1. BACKGROUND

[0001] Cyclic GMP-AMP synthase (cGAS) (UniProtKB - Q8N884) is an enzyme that acts as a DNA sensor to elicit an immune response to pathogens via activation of the stimulator of interferon genes (STING) receptor. Aberrant activation of cGAS by self-DNA is shown to underlie debilitating and sometimes fatal autoimmune diseases. Knockout studies in animal models have indicated that inhibiting cGAS is a promising approach for therapeutic intervention. Additionally, recent studies have shown that the cGAS-STING pathway plays a key role in the innate immune response to tumors, and stimulation of the pathway is a promising strategy being tested clinically for cancer immunotherapy.

[0002] An ongoing need exists in the art for effective treatments of human autoimmune and auto- inflammatory diseases, such as systemic lupus erythematosus (SLE), scleroderma, psoriasis, Aicardi Goutieres syndrome (AGS), Sjogren s syndrome, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, diabetes, cardiovascular, and neurodegenerative diseases. Accordingly, there remains a need to find potent and selective small molecule inhibitors of cGAS useful for the treatment of these and other debilitating human diseases associated with the aberrant activation of cGAS.

2. SUMMARY

[0003] The present disclosure relates to small molecule cGAS antagonist compounds, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy. In particular, the present disclosure provides quinoline cGAS antagonist compounds, which find utility as inhibitors of cGAS. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the inhibition of cGAS. In addition, the disclosure provides methods of using the compounds described herein for the treatment of inflammatory, allergic, autoimmune, and infectious diseases. The compounds can also be used for the treatment of senescence- or age- related diseases, such as neurodegenerative diseases, cardiovascular diseases, liver and renal diseases, cancer, and premature aging.

[0004] It has now been found that compounds of the disclosure, and pharmaceutically acceptable compositions thereof, are effective for the inhibition of cGAS. Such compounds of the disclosure have the general formula 1:

I or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0005] Compounds of the present disclosure, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions, associated with aberrant activation of cGAS. Such diseases, disorders, or conditions include those described herein.

[0006] Compounds provided by the present disclosure are also useful for the study of cGAS enzymes in biological and pathological phenomena and the comparative evaluation of new cGAS antagonists or other regulators of cGAS, signaling pathways, and cytokine levels in vitro or in vivo.

3. DETAILED DESCRIPTION

[0007] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. 3.1. Definitions

[0008] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 ^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0009] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 to 3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1 to 2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0010] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups arc well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

In some embodiments, bicyclo[l.l.l.]pentane is a phenyl isostere.

[0011] The term “lower alkyl” refers to a CM straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0012] The term “lower haloalkyl” refers to a CM straight or branched alkyl group that is substituted with one or more halogen atoms.

[0013] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom in a heterocyclic ring.

[0014] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0015] As used herein, the term “bivalent Crs (or Crs) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0016] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2) _n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0017] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0018] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[0019] The term “halogen” means F, Cl, Br, or I.

[0020] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0021] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 147t electrons shared in a cyclic array; and having, in addition to carbon atoms, from 1 to 5 heteroatoms. The term “heteroatom” in the context of “heteroaryl” particularly includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic or bicyclic. A heteroaryl ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0022] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring may have 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen.

[0023] A heterocyclic ring can be attached to a provided compound at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3/7-indolyl. chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0024] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0025] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0026] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH ₂ )o-6R°; -(CIU jo eOR ⁰ ; -0(CH2)o-6R°; -O-(CH ₂ )tv6C(O)OR°; - (CH ₂ )O 6CH(OR ^O ) ₂ ; -(CH ₂ )O gSR°; -(CH ₂ )o 6 Ph, which Ph may be substituted with R°; -(CH ₂ )o 60(CH ₂ )o iPh which Ph may be substituted with R°; -CH=CHPh, which Ph may be substituted with R°; -(CH ₂ )o- 60(CH ₂ )O-I -pyridyl which pyridyl may be substituted with R°; -NO ₂ ; -CN; -Ns; -(CH ₂ )o-6N(R°)2; - (CH ₂ )O-6N(R ⁰ )C(0)R°; -N(R°)C(S)R°; -(CH ₂ )O-6N(R ⁰ )C(0)NR ⁰ ₂ ; -N(R ^O )C(S)NR° ₂ ; -(CH ₂ )O- ₆ N(R ^O )C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R ^O )C(O)NR° ₂ ; -N(R°)N(R°)C(O)OR°; -(CH ₂ )O- ₆ C(O)R ^O ; -C(S)R°; -(CH ₂ )O-6C(0)OR°; -(CH ₂ )O-6C(0)SR°; -(CH ₂ )o-6C(0)OSiR°3; -(CH ₂ )o-60C(0)R°; - OC(0)(CH ₂ )O-6SR ⁰ ,-(CH ₂ )O-6SC(0)R ⁰ ; -(CH ₂ )O-6C(0)NR ⁰ 2; -C(S)NR° ₂ ; -C(S)SR°; -SC(S)SR°, - (CH ₂ )O-60C(0)NR° ₂ ; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH ₂ C(O)R ^O ; -C(NOR°)R°; -(CH ₂ )„ ₆ SSR ^O ; -(CH ₂ )O-6S(0) ₂ R ⁰ ; -(CH ₂ )(V6S(O)2OR ^O ; -(CH2)O- ₆ OS(0) ₂ R ⁰ ; -S(O) ₂ NR ^O ₂ ; -(CH ₂ )O-6S(0)R°; - N(R ⁰ )S(0) ₂ NR ⁰ ₂ ; -N(R ^O )S(O) ₂ R°; -N(OR°)R°; -C(NH)NR ^O ₂ ; -P(O) ₂ R°; -P(O)R° ₂ ; -P(O)(OR ^O ) ₂ ; - OP(O)(R°)OR°; -OP(O)R° ₂ ; -OP(O)(OR ^O ) ₂ ; SiR°3; -(Ci-4 straight or branched alkylene)O-N(R°) ₂ ; or - (Ci-4 straight or branched alkylcnc)C(O)O-N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, -CH ₂ -(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0027] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH ₂ )Q_ ₂ R*, - (haloR*), -(CH ₂ )O-20H, -(CH ₂ )O_ ₂ OR*, -(CH ₂ )O-2CH(OR*) ₂ , -O(haloR’), -CN, -N ₃ , -(CH ₂ )o-2C(0)R*, - (CH ₂ )O-2C(0)OH, -(CH ₂ )O_ ₂ C(0)OR*, -(CH ₂ )O- ₂ SR*, -(CH ₂ )O-2SH, -(CH ₂ )O-2NH ₂ , -(CH ₂ )O-2NHR*, - (CH ₂ )O-2NR*2, -NO ₂ , -SiR*3, -OSiR*!, -C(O)SR* -(Cin straight or branched alkylene)C(O)OR*, or - SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CH aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, or a 5- to 6- membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0028] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR* ₂ , =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O) ₂ R*, =NR*, =N0R*, -O(C(R“ ₂ )) ₂ 3O-, or -S(C(R* ₂ )) ₂ 3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6- membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* ₂ )2- ₃ O-, wherein each independent occurrence of R’ is selected from hydrogen, Ct-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, - O(haloR*), -CN, -C(O)OH, C(O)OR*, -NH ₂ , -NHR*, -NR* ₂ , or -NO ₂ , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ' . -NR ¹ ,, -C(O)R ^f , -C(O)OR ^t , -C(O)C(O)R ^t , -C(O)CH ₂ C(O)R ^t , -8(0)^, -S(O) ₂ NR ¹ ₂ , -C(S)NR ^t ₂ , - C(NH)NR ^t ₂ , or -N(R ^t )S(O) ₂ R ^t ; wherein each R is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitr ogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R \ taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] Suitable substituents on the aliphatic group of R are independently halogen, -R*, - (haloR*), - OH, -OR*, -0(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH ₂ , -NHR*, -NR* ₂ , or -NO ₂ , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] As used herein, the term “provided compound” refers to any genus, subgenus, and/or species set forth herein.

[0033] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge ct al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoro acetic acid (TFA), oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulf onate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. In certain embodiments, some of the compounds disclosed herein are prepared as TFA salts.

[0034] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C i 4alkyl )4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.

[0035] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0036] As used herein, the term “antagonist” is defined as a compound that binds to and/or inhibits cGAS with measurable affinity. Tn certain embodiments, a cGAS antagonist has an TC.50 and/or binding constant of less than about 30 pM or less than about 2 pM.

3.2. Compounds of the Present Disclosure

[0037] Compounds of the present disclosure, and compositions thereof, are useful as cGAS antagonists. In some embodiments, a provided compound inhibits cGAS.

