-dicarboxylate (900 mg, 1.63 mmol, 47% yield) as a colorless gum. MS (ESI): m/z 551.2 [M+H]+.

Synthesis of (2R,5R)-3-((4-(benzyloxy)-3-fluorophenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

Similar procedure was followed as described for Step 4 of Example 1, to obtain (2R,5R)-3-((4-(benzyloxy)-3-fluorophenyl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (700 mg, 1.33 mmol, 81% yield) as a colorless sticky gum. This was used as such for the next step without further purification. MS (ESI): m/z 523.1 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (2R,5R)-3-((4-(benzyloxy)-3-fluorophenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.96 mmol, 72% yield) as a colorless oil. This was used as such for the next step without further purification. MS (ESI): m/z 620.1 [M−H]−.

To a stirred solution of 2-methoxyethyl (2R,5R)-3-((4-(benzyloxy)-3-fluoro-phenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.96 mmol) in MeOH (10 mL) was added Pd/C (180 mg, 30% w/w) under N2 atmosphere. The reaction was stirred under H2 balloon pressure for 6 h while being monitored by TLC. Reaction mixture was filtered through a celite bed and washed with MeOH (20 mL). The filtrate was evaporated under reduced pressure to afford 2-methoxyethyl (2R,5R)-3-((3-fluoro-4-hydroxyphenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.94 mmol, quantitative) as colorless liquid; MS (ESI): m/z 530.1 [M−H]−.

To a stirring solution of 2-methoxyethyl (2R,5R)-3-((3-fluoro-4-hydroxyphenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.37 mmol) in ACN (4 mL) was added K2CO3 (155 mg, 1.13 mmol) under nitrogen at 0-10° C. and stirred for 20 min. 2-Chlorobenzo[d]oxazole (63 mg, 0.41 mmol) in ACN (2 mL) was added to the reaction and stirred at 50° C. for 6 h while being monitored by TLC. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, 50-80% EtOAc in hexanes) to afford 2-methoxyethyl (2R,5R)-3-((4-(benzo[d]oxazol-2-yloxy)-3-fluorophenyl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.18 mmol, 50% yield) as a colorless gum; MS (ESI): m/z 649.4 [M+H]+.

Similarly, below examples were prepared by following the same or analogous process as described in Example 79.

Ex.
Structure
Name
Analytical data

To a stirring solution of 2-ethyl 8-(2-methoxyethyl) (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (800 mg, 2.79 mmol) in THF (8 mL) under nitrogen at 0-10° C. was added DIPEA (1.47 mL, 8.37 mmol) and stirred for 20 min. 6-(Benzyloxy)-pyridine-3-sulfonyl chloride (1.27 g, 4.18 mmol) in THF (10 mL) was added and the reaction mixture was stirred at 60° C. for 16 h while being monitored by TLC. The reaction was cooled to RT, diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh, 25-30% EtOAc in hexanes) to afford 2-ethyl 8-(2-methoxyethyl) (2S,5R)-3-((6-(benzyloxy)pyridin-3-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (820 mg, 1.53 mmol, 55% yield) as a colorless gum. MS (ESI): m/z 534.2 [M+H]+.

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

Similar procedure was followed as described for Step 4 of Example 1, to obtain (2R,5R)-3-((6-(benzyloxy)pyridin-3-yl)sulfonyl)-8-((2-methoxyethoxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (600 mg, 1.18 mmol, 77% yield) as a colorless gum. This was used as such for the next step without further purification. MS (ESI): m/z 506.2 [M+H]+.

Similar procedure was followed as described for Step 3 of Example 10, to obtain 2-methoxyethyl (2R,5R)-3-((6-(benzyloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.99 mmol, 84% yield) as a colorless oil. This was used as such for the next step without further purification. MS (ESI): m/z 603.3 [M−H]−.

To a stirred solution of 2-methoxyethyl (2R,5R)-3-((6-(benzyloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.58 mmol) in MeOH (10 mL) was added Pd/C (105 mg, 30% w/w) under N2 atmosphere. The reaction was stirred under H2 balloon pressure for 16 h while being monitored by TLC. Reaction mixture was filtered through a celite bed and washed with MeOH (20 mL). The filtrate was evaporated under reduced pressure to afford 2-methoxyethyl (2R,5R)-3-((6-hydroxypyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.48 mmol, 83% yield) as colorless liquid; MS (ESI): m/z 513.2 [M−H]−.