[0038] The present disclosure provides a compound, wherein the compound is of formula I:

I or is a pharmaceutically acceptable salt thereof, wherein:

Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy;

HetAr is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the 5- to 6-membered heteroaryl ring is not imidazole or pyrazole; HetCy is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

R ² is halogen, -OR, -NR ₂ , -NRNR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -NRSO ₂ R, -SR, -SO ₂ R, -SO ₂ NR ₂ . -S(O)R, or R ^B , particularly -NR ₂ or R ^B : each R ³ is independently halogen, -OR, -NR ₂ , -SR, or R ^c , particularly halogen, such as chloro;

R ^B and R ^c , independently, are an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic; benzyl; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, phosphorus, and sulfur; and n is 1, 2, 3, or 4; provided that the compound is preferably not:

[0039] In some embodiments, the above defined compound (i.e., the compound of formula I or a pharmaceutically acceptable salt thereof) is not a compound that is specifically disclosed in international application no. PCT/US2021/49084.

[0040] In certain embodiments, the present disclosure provides a compound, wherein the compound is of formula I, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl.

[0041] In certain embodiments, the present disclosure provides a compound of formula I, wherein Ring A is optionally substituted HetAr. For example, in certain embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted thienyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. In further such embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted thienyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, and pyrimidinyl. In preferred embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted triazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.

[0042] In certain embodiments, the present disclosure provides a compound of formula I, wherein Ring A is an optionally HetCy. For example, in certain embodiments, Ring A is optionally substituted HetCy, and HetCy is selected from optionally substituted tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl indolinyl, 3/7-indolyl, chromanyl, phenanthridinyl, tetrahydroquinolinyl 4H-quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. In further such embodiments, Ring A is optionally substituted HetCy, and HetCy is selected from optionally substituted morpholinyl, piperazinyl, 2,5-dihydro-lH-pyrrole and 2,3-dihydro-lH-pyrrole.

[0043] In certain embodiments, the present disclosure provides a compound, wherein the compound is of formula 1, wherein:

Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy;

R ² is R ^B , wherein R ^B is a substituted 4- to 7-membered saturated heterocyclic ring (e.g., monocyclic or bicyclic) having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur (particularly pyrrolidine, piperidine, morpholine, and piperazine, preferably pyrrolidine), e.g., substituted with one or two groups selected from halogen, =0, =CH2, Ci- ₄ alkyl, C i rhaloalkyl, C ₃ -6cycloalkyl, -OH, -(CH ₂ )I- ₂ -OH, -OC _M alkyI, -(CH ₂ ) ₀₂ CO ₂ H, -(CH ₂ )^ ₂ O(CH ₂ )I_ ₅ CO ₂ H, - (CH ₂ )O_ ₂ 0(CH ₂ )I -5CO2C1 _ ₄ alkyl, -(CH ₂ ) _{0 2} CO ₂ CI ₄ alkyl, -NH ₂ , -(CH ₂ ) _{O 2} CONH ₂ , -(CH ₂ )O ₂ CONR ^a - (CH ₂ )I ₂ CO ₂ H, -(CH ₂ ) ₀₂ SO ₃ H, -(CH ₂ ) ₀₂ SO ₂ NH ₂ , -(CH ₂ ) _{0 2} SO ₂ NHCi ₄ alkyl, or -iCH ₂ ) _{() 2} NR ^a SO ₂ Ci- ₄ alkyl, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0044] In other embodiments, the present disclosure provides a compound of formula I, wherein: Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy;

R ² is -NR ₂ , wherein one R is H or lower alkyl (particularly methyl), and the other R is substituted C1-6 aliphatic, including optionally substituted -Ci-salkylene-X; wherein X is selected from -OH, -OCi 4alkyl, -O-Cr ₄ alkylene-CO ₂ H, -O-Ci ₄ alkylene-CO ₂ Ci- ₄ alkyl, -CO ₂ H, -CO ₂ Ci- ₄ alkyl, -NH ₂ , -CONH ₂ , -CONHCI ₄ alkyl, -CONR ^a -(CH ₂ )i 2-OH, -CONR ^a -(CH ₂ )i ₂ -COOH, -C0NR ^a -(CH ₂ )i ₂ - CONH2, -SO3H, -SO2NH2, -SO ₂ NHCi ₄ alkyl, -NR ^a SO ₂ Ci. ₄ alkyl, -P(O)(OH) ₂ , and -OP(O)(H)(OH), wherein R ^a , independently for each occurrence, is H or C 1 ₄ alkyl: and each R ³ is independently halogen, such as chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0045] In some embodiments, the present disclosure provides a compound of formula I, wherein:

Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy;

R ² is R ^B , wherein R ^B is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur (particularly imidazole or pyrazole, including 1 -imidazole or 4-pyrazole); and each R ³ is independently halogen, such as chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0046] In other embodiments, the present disclosure provides a compound of formula I, wherein:

Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy;

R ² is substituted phenyl (particularly substituted with one or two groups selected from halogen, Ci- ₄ alkyl, -OH, -OCi ₄ alkyl, -CO ₂ H, -CO2C1 ₄ alkyl, -(CH ₂ )^ ₂ O(CH ₂ )I 5CO2H, -(CH ₂ )(V2O(CH2)I 5CO2C1 4alkyl, -NH ₂ , and -CONH ₂ ); and each R ³ is independently halogen, such as chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0047] In other embodiments, the present disclosure provides a compound of formula I, wherein:

Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy;

R ² is R ^B , wherein R ^B is an optionally substituted C1-6 aliphatic, preferably a substituted Ci galiphatic (particularly -(CR ₂ )I- ₄ NR(CR ₂ )O-6C0 ₂ R); and each R ³ is independently halogen, such as chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0048] In certain embodiments, the disclosure provides a compound, wherein the compound is of formula I, wherein:

Ring A is an optionally substituted group selected from phenyl, HetAr, and HetCy; each R ³ is independently halogen, -OR, -NR ₂ , -SR, or R ^c ; Ring Bl is phenyl, preferably substituted phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring B2 is phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6- membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,

R ⁵ is -(CR ₂ )(WOR, -(CR2K5CO2R, -(CR ₂ )O-5CONR ₂ , -(CR ₂ )^C(O)NR(CR ₂ )(^CO ₂ R, -(CR ₂ )O- 4C(0)NR(CR ₂ )O- ₄ CONR ₂ , -(CR ₂ )O- ₄ NRC(0)R, -(CR ₂ ) _M SO ₃ R, -(CR ₂ )O- ₄ S0 ₂ NR ₂ , -(CR ₂ )O- 4OSO ₂ NR ₂ , -(CR ₂ )O- ₄ NRSO ₂ R. -(CR ₂ )O- ₄ NRS0 ₂ OR, -(CR ₂ )O- ₄ OP(OR) ₂ , -(CR ₂ )O^OP(0)(OR) ₂ , -(CR ₂ )(MP(O)(OR) ₂ , -(CR ₂ )0^OP(O)(H)OR, or R ^B ; each R ⁶ is independently halogen, =0, =CH ₂ , Ci- ₄ alkyl, Cr ₄ haloalkyl, C3 gcycloalkyl, -COR, -(CR ₂ )o- 4CO ₂ R (e.g., -(CH ₂ )O- ₂ C0 ₂ H or -(CH ₂ ) _{0 2} CO ₂ C, _ ₄ alkyl), -(CH ₂ )O- ₂ 0(CH ₂ )I- ₅ C0 ₂ H, -(CH ₂ )O- 2O(CH ₂ )i_5CO ₂ Ci- ₄ alkyl, -(CH ₂ ) ₀₂ CONR ^a -(CH ₂ ) _{1 2} CO ₂ H; -(CR ₂ )o- ₄ CONR ₂ (e.g., -(CH ₂ ) ₀ . 2CONH ₂ ), -OR (e.g., -OH or -OC _M alkyl), -(CR ₂ ) _M 0R (e.g., (CH ₂ )I ₂ -OH), -NR ₂ (e.g., -NH ₂ ), -(CR ₂ )MNR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO ₂ R, -S(O)R, -(CR ₂ )O- ₄ S0 ₃ R (e.g., -(CH ₂ )O ₂ S0 ₃ H), -(CR ₂ ) _{() 4} SO ₂ NR ₂ (e.g., -(CH ₂ ) ₀₂ SO ₂ NH ₂ or -(CH ₂ ) _{0 2} SO ₂ NHCi ₄ alkyl), -(CR ₂ )o- 4OSO ₂ NR ₂ , -(CR ₂ )(MNRSO ₂ R (e.g., -(CH ₂ ) _{0 2} NR ^a SO ₂ Cr ₄ alkyl), -(CR ₂ )(MNRSO ₂ OR, -(CR ₂ )O- 4OP(OR) ₂ , -(CR ₂ )O^OP(0)(OR) ₂ , -(CR ₂ )(MP(O)(OR) ₂ , -(CR ₂ )(M0P(0)(H)0R, -B(OR) ₂ , or R ^B , wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl;

R ^B and R ^c , independently, are an optionally substituted group selected from C1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R ^a is independently H or Ci calkyl; each m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; q is 0, 1, or 2.

[0049] In some embodiments, Ring A is unsubstituted phenyl. In preferred embodiments, Ring A is substituted phenyl. In some embodiments, Ring some embodiments, Ring

. In some embodiments, Ring embodiments, Ring

[0050] In some embodiments, Ring A is an optionally substituted HetCy, wherein HetCy is a 4- to 7- membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is unsubstituted HetCy. In other embodiments, Ring A is substituted HetCy.

[0051] In some embodiments, Ring A is an optionally substituted HetCy, wherein HetCy is a 4- to 7- membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted . In some

H embodiments, Ring A is an optionally substituted ~wl~w . In some embodiments, Ring A is an optionally substituted

[0052] In other embodiments, Ring A is an optionally substituted HetCy, wherein HetCy is a 4- to 7- membered partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is and optionally substituted . In some embodiments, Ring A is and optionally substituted

[0053] In some embodiments, Ring A is an optionally substituted HetAr, wherein HetAr is a 5- to 6- membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the 5- to 6-membered heteroaryl ring is not imidazole or pyrazole. In certain embodiments, Ring A is unsubstituted HetAr. In other embodiments, Ring A is substituted HetAr. In some embodiments, Ring A is and optionally substituted . In some embodiments, Ring A is and

HN-N optionally substituted . In some embodiments, Ring A is an optionally substituted . In

N=N some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is an

N-NH N-N optionally substituted . In some embodiments, Ring A is an optionally substituted . j _n some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is an optionally substituted ~wlvw . j _n some embodiments, Ring A is an optionally substituted . In

HN-N some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is an optionally substituted . In some N-S embodiments, Ring A is an optionally substituted In some embodiments, Ring A is an optionally

N-0 substituted . In some embodiments, Ring A is an optionally substituted embodiments, Ring A is an optionally substituted In some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is an optionally substituted embodiments, Ring A is an optionally substituted In some embodiments, Ring A is an optionally substituted . In some embodiments, Ring A is an optionally substituted

[0054] In some embodiments, Ring A is selected from those groups depicted in Table 1.

[0055] In some embodiments, Ring A is selected from those groups depicted in Table 2.

[0056] In some embodiments, at least one occurrence of R ³ is halogen, such as chloro or bromo. In some embodiments, at least one occurrence of R ³ is chloro. In some embodiments, at least one occurrence of

R ³ is bromo, such at the 7-position with respect to the quinoline ring. In some embodiments, n is 2 and both R ³ are halo, such as both R ³ are chloro. In some embodiments, n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring. In some embodiments, n is 2 and one occurrence of R ³ is chloro, and the other occurrence of R ³ is bromo, such as bromo at the 7-position and chloro at the 8- position with respect to the quinoline ring. In some embodiments, n is 3 and all occurrences of R ³ are halo, such as bromo at the 6-position and chloro at the 7- and 8-positions with respect to the quinoline ring.

[0057] In certain embodiments, at least one occurrence of R ³ is optionally substituted Ci-6 aliphatic, such as methyl. In some embodiments, n is 2 and one occurrence of R ³ is halo, such as bromo, and the other occurrence of R ³ is optionally substituted Ci-6 aliphatic, such as methyl. In some embodiments, n is 2 and one occurrence of R ³ is bromo at the 7-position with respect to the quinoline ring, and the other occurrence of R ³ is methyl at the 8-position with respect to the quinoline ring.

[0058] In some embodiments, R ² is -NR ^a R ³ .

[0059] In some embodiments, R ^s is -(CR ₂ ) _2-4 OR, -(CR ₂ )o-sC0 ₂ R, -(CR ₂ )o-5CONR2, -(CR ₂ )o- ₄ C(0)NR(CR ₂ )o- ₄ C0 ₂ R, -(CR ₂ )O- ₄ C(0)NR(CR ₂ )O- ₄ CONR ₂ , -(CR ₂ )O-4NRC(0)R, -(CR ₂ )O- ₄ S0 ₃ R, -(CR ₂ )O- ₄ SO ₂ NR ₂ , -(CR ₂ )O- ₄ OS0 ₂ NR ₂ , -(CR ₂ )O- ₄ NRS0 ₂ R, -(CR ₂ )O-4NRS0 ₂ OR, -(CR ₂ )(MOP(OR) ₂ , -(CR ₂ )O- ₄ OP(O)(OR) ₂ , -(CR ₂ )O^P(0)(OR) ₂ , or -(CR ₂ )o- ₄ OP(0)(H)OR.

[0060] In some embodiments, R ⁵ is -(CR ₂ ) _2-4 OR, -(CR ₂ )I-SCO ₂ R, -(CR ₂ )I-5CONR ₂ , -(CR ₂ )O- ₄ C(0)NR(CR ₂ )O- ₄ C0 ₂ R, -(CR ₂ )O- ₄ C(0)NR(CR ₂ )O- ₄ CONR ₂ , -(CR ₂ )O- ₄ NRC(0)R, -(CR ₂ )O- ₄ S0 ₃ R, -(CR ₂ )O- ₄ SO ₂ NR ₂ , -(CR ₂ )O- ₄ OS0 ₂ NR ₂ , -(CR ₂ )O- ₄ NRS0 ₂ R, -(CR ₂ )O-4NRS0 ₂ OR, -(CR ₂ )(MOP(OR)2, -(CR ₂ )O- ₄ OP(O)(OR) ₂ , -(CR ₂ )O^P(0)(OR) ₂ , or -(CR ₂ )o- ₄ OP(0)(H)OR.

[0061] In some embodiments, R ^s is -(CH ₂ ) _{2 4} OH, -(CH ₂ ) _{2 4} O(CH ₂ )I 5CO2H, -(CH ₂ ) _{2 4} O(CH ₂ )I SCO ₂ CI ₄ alkyl, -(CH ₂ )O- ₃ CH(CH20H) ₂ , -(CH ₂ ) _2-t OCMalkyl, -(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )i_ ₅ CO ₂ Ci- ₄ alkyl, -(CH ₂ )I- ₄ CONH ₂ , -(CH ₂ )i_4CONHCi- ₄ alkyl, XCH ₂ )i_ ₄ CON(Ci ₄ alkyl) ₂ , -(CH ₂ )I ₄ C(O)NR ^a (CH ₂ )i ₄ CO ₂ H, -(CH ₂ )I_ ₄ C(O)NR ^a (CH ₂ ) _M CONH ₂ , -(CH ₂ )i^C(O)NR ^a (CH ₂ )i_ ₄ CONHCi ₄ alkyl, -(CH ₂ )i_ ₄ C(O)NR ^a (CH ₂ )i_ ₄ CON(Ci. ₄ alkyl) ₂ , -(CH.I^NR^COXCHZIJ-SCOZH, -(CHzl^NR^lOXCHzlj-sCOzCi ^alkyl, -(CH ₂ )z- ₄ SO ₃ H, -(CH ₂ ) ₂ ^SO ₃ Ci- ₄ alkyl, -(CH ₂ ) _{2 4} SO ₂ NH ₂ , -(CH ₂ ) ₂ ^SO ₂ NHCi- ₄ alkyl, -(CH ₂ ) _2-4 SO ₂ N(Ci ₄ alkyl) ₂ , - (CH ₂ ) _{2 4} OSO ₂ NH ₂ , -(CH ₂ J _{2 4} NR\SO ₂ CI ₄ alkyl. -(CH ₂ ) _{2 4} NR ^a SO ₃ H, -(CH ₂ )^OP(OH) ₂ , -(CH ₂ )I_ ₄ P(O)(OH) ₂ , -(CH ₂ ) I ₄ P(O)(OH)( C)C I _ ₄ alkyl), or -(CH ₂ ) _2-4 OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci-6alkyl.

[0062] In some embodiments, R ⁵ is -(CH ₂ ) _{2 4} OH, -(CH ₂ ) ₂ 4O(CH ₂ )I 5CO2H, -(CH ₂ ) ₂ 4O(CH ₂ )I sCO ₂ Ci ₄ alkyl, -(CH ₂ )(K ₃ CH(CH2OH) ₂ , -(CH ₂ ), ₅ CO ₂ H, -(CH ₂ )I sCONHz, -(CH ₂ )I ₄ C(O)NR ^a (CH ₂ )i^CO ₂ H, - (CHz)i ₄ C(O)NR ^a (CH ₂ )i ₄ CONH ₂ . -(CH ₂ )o ₄ NR<:(O)(CH ₂ ) I ₅ CO ₂ H, -(CH ₂ )o^NR ^a C(0)(CH ₂ )i ₅ CO ₂ Ci ₄ alkyl, (CH,): ₄ SO ₃ H. -I'CH ₂ ) _{2 4} SO ₂ NH ₂ , (CH ₂ ) _{2 4} SO ₂ NR ^a C, ₄ alkyl, (CH ₂ ) _{2 4} NR ^a SO ₂ C, ₄ alkyl. -I'CH ₂ ), ₄ P(O)(OH) ₂ , or -(CH ₂ ) _2-4 OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl.

Y B1 V(R ⁶ ) _m

[0063] In some embodiments, R ² is ^x - . In some embodiments, m is 1, 2, 3, or 4.

[0064] In some embodiments, Ring Bl is substituted phenyl. In some embodiments, the phenyl is substituted with one or more carboxyl groups.

[0065] In some embodiments, Ring Bl is a 3-carboxyphenyl group that is optionally substituted with one or more R ⁶ groups. [0066] In some embodiments, Ring Bl is a 3,5-dicarboxyphenyl group that is optionally substituted with one or more R ⁶ groups.