To a stirring solution of 2-methoxyethyl (2R,5R)-3-((6-hydroxypyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.46 mmol) in ACN (5 mL) was added K2CO3 (192 mg, 1.38 mmol) under nitrogen at 0-10° C. and stirred for 20 min. 2-Chlorobenzo[d]oxazole (79 mg, 0.51 mmol) in ACN (2 mL) was added to the reaction and stirred at 50° C. for 6 h while being monitored by TLC. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, 60-80% EtOAc in hexanes) to afford 2-methoxyethyl (2R,5R)-3-((6-(benzo[d]oxazol-2-yloxy)pyridin-3-yl)sulfonyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.24 mmol, 51% yield) as a colorless gum; MS (ESI): m/z 630.2 [M−H]−.

Matrix Metalloproteinase Inhibition Assays

The inhibitory activities of the compounds of the invention were assessed in 96-well microplate format using MMP1, MMP2, MMP9 and MMP13 colorimetric assay kits and TACE fluorometric assay kit from Enzo Life Sciences, Inc. The inhibitory effect of the compounds of the invention on ADAM10 activity were evaluated in 96-well microplate format using fluorometric assay from AnaSpec, Inc.

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

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

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

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

The TACE Fluorometric Drug Discovery Kit (catalog #BML-AK310) is a complete assay system designed to screen ADAM17 (TACE) inhibitors using a quenched fluorogenic peptide: Mca-PLAQAV-Dpa-RSSSR—NH2. Mca fluorescence is quenched by the Dpa group until cleavage by proteases separates the two moieties leading to an increase in Mca fluorescence.

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

The inhibitory activities of the compounds of the invention against MMP1, MMP2, MMP9 and MMP13 were tested according to the manufacturer's assay protocols and the absorbance at 415 nm was monitored using the Tecan Infinite® 200 Pro F Nano+ microplate reader.

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

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

The normalized values were analyzed using GraphPadPrism 9 for Windows (GraphPad Software, San Diego, CA, USA) software by plotting inhibition curves and determining the IC50 values (in nM).

The calculated IC50 values were divided into the following classes:

The inhibitory activity classes of the exemplary compounds according to the invention are presented in Table 16.

MMP
MMP
MMP
MMP

B
A
A
A
C
C

B
B
B

C
C
C

B
C
B

B
A
A
A
B
B

C
A
A
A
C

B
A
A
A
B
B

B
A
A
A
B
C

B
A
A
A
B
C

B
A
A
A
C
D

C
A
A
B
C

C
B
A
B
C

C
B
A
A
C

C
A
A
A
C

C
B
B
B
B

C
A
B
B
C

D
C
C
C
D

C
A
A
A
C
C

C
A
A
A
C
D

B
A
A
A
B
C

B
A
A
A
B
D

B
A
A
A
B
D

B
A
B
B
C

C
A
A
A
B
C

C
A
A
A
D
D

D
A
B
B
C

D
A
B
B
C

B
A
A
A
C
D

B
A
A
A
C
D

B
A
A
A
C
D

D
A
A
A
D
D

B
A
A
A
C
D

C
A
A
A
C
D

C
A
A
A
C
C

B
A
A
A
B

A
A
A
A
B
C

C
B
B
B
B

C
B
B
B
B

B
A
A
A
B
D

B
A
A
A
B

A
A
A
A
B
B

C
B
B
B
B

C
A
A
A
C

B
A
A
A
A
B

B
A
A
A
B
C

D
B
B
B
B

D
C
C
C
B

C
A
A
A
A
B

D
B
B
B
C

D
B
B
B
C

C
A
B
A
D

C
A
B
A
D

B
A
A
A
C
D

C
A
A
A
C
D

C
A
A
A
C
D

D
A
A
A
C
D

C
A
A
A
C
D

C
A
A
A
D
D

C
A
A
A
D
D

C
A
A
A
D

C
A
B
A
D

C
A
A
A
D
D

C
A
A
A
C
C

C
B
B
B
C

B
A
A
A
C
D

C
A
A
A
C
D

B
A
A
A
C
D

C
A
B
A
C

C
A
B
B
C

D
A
A
A
C
D

C
A
B
A
D

C
A
A
A
D
D

D
A
A
A
C
C

D
D
C
D
D

C
B
B
B
C

D
B
B
B
C

D
B
B
C
C

D
C
C
C
C

D
B
C
B
C

D
C
C
C
C

D
D
C
D
C

D
C
C
C
B

C
C
C

D
D
D