[0067] In some embodiments, Ring Bl is a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0068] In some embodiments, Ring Bl is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0069] In some embodiments, R ² is , wherein X is absent (i.e., a bond in the ring), -

CR2-, -NR-, -O-, -S-, or -SO2-; and p is 0, 1, or 2. In some embodiments, X is -CR2-, -NR-, or -O-. In some embodiments, p is 1. In some embodiments, m is 1, 2, 3, or 4.

[0070] In some embodiments, each R ⁶ is independently halogen, -Ci. ₄ alkyl, -Ci. ₄ haloalkyl, C ₃ ecycloalkyl, -(CH ₂ )„ ₄ CO ₂ H. -(CHz^COzCi ralkyl, -(CHz^COzCwhaloalkyl, -(CH ₂ )o- ₄ CONH ₂ . - (CH ₂ )o-4CONHCi 4alkyl, -(CH ₂ )o^CON(Ci ₄ alkyl)2, -(CH ₂ )o- ₄ CO(?/-prolinc), -(CH ₂ )o ^C(O)NR ^a (CH ₂ )i- 4CO2H, -(CH ₂ )O ₄ C(O)NR '(CH ₂ ) I 4CONH2. -(CH ₂ )o ₄ C(O)NR4CH ₂ ii ₄ CONHC I ₄ alkyl. -(CH ₂ )o- ₄ C(O)NR ^a (CH ₂ )i^CON(Ci- ₄ alkyl)2, -OH, -(CH ₂ )L ₄ OH. -(CH ₂ )o^OCi. ₄ alkyl, -1CH ₂ )O ₄ O1CH ₂ )I <CO ₂ H. - (CH ₂ )o-40(CH ₂ )i-5C02Ci.4alkyl, -(CH ₂ )(MOC(O)Ci- ₄ alkyl, -NH ₂ , -(CH ₂ )MNH ₂ , -(CH ₂ )o-4NHCi. ₄ alkyl, - (CH ₂ )o-4N(Ci. ₄ alkyl) ₂ , -(CH ₂ )o- ₄ S0 ₃ H, -(CH ₂ )(MSO ₂ NH2, -(CH^SO^HCwalkyl, -(CH ₂ )o-4NR ^a S0 ₂ Ci. ₄ alkyl, -(CH ₂ )O^OP(OH) ₂ , -(CH ₂ )o- ₄ OP(OH)(OCi. ₄ alkyl), or -(CR ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or C«alkyl.

[0071] In some embodiments, each R ⁶ is independently halogen, -Ci- ₄ alkyl, -Ci- ₄ haloalkyl, C ? ecycloalkyl, -(CI I ₂ ) _{() 4} CO ₂ I I. -(CH ₂ )(wCO2Ci- ₄ alkyl, -(CI I ₂ ) _{() 4} CO(;V-prolinc). -(CH ₂ )o-4C(0)NR ^a (CH2)i- 4CO2H, -OH, -(CH ₂ )I ₄ OH, -(CH ₂ )O-40CI _ ₄ alkyl, -(CH ₂ k ₄ O(CH ₂ )i 5CO2H, -(CH ₂ )O-40(CH ₂ )I -5CO2C1- ₄ alkyl, -(CH ₂ )<MOC(O)Ci- ₄ alkyl, -I CH ₂ )O ₄ SO ₃ H. -(CH ₂ )o ₄ SO ₂ NH ₂ . -(CH ₂ )o-4NR ^a S0 ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ OP(OH) ₂ , or -(CR ₂ )O-40P(0)(H)OH.

[0072] In some embodiments, R ^c is independently halogen, -Ci- ₄ alkyl, -Ci- ₄ haloalkyl, C ₃ ecycloalkyl, - (CH ₂ )o 2CO2H, -(CH ₂ )o-2C02Ci. ₄ alkyl, -(CH ₂ ) _M CO(lV-proline), -(CH ₂ )o .CiOtNRdCH,), ₄ CO,H. -OH, - (CH ₂ )I- ₂ OH, -(CH ₂ )<wOCi- ₄ alkyl, -(CH ₂ )^4O(CH ₂ )i_ ₅ CO ₂ H, -(CH ₂ )^O(CH ₂ )i_5CO ₂ Ci-4alkyl, -(CH ₂ )^ ₂ OC(O)Ci ₄ alkyl, -(CH ₂ )o- ₂ S0 ₃ H, -(CH ₂ ) _{0 2} SO ₂ NH ₂ , -(CH ₂ )o- ₂ NR ^a S0 ₂ Co- ₂ alkyl, (CH ₂ ) ₀₂ OP(OH) ₂ , or - (CR2) 0 ₂ OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl. [0073] In some embodiments, each R ⁶ is independently halogen, -Ci_ ₄ alkyl, -Ci_ ₄ haloalkyl, C ₃ _

₆ cycloalkyl, -(CH ₂ )I ₄ CO ₂ H, -(CH ₂ ) _M CO(2V-proline), -(CH ₂ ), ₄ C(O)NRVCH ₂ ), ₄ CO ₂ H, -OH, -(CH ₂ )i- ₄ OH, (CH ₂ )O^O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )O- ₄ 0(CH ₂ )I ₅ CO ₂ CI _ ₄ alkyl, -(CH ₂ )I ₄ SO ₃ H, -(CH ₂ )I ₄ SO ₂ NH ₂ , - (CH ₂ )i- ₄ NR ^a SO ₂ Ci- ₄ alkyl, -(CI I ₂ )r ₄ OP(OI I) ₂ , or -(CR ₂ ) _M OP(O)(H)OH.

[0074] In some embodiments, each R ⁶ is independently halogen, -Ci- ₄ alkyl, -Ci- ₄ haloalkyl, -CO ₂ H, - CO ₂ Cn ₄ alkyl, -CO(N-proline), -CH ₂ CO ₂ H, -OH, -OCi- ₄ alkyl, -(CH ₂ )^ ₄ O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )o_ ₄ O(CH ₂ )i_ ₅ CO ₂ Ci- ₄ alkyl, -OC(O)Ci- ₄ alkyl, -SO ₃ H, -SO ₂ NH ₂ , -NR ^a SO ₂ Cn ₄ alkyl, -OP(OH) ₂ , or - OP(O)(H)OH.

[0075] In some embodiments, R ² is . In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1 or 2.

[0076] In some embodiments, R ² is . In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1 or 2.

[0077] In some embodiments, each R ⁶ is independently halogen, =CH ₂ , =0, -Ci ₄ alkyl, -Ci ₄ haloalkyl, Cs ecycloalkyl, -(CH ₂ ) _{0 4} CO ₂ H, -(CH ₂ ) _0-4 CO ₂ CMalkyl, -(CH ₂ )o^C0 ₂ Ci- ₄ haloalkyl, -(CH ₂ ) _{0 4} CONH ₂ , - (CH ₂ )o- ₄ CONHCi- ₄ alkyl, -(CH ₂ ) _{4 4} CON(CI ₄ alkyl) ₂ , -(CH ₂ )o- ₄ CO(A'-proline), -(CH ₂ )o ₄ CO(/V-pyrrolidine- 3-carboxylic acid), -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i^C0 ₂ H, -iCH ₂ )o ₄ CYO)NR ^a -CH(Ci ₄ alkyl)-CO ₂ H. -iCH ₂ ) _{4 4} C(O)NR ^a (CH ₂ )^CONH ₂ , -(CH ₂ )o ₄ C(O)NR ^a fCH ₂ ), ₄ CONHC, _ ₄ alkyl, -(CH ₂ )„ ₄ C(O)NR ^a (CH ₂ ), ₄ CON(Ci- ₄ alkyl) ₂ , -OH, -(CH ₂ ) _M OH, -(CH^OCwalkyl, -(CH ₂ ) ₀ ^O(CH ₂ ) _1-5 CO ₂ H, -(CH ₂ )O^O(CH ₂ )I_ ₅ CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^OC(0)Ci- ₄ alkyl, -NH ₂ , -(CH ₂ ) _M NH ₂ , -(CH ₂ )o^NHCi ₄ alkyl, -(CH ₂ )o_ ₄ NR ^a C(O)Ci- ₄ alkyl, -(CH ₂ )o^NR ^a C(0)Ph, dCH ₂ ) _{0 4} NR ^a CO(CH ₂ )i ₄ OH, -(CH ₂ )o- ₄ N(Ci- ₄ alkyl) ₂ , -(CH ₂ )o- 4SO3H, -(CH ₂ )O ₄ SO ₂ NH ₂ , -(CH ₂ )O- ₄ SO ₂ NR ^a Ci ₄ alkyl, -(CH ₂ )o- ₄ NR ^a S0 ₂ Ci ₄ alkyl, -(CH ₂ ) _{0 4} NR ^a SO ₂ Ph, - (CH ₂ )o- ₄ NR ^a S0 ₂ (CH ₂ )i_ ₄ C0 ₂ H, -(CH ₂ )o- ₄ OP(OH) ₂ , -(CH ₂ )o- ₄ OP(OH)(OCi_ ₄ alkyl), or -(CR ₂ )o- ₄ OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ealkyl.

[0078] In some embodiments, each R ⁶ is independently halogen, =CH ₂ , =0, -Ci_ ₄ alkyl, -Ci ₄ haloalkyl, C ₃ -6cycloalkyl, -(CH ₂ ) _{4 4} CO ₂ H, -(CH ₂ )o_ ₄ C0 ₂ C _M alkyl, -(CH ₂ )o^C0 ₂ Ci_ ₄ haloalkyl, -(CH ₂ )„ ₄ CO(/V- proline), -(CH ₂ )o-^CO(iV-pyrrolidine-3-carboxylic acid), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i- ₄ C0 ₂ H, -(CH ₂ )Q_ ₄ C(O)NR ^a -CH(Ci- ₄ alkyl)-CO ₂ H, -OH, -(CH ₂ )I_ ₄ OH, -OCi ₄ alkyl, -(CH ₂ )o_ ₄ 0(CH ₂ )i_ ₅ C0 ₂ H, -(CH ₂ )Q_ ₄ O(CH ₂ )i_ ₅ CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^NR ^a C(0)Cr ₄ alkyl, -(CH ₂ )o^NR ^a C(0)Ph, -1CH ₂ ) _{O 4} NR ^a CO(CH ₂ )i ₄ OH, -(CH ₂ )O- ₄ S0 ₃ H, -(CH ₂ )O- ₄ S0 ₂ NH ₂ , -(CH ₂ )O ₄ NR ^a SO ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ NR ^a S0 ₂ Ph, -(CH ₂ )o_ 4NR ^a SO ₂ (CH ₂ )i ₄ CO ₂ H, -(CH2)(WOP(OH) ₂ , or -(CR ₂ )(V4OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl.

[0079] In some embodiments, each R ⁶ is independently halogen, =CH2, =0, -Ci-4alkyl, -Ci 4haloalkyl, - CO2H, -CChCi-ralkyl, -C0 ₂ Ci ₄ haloalkyl, -CO(Al-proline), -CO(A^-pyrrolidine-3-carboxylic acid), - C(O)NR ^a (CH ₂ )i-4CO ₂ H, -C(O)NR ^a -CH(Ci- ₄ alkyl)-CO ₂ H, -OH, -OCi- ₄ alkyl, (CH ₂ )^ ₄ O(CH ₂ )I ₅ CO ₂ H, - (CH ₂ )o-40(CH ₂ )i_5C0 ₂ Ci-4alkyl, -NR ^a C(O)Ci- ₄ alkyl, -NR ^a C(O)Ph, -NR ^a CO(CH ₂ )i ₄ OH, -SO3H, - SO ₂ NH ₂ , -NR ^a SO ₂ Ci- ₄ alkyl, -NR ^a SO ₂ Ph, -NR ^a SO ₂ (CH ₂ )i ₄ CO ₂ H, -OP(OH) ₂ , or -OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl.

[0080] In some embodiments, each R ⁶ is independently fluoro, =0, =CH ₂ , methyl, cyclohexyl, morpholinyl, phenyl, -CF3, -OMe, -OtBu, -CO ₂ H, -CO ₂ Ci ₄ alkyl, -CO2Ci-4haloalkyl, -(CH ₂ )I-4O(CH ₂ )I_ 5CO2H, -(CH ₂ )I^O(CH ₂ )I ₅ CO ₂ Ci ₄ alkyl, or -OH.

[0081] In some embodiments, Ring Bl is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein a carbon atom of the 5- to 6-membered heteroaryl ring is directly bonded to the carbon at the 2-position of the quinolone ring;

[0082] In some embodiments, Ring B 1 is imidazole or pyrazole. In some embodiments, the imidazole or pyrazole are unsubstituted.

[0083] In some embodiments,

[0084] In some em ubodiments, R 2 i ■s . In some embodiments, m is 1, 2, 3, or 4.

[0085] In some embodiments, Ring B2 is phenyl.

[0086] In some embodiments, Ring B2 is a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments, Ring B2 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. embodiments, R ² is . In some embodiments, R , ² is . | _n some embodiments, X is -CR2-, -NR-, or -O-. In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some embodiments, m is 1 or 2.

[0089] In some embodiments, each R ⁶ is independently halogen, -(CH2)tv ₄ CO2H, -(CH2)o- ₄ C02Ci- ₄ alkyl, -(CH ₂ )O- ₄ CONH ₂ , -(CH ₂ )o- ₄ CONHCi_ ₄ alkyl, -(CH2)o^CON(Cv ₄ alkyl) ₂ , -(CH ₂ )o- ₄ CO(A-proline), -(CH ₂ )o- ₄ C(O)NR ^a (CH ₂ )i ₄ CO ₂ H. -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i- ₄ CONH2, -(CH ₂ )o ₄ C(O)NR ^a (CH ₂ )i ₄ CONHC, _ ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i^CON(Ci- ₄ alkyl) ₂ , -OH, -1CH ₂ ) I ₄ OH. -(CH ₂ )o- ₄ OCi ₄ alkyl, -NH ₂ , -1CH ₂ ) I ₄ NH ₂ . -(CH ₂ )o- ₄ NHCi- ₄ alkyl, -(CH ₂ )o- ₄ N(Ci- ₄ alkyl)2, -(CH ₂ )o- ₄ S0 ₃ H, -(CH ₂ )o ₄ SO ₂ NH ₂ . -(CH2)(MSO ₂ NHCI- ₄ alkyl, -(CH ₂ )O- ₄ NR\SO ₂ C _ ₄ alkyl, -(CH ₂ )o- ₄ OP(OH) ₂ , -(CH ₂ )o->OP(OH)(OCi- ₄ alkyl), or -(CR ₂ )o- ₄ OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl.

[0090] In some embodiments, each R ⁶ is independently halogen, -(CH2)o~ ₄ C02H, -(CH ₂ k ₄ COOV- proline), -(CH ₂ )o ₄ C(O)NR ^a (CH ₂ )i ₄ CO ₂ H, -OH, -(CH ₂ )I ₄ OH. -I'CH ₂ )O 4SO3H. -(CH ₂ )o ₄ SO ₂ NH ₂ . -(CH ₂ )o- ₄ NR ^a SO2Ci_ ₄ alkyl, -(CH2)o^tOP(OH) ₂ , or -(CR ₂ )O^IOP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl.

[0091] In some embodiments, each R ⁶ is independently halogen, -CO2H, -CO(iV-proline), - C(O)NR ^a (CH ₂ )i- ₄ CO ₂ H, -OH, -SO ₃ H, -SO ₂ NH ₂ , -NR ^a SO ₂ Ci- ₄ alkyl, -OP(OH) ₂ , or -OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl.

[0092] In some embodiments, R ⁶ is not R ^B .

[0093] In some embodiments, m is at least 1, and at least one R ⁶ includes a terminal -CO2H or -CO2C1 4alkyl group.

[0094] In some embodiments, at least one R ⁶ is -(CH2)(MO(CH2)I 5CO2H, -(CH2)O-40(CH2)I-SC02CI- ₄ alkyl, -(CH ₂ )o 4CO2H or -(CH ₂ )o^C02Ci- ₄ alkyl.

[0095] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the present disclosure provides a method of antagonizing cyclic GMP- AMP synthase (cGAS) in a patient in need thereof, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [0097] In some embodiments, the present disclosure provides a method of treating an inflammatory, allergic, or autoimmune disease in a patient in need thereof, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0098] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is -NR2 thereby forming a compound of formula I-a-1:

I-a-1 or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R, R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0099] In certain embodiments, the present disclosure provides a compound of formula I-a-1, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0100] In certain embodiments, the present disclosure provides a compound of formula I-a-1, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-1, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-1, wherein Ring A is an optionally HetAr.

[0101] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is - NRR ⁵ thereby forming a compound of formula I-a-2:

I-a-2 or a pharmaceutically acceptable salt thereof, wherein: R ⁵ is -(CR ₂ )2^OR, -(CR ₂ )O-6C0 ₂ R, -(CR ₂ )o- _fi CONR ₂ , -(CR^CONR/CR^CChR, -(CR ₂ )o- 6C(0)NR(CR ₂ )O-6CONR2, -(CR2)O-4NRC(0)R, -(CR ₂ )(MSO ₃ R, -(CR ₂ )O-6S02NR ₂ , -(CR ₂ )O- 6OSO2NR2, -(CRzio-eNRSOzR, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , - (CR ₂ )O- ₆ P(0)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, or R ^B ; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0102] In certain embodiments, the present disclosure provides a compound of formula I-a-2, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-2, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-2, wherein Ring A is an optionally HetAr.

[0103] In certain embodiments, the present disclosure provides a compound of formula I-a-2, wherein R ⁵ is -(CR ₂ )2- ₄ OR, -(CR ₂ )I 4CO2R. -(CR ₂ )i- ₄ CONR ₂ , -(CR ₂ )o-6C(0)NR(CR ₂ )o-6C0 ₂ R, -(CR ₂ )O- ₆ C(0)NR(CR ₂ )O-6CONR ₂ , -(CR ₂ )O- ₄ NRC(0)R, -(CR ₂ )O-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR ₂ , - (CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , -(CR ₂ )0-6OP(O)(OR) ₂ , -(CR ₂ )O-6P(0)(OR) ₂ , - (CR ₂ )O-60P(0)(H)OR, or R ^B .

[0104] In some embodiments, the present disclosure provides a compound of formula I-a-2, wherein R ⁵ is not R ^B .

[0105] In some embodiments, the present disclosure provides a compound of formula I-a-2, wherein R in -NRR ⁵ is R ^a , which is H or Ci-6alkyl.

[0106] In certain embodiments, the present disclosure provides a compound of formula I-a-1, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0107] In certain embodiments, the present disclosure provides a compound of formula I-a-2, wherein:

R in -NRR ⁵ is H or lower alkyl, particularly methyl;

R ⁵ is -(CR ₂ )O-60R, -(CR ₂ )O-6C0 ₂ R, -(CR ₂ )O-6CONR ₂ , -(CR ₂ )O-6C(0)NR(CR2)O-6C0 ₂ R, -(CR ₂ )O- 6C(0)NR(CR ₂ )O-6CONR ₂ , -(CR ₂ )O- ₄ NRC(0)R, -(CR ₂ )O-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR ₂ )O- 6OSO ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , - (CR ₂ )0- ₆ P(O)(OR) ₂ , or -(CR ₂ )O- ₆ OP(0)(H)OR; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0108] In particular embodiments, the present disclosure provides a compound of formula I-a-2, wherein:

R in -NRR ⁵ is H or lower alkyl, particularly methyl;

R ⁵ is -(CH ₂ )2 ₄ OH, -(CH ₂ ) _{2 4} O(CH ₂ )I 5CO2H, -(CH ₂ )2^O(CH ₂ )I 5CO2C1 ₄ alkyl, -(CH2)o^ ₃ CH(CH ₂ OH)2, - (CH ₂ ) _2-4 OCi. ₄ alkyl, -(CH ₂ ), ₄ CO ₂ H. -(CH ₂ )i- ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )I- ₄ CONH ₂ , -(CH ₂ ) I ₄ CONHC, 4alkyl, -(CH ₂ )i^CON(Ci- ₄ alkyl) ₂ , -(CH ₂ ) _M C(O)NR ^a (CH ₂ ) _M CO ₂ H, -(CH ₂ ) _M C(O)NR ^a (CH ₂ ) ₁ _ 4CONH ₂ , -(CH ₂ )I ₄ C(O)NRXCH ₂ ) I ₄ CONHCi ₄ alkyl. -(CH ₂ )i_ ₄ C(O)NR ^a (CH ₂ ) _M CON(Ci ₄ alkyl) ₂ , -(CH ₂ )o 4NR ^a C(0)(CH ₂ )i ₅ CO ₂ H, -(CH ₂ )o^NR ^a C(0)(CH ₂ )i_ ₅ C0 ₂ Ci ₄ alkyl, -(CH ₂ ) _2-4 SO ₃ H, - (CH ₂ ) _2-4 SO ₃ Ci- ₄ alkyl, -(CH ₂ ) _{2 4} SO ₂ NH ₂ , -(CH ₂ ) _M SO ₂ NHCi- ₄ alkyl, -(CH ₂ ) ₂ ^SO ₂ N(Ci ₄ alkyl) ₂ , - (CH ₂ ) _{2 4} OSO ₂ NH ₂ , -(CH ₂ ) _2.4 NR ^; 'SO ₂ CI _ ₄ alkyl, -(CH ₂ ) _2-4 NR ^a SO ₃ H, -(CH ₂ )I^OP(OH) ₂ , -(CH ₂ )I_ 4P(O)(OH) ₂ , -(CH ₂ )i^P(O)(OH)(OCi. ₄ alkyl), or -(CH ₂ ) _2-4 OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0109] In particular embodiments, the present disclosure provides a compound of formula I-a-2, wherein:

R in -NRR ⁵ is H or lower alkyl, particularly methyl;

R ⁵ is -(CH ₂ ) _{2 4} OH, -(CH ₂ ) _M CH(CH ₂ OH) ₂ , -(CH ₂ ) ₂ 4OC1 ₄ alkyl, -(CH ₂ )I ₄ CO ₂ H, -(CH ₂ )I ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )i ₄ CONH ₂ . -(CH ₂ ) _M CONHCi. ₄ alkyl, -(CH ₂ ) _M CON(Ci- ₄ alkyl) ₂ , -(CH ₂ ), ₄ C(O)NR7CH ₂ ), 4CO ₂ H, -(CH ₂ )I. ₄ C(O)NRXCH ₂ ) I ₄ CONH ₂ . -(CH ₂ )L ₄ C(O INRXCH ₂ ) I ₄ CONHCI _ ₄ alkyl, -(CH ₂ )I. 4C(O)NR ^a (CH ₂ )i^CON(Ci. ₄ alkyl) ₂ , -(CH ₂ ) _{2 4} SO ₃ H. -(CH ₂ ) _2-4 SO ₃ Ci. ₄ alkyl, -(CH ₂ ) ₂ ^SO ₂ NH ₂ , -(CH ₂ ) ₂ ^SO ₂ NHCwalkyl, -(CH ₂ ) ₂ ^SO2N(Ci. ₄ alkyl) ₂ , -(CH ₂ ) ₂ ^OSO ₂ NH ₂ , -(CH ₂ ) _2-4 NR ^a SO ₂ Ci. 4alkyl, -(CH ₂ ) _{2 4} NR ^a SO ₃ H, -(CH ₂ )I ₄ OP(OH) ₂ , -(CH ₂ )I ₄ P(O)(OH) ₂ , -(CH ₂ )I ₄ P(O)(OH)(OCI 4alkyl), or -(CH ₂ ) ₂ ^OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci 4alkyl; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0110] In further particular embodiments, the present disclosure provides a compound of formula I-a-2, wherein: R in -NRR ⁵ is H or lower alkyl, particularly methyl;

R ⁵ is -(CH ₂ ) _{2 4} OH, -(CH ₂ ) _{2 4} O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ ) ₂ ^O(CH ₂ )! -5CO2C1 _ ₄ alkyl, -(CH ₂ )^ ₃ CH(CH ₂ OH) ₂ , - (CH ₂ )1 ₄ CO ₂ H, (CH ₂ )! ₄ CONH ₂ , -(CH ₂ )! ₄ C(O)NR ^a (CH ₂ )! ₄ CO ₂ H, -(CH ₂ )I _ ₄ C(O)NR ^a (CH ₂ ) ₁ _ 4CONH ₂ , -(CH ₂ )o- ₄ NR ^a C(0)(CH ₂ )i_ ₅ C0 ₂ H, -(CI I ₂ )o _ ₄ NR ^a C(O)(CI I ₂ )i_ ₅ CO ₂ Ci ₄ alkyl, -(CI >2)2 4SO ₃ H, -(CH ₂ ) _{2 4} SO ₂ NH ₂ , -(CH ₂ ) _{2 4} SO ₂ NR ^a Ci ₄ alkyl, -(CH ₂ ) _2-4 NR ^a SO ₂ Ci ₄ alkyl, -(CH ₂ )i_ 4P(O)(OH) ₂ , or -(CH ₂ ) _{2 4} OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0111] In further particular embodiments, the present disclosure provides a compound of formula La-2, wherein:

R in -NRR ⁵ is H or lower alkyl, particularly methyl;

R ⁵ is -(CH ₂ ) _{2 4} OH, -(CH ₂ ) _M CH(CH ₂ OH) ₂ , -(CH ₂ )I ₄ CO ₂ H, -(CH ₂ )I ₄ CONH ₂ , -(CH ₂ )I ₄ C(O)NR ^a (CH ₂ )i 4CO ₂ H, -(CH ₂ )I ₄ C(O)NR ^a (CH ₂ )i^CONH ₂ , -(CH ₂ ) _{2 4} SO ₃ H. -(CH ₂ ) _{2 4} SO ₂ NH ₂ , -(CH ₂ ) _{2 4} SO ₂ NR ^a Ci- ₄ alkyl, -(CH ₂ ) _{2 4} NR<SO ₂ G ₄ alkyl. -(CH ₂ ) _M P(O)(OH) ₂ , or -(CH ₂ ) _{2 4} OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0112] In certain embodiments, for the above disclosed compounds of formula La-2, R ⁵ includes a terminal -CO ₂ H group. For example, in certain instances, R ⁵ includes a terminal -(CH ₂ )o_ ₄ C0 ₂ H group.

[0113] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is thereby forming a compound of formula I-a-3:

La-3 or a pharmaceutically acceptable salt thereof, wherein: Ring Bl is phenyl, preferably substituted phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; each R ⁶ is independently halogen, -COR, -(CR2)o-eC02R, -(CR2)o-eCONR2, -OR, -(CR2)I-4OR, -NR2, -(CR ₂ )I-4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o-6S02NR ₂ , -(CR ₂ )O-60S0 ₂ NR2, -(CR2)O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 0, 1, 2, 3, or 4, particularly 1, 2, 3, or 4; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0114] In certain embodiments, the present disclosure provides a compound of formula I-a-3, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-3, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-3, wherein Ring A is an optionally HetAr.

[0115] In certain embodiments, the present disclosure provides a compound of formula I-a-3, wherein Ring Bl is phenyl, particularly substituted phenyl. In other embodiments, Ring Bl is not phenyl. For example, Ring Bl may be a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, Ring Bl is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.

[0116] In some embodiments, the present disclosure provides a compound of formula I-a-3, wherein R ⁶ is not R ^B .

[0117] In certain embodiments, the present disclosure provides a compound of formula I-a-3, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0118] In certain embodiments, for the above disclosed compounds of formula I-a-3, m is 1 or 2, and at least one R ⁶ includes a terminal -CO2H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )O- 4CO2H or -(CH ₂ )<MO(CH ₂ )I 5CO2H. [0119] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is thereby forming a compound of formula I-a-4: or a pharmaceutically acceptable salt thereof, wherein: each R ^c is independently halogen, -COR, -(CR2)o-6C0 ₂ R, -(CR2)o~6CONR ₂ , -OR, -(CR ₂ )I-4OR, -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )O-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR2, -(CR2)O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR) ₂ , -(CR ₂ )O- ₆ P(0)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 0, 1, 2, 3, or 4, particularly 1, 2, 3, or 4; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0120] In certain embodiments, the present disclosure provides a compound of formula I-a-4, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-4, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-4, wherein Ring A is an optionally HetAr.

[0121] In some embodiments, the present disclosure provides a compound of formula I-a-4, wherein R ⁶ is not R ^B .

[0122] In certain embodiments, the present disclosure provides a compound of formula I-a-4, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0123] In certain embodiments, for the above disclosed compounds of formula I-a-4, m is 1 or 2, and at least one R ⁶ includes a terminal -CO ₂ H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )o 4CO.H or -(CH ₂ ) _M O(CH ₂ )i 5CO2H. [0124] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is thereby forming a compound of formula I-a-5:

I-a-5 or a pharmaceutically acceptable salt thereof, wherein: each R ⁶ is independently halogen, =0, -COR, -(CR2)o-6C0 ₂ R, -(CR ₂ )o-6CONR2, -OR, -(CR ₂ ) I rOR. -NR2, -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, - (CR ₂ )O-6S0 ₂ NR2, -(CR ₂ )O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , -(CR2)O- ₆ OP(0)(OR)2, -(CR ₂ )O- ₆ P(0)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, -B(OR) ₂ , or R ^B ;

X is absent (i.e., a bond in the ring), -CR ₂ -, -NR-, -0-, -S-, or -S0 ₂ -; particularly -CR ₂ -, -NR-, -0-, -S-, or -SO2-; more particularly -CR ₂ -, -NR-, or -0-; m is 0, 1, 2, 3, or 4, particularly 1, 2, 3, or 4; p is 0, 1, or 2, particularly 1; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0125] In certain embodiments, the present disclosure provides a compound of formula I-a-5, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-5, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-5, wherein Ring A is an optionally HetAr.

[0126] In some embodiments, the present disclosure provides a compound of formula I-a-5, wherein R ⁶ is not R ^B .

[0127] In certain embodiments, the present disclosure provides a compound of formula I-a-5, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring. [0128] In certain embodiments, the present disclosure provides a compound of formula La-5, wherein: each R ⁶ is independently halogen, -Ci^alkyl, -Ci-^aloalkyl, =CR2, =0, -COR, -(CR2)o-6C02R, -(CR ₂ )o- 6CONR ₂ , -OR, -(CR ₂ )I- ₄ OR, -NR ₂ , -(CR ₂ ) _M NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , - SR, -SO2R, -S(O)R, -(CR ₂ )o- ₆ S0 ₃ R, -(CR ₂ )O- ₆ S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR2, -(CR ₂ )O- ₆ NRS0 ₂ R, - (CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR)2, -(CR ₂ )O- 6OP(O)(H)OR, or -B(OR) ₂ ; m is 1, 2, 3, or 4, particularly 1 or 2; p is 0 or 1, particularly 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0129] In particular' embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, -Cwalkyl, -Ci- ₄ haloalkyl, =CH2, =0, -tCkhto 4CO2H, -(CFDo-rCChCi- 4alkyl, -(CH ₂ )O^O(CH ₂ )I 5CO2H, -(CH ₂ )o- ₄ 0(CH ₂ )i -5CO2C1 ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I 4CHFCO2H, -(CH ₂ )MO(CH ₂ )I 4CHFCO2C1 ₄ alkyl, -(CH ₂ )r ₄ OCH(CH ₃ )(CH ₂ ) I ₄ CO ₂ H. -(CH ₂ )I 4OCH(CH ₃ )(CH ₂ )I ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )MO(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -(CH ₂ )I- ₄ CXCH ₂ )I 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CH0H(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH(CH ₂ )MO(CH ₂ )I 5CO2C1 4alkyl, -CHCF ₃ (CH ₂ )I- ₄ O(CH2)I-5CO ₂ H, -CHCF ₃ (CH ₂ ) _M O-(CH ₂ )i_ ₅ CO ₂ Ci. ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ )I ₅ CONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a OH, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a CN, -(CH ₂ )I 4O(CH ₂ )I_5P(O)OH ₂ , -(CH ₂ )O 4CONH2. -(CH ₂ )o-4CONHCi. ₄ alkyl, -(CH2)o^CON(Ci ₄ alkyl) ₂ , - (CH ₂ )O- ₄ CO(/V-prolinc). -(CH ₂ )o ₄ OV-pyrazolc)-(CH2)o ₄ CO ₂ H. -( CH ₂ )o ₄ CO(/V-pyi'azolc)-(CH ₂ )o 4CO ₂ Ci- ₄ alkyl, -fCHz),, ₄ (/V-pyiTole)-(CH ₂ )o ₄ CO ₂ H. -(CH ₂ )o- ₄ CO(?/-pyrrole)-(CH2)o- ₄ C0 ₂ Ci. 4alkyl, -(CH ₂ )o ₄ -0(phciiyl)-(CH ₂ )o ₄ CO ₂ H. -(CH ₂ )o- ₄ -0(phenyl)-(CH ₂ )o-4C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o~4- 0(cycloalkane)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o ₄ -Oi'cycloalkanc)-(CH ₂ )o 4CO2C1 ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i 4CO2H. -(CH ₂ )tr4C(O)NR ^a (CH ₂ )i ₄ CONH ₂ , -(CH ₂ ) ₀ ^ ₄ C(O)NR ^a (CH ₂ ) _{1 4} CONHCi. ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i^CON(Ci. ₄ alkyl)2, -OH, -(CH ₂ )I ₄ OH, -(CH ₂ )(MOCI. 4alkyl, -NH ₂ , -(CH ₂ )O ₄ NR ^; '(CH ₂ ) I ₄ CO ₂ H. -(CWO 4\R7CH ₂ )I ₄ CO ₂ C, _ ₄ alkyl, -(CH ₂ )O- ₄ N[(CH ₂ )I- 4CO ₂ Ci- ₄ alkyl] ₂ , -(CH ₂ )I- ₄ NH ₂ , -(CH ₂ )o^NHCi ₄ alkyl, -(CH ₂ )o^N(Ci ₄ alkyl) ₂ , -(CH ₂ ) _{0 4} SO ₃ H. - (CH ₂ )O- ₄ S0 ₂ NH ₂ , -(CH ₂ )(MSO ₂ NHCi- ₄ alkyl, -(CH ₂ ) _{0 4} NR 'SO ₂ CI ₄ alkyl. -(CH ₂ )o^OP(OH) ₂ , - (CH ₂ )o- ₄ OP(OH)(OCi ₄ alkyl), or -(CR ₂ )Q- ₄ OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl;

X is -CH ₂ -, -NH-, or -O-; m is 1, 2, 3, or 4, particularly 1 or 2; p is 1; and each R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0130] In particular embodiments, the present disclosure provides a compound of formula I-a-5, wherein each R ^fi is independently fluoro, -methyl, -methoxy, -(Ctfch-sCChH, -(CH2)i-5CO ₂ Ci-4alkyl, -(CH ₂ )o- ₄ O(CH ₂ )I 5CO2H, -(CH2)o-40(CH2)i-5C02Ci-4alkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0131] In particular' embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, -Ci ralkyl, -C 1 rhaloalkyl, -C3 r, cycloalkyl, =CH2, =0, -(CH2)(V4CO ₂ H, - (CH ₂ )o-4C02Ci- ₄ alkyl, -(CH ₂ )O-40(CH ₂ )I_ ₅ C02H, -(CH ₂ )^4O(CH ₂ )i_5CO ₂ Ci. ₄ alkyl, -(CH ₂ )o_ 4CONH2, -(CH ₂ )o_4CONHCi- ₄ alkyl, -(CH ₂ )o_4CON(Ci- ₄ alkyl) ₂ , -(CH ₂ )<> rCOi/V-proline), -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CO ₂ H, -(CH ₂ )o^C(0)NR ^a (CH ₂ )i ₄ CONH ₂ , -(CH ₂ )o^C(0)NR ^a (CH ₂ )i 4CONHCi. ₄ alkyl, -(CH ₂ )o . ₄ C(O)NR ^a (CH ₂ )i ₄ CON(C I . ₄ alkyl) ₂ , -OH, -(CH ₂ )I ₄ OH, -(CH ₂ )<MOCI. 4alkyl, -NH ₂ , -(CH ₂ )r ₄ NH ₂ . -(CHj^NHCwalkyl, -(CH ₂ )(MN(Ci-4alkyl) ₂ , -<CH ₂ )O 4SO3H, - (CH ₂ )(MSO ₂ NH ₂ , -(CH ₂ )(MSO2NHCi-4alkyl, -(CH ₂ )o-4NR ^a S02Cr ₄ alkyl, -(CH ₂ )<MOP(OH) ₂ , - (CH ₂ )o- ₄ OP(OH)(OCi 4alkyl), or -(CR ₂ )O_ ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl;

X is -CH ₂ -, -NH-, or -O-; m is 1, 2, 3, or 4, particularly 1 or 2; p is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0132] In further particular embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, -Cwalkyl, -Ci rhaloalkyl, -C3 ecycloalkyl, =CH ₂ , -(CH2)o-4C0 ₂ H, - (CH ₂ )I-4O(CH ₂ )I-5CO2H, -(CH ₂ )MO(CH ₂ )i-5CO ₂ CMalkyl, -(CH ₂ )o rCOi/V-proline). -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i 4CO2H. -OH, -(CH ₂ )I ₄ OH, -(CH ₂ )o rSChH. -(CH ₂ )o ₄ SO ₂ NH ₂ . -(CH ₂ )^ 4NR ^a SO ₂ Ci ₄ alkyl, -(CH ₂ )<U3P(OH) ₂ , or -(CR ₂ )o ^0P(0)(H)0H;

X is -CH ₂ -, -NH-, or -O-; m is 1 or 2; p is 1; and each R ³ is independently halogen, such as chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0133] In certain embodiments, for the above disclosed compounds of formula I-a-5, m is 1 or 2, and at least one R ⁶ includes a terminal -CO2H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )O- 4CO2H or (CH ₂ )(MO(CH2)I 5CO2H.

[0134] In particular embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, -Cwalkyl, -Ci-4haloalkyl, =CH ₂ , =0, -(CH ₂ )o-4C0 ₂ H, -(CH2)o~4C0 ₂ Ci- 4alkyl, -(CH ₂ )o 4CONH2. -(CH ₂ )(MCONHCMalkyl, -(CH ₂ )(^CON(Ci-4alkyl)2, -<CH ₂ )o 4COOV- proline), -(CH ₂ )o ₄ CU))NRdCH ₂ )i ₄ CO ₂ H. -(CH2)(MC(O)NR ^a (CH ₂ )i-4CONH ₂ , -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CONHCi ₄ alkyl, -(CH ₂ )o ^C(O)NR ^a (CH ₂ )i.4CON1 Ci . ₄ alkyl) ₂ , -OH, -(CH ₂ )I_ 4OH, -(CH ₂ )O- ₄ OCI _ ₄ alkyl, -(CH ₂ ), ₄ 0<CH ₂ ) 5CO2H, -(CH ₂ )(MO(CH2)I 5CO2C1 4alkyl, -NH ₂ , -(CH ₂ )I^NH ₂ , -(CH ₂ )o-4NHCi. ₄ alkyl, -(CH ₂ )o^N(Ci. ₄ alkyl)2, -<CH ₂ )o rSO.H, - (CH ₂ )O-4S0 ₂ NH ₂ , -(CH ₂ )o^S0 ₂ NHCi.4alkyl, -(CH ₂ )o-4NR ^a S02Ci. ₄ alkyl, -(CH ₂ )o^OP(OH) ₂ , - (CH2)o-40P(OH)(OCi 4alkyl), or -(CR2)D-4OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl;

X is -CH ₂ -, -NH-, or -O-; m is 1, 2, 3, or 4, particularly 1 or 2; p is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0135] In further particular embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, -Ci lalkyl. -Ci ₄ haloalkyl, =CH ₂ , -(CH ₂ )o ICO ₂ H, -(CH ₂ )o iCOGV- proline), -(CH ₂ )o ₄ C(O)NR ^a (CH ₂ )i ₄ CO ₂ H. -OH, -(CH ₂ )I ₄ OH, -(CH ₂ )^ ₄ O(CH ₂ )I 5CO2H, -(CH ₂ )<> 4O(CH ₂ )i-5CO ₂ Ci-4alkyl, -(CH ₂ )o^S03H, -(CH ₂ )o-4S02NH ₂ , -(CI I ₂ )o 4NR ^a SO ₂ Ci ₄ alkyl. -(CH ₂ )o- 4OP(OH) ₂ , or -(CR ₂ )tv ₄ OP(O)(H)OH;

X is -CH ₂ -, -NH-, or -O-; m is 1 or 2; p is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0136] In certain embodiments, for the above disclosed compounds of formula I-a-5, m is 1 or 2, and at least one R ⁶ includes a terminal -CO2H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )O.4CO2H or -(CH ₂ )(MO(CH2)I _ ₅ CO ₂ H.

[0137] In particular embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, =0, -(CH ₂ )o- 4CO2H, -(CH ₂ )<> ₄ CO ₂ C 1 ₄ alkyl. -(CH ₂ )o-4CONH2, -(CH ₂ )Q_ 4CONHCi- ₄ alkyl, -(CH ₂ )o- ₄ CON(Ci ₄ alkyl) ₂ , -(CH ₂ )o- ₄ CO(^-proline), -(CH ₂ )o^C(0)NR ^a (CH ₂ )i- 4CO ₂ H, -(CH ₂ )O ₄ C(O)NRXCH ₂ ) I ₄ CONH ₂ . 4CH ₂ )O 4C(OiNR fCH ₂ )i 4CONHC1 ₄ alkyl. -(CH ₂ )o- 4C(O)NR4CH ₂ )I ₄ CC)N(CI ₄ alkyl) ₂ . -OH, -(CH ₂ )I ₄ OH, -(CH ₂ )o- ₄ OCi ₄ alkyl, -NH ₂ , -(CH ₂ )i_ ₄ NH ₂ , -(CH ₂ )o-4NHCi. ₄ alkyl, -(CH ₂ )o- ₄ N(Ci. ₄ alkyl) ₂ , -(CH^SOsH, -(CH ₂ )o- ₄ S0 ₂ NH ₂ , -(CH ₂ )o_ 4SO ₂ NHCi- ₄ alkyl, -(CH ₂ )o ₄ NR ^J SO ₂ C, ₄ alkyl. -(CH ₂ )„ ₄ OP(OH) ₂ . -(CH ₂ )o^OP(OH)(OCi ₄ alkyl), or -(CR ₂ )O-40P(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl;

X is -CH ₂ -, -NH-, or -O-; m is 1, 2, 3, or 4, particularly 1 or 2; p is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0138] In further particular embodiments, the present disclosure provides a compound of formula I-a-5, wherein: each R ⁶ is independently halogen, -(CH ₂ )o- ₄ C0 ₂ H, -I'CH ₂ )O ₄ CO(/V-proliiic), -(CH ₂ )o-4C(0)NR ^a (CH ₂ )i_ 4CO ₂ H, -OH, -(CH ₂ )I. ₄ OH. -(CH ₂ )O 4SO3H, 4CH ₂ )O ₄ SO ₂ NH ₂ . -(CH ₂ ) _{O 4} NR"SO ₂ CI ₄ alkyl. - (CH ₂ )(V ₄ OP(OH) ₂ , or -(CR ₂ )(V ₄ OP(O)(H)OH;

X is -CH ₂ -, -NH-, or -O-; m is 1 or 2; p is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0139] In certain embodiments, for the above disclosed compounds of formula I-a-5, m is 1 or 2, and at least one R ⁶ includes a terminal -CO ₂ H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )O- ₄ CO ₂ H or -(CH ₂ ) _M O(CH ₂ )i ₅ CO ₂ H. [0140] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is thereby forming a compound of formula I-a-6:

I-a-6 or a pharmaceutically acceptable salt thereof, wherein: each R ⁶ is independently halogen, =0, =CR2, -COR, -(CR ₂ )o-6C0 ₂ R, -(CR ₂ )o-fiCONR ₂ , -OR, -(CR ₂ )i- 4OR, -NR ₂ , -(CR ₂ )MNR2, -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )O- 6SO ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR ₂ , -(CR ₂ )(WNRSO ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR) ₂ , -(CR ₂ )O- ₆ P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 0, 1, 2, 3, or 4, particularly 1, 2, 3, or 4; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0141] In certain embodiments, the present disclosure provides a compound of formula I-a-6, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-6, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-6, wherein Ring A is an optionally HetAr.

[0142] In some embodiments, the present disclosure provides a compound of formula I-a-6, wherein R ⁶ is not R ^B .

[0143] In certain embodiments, the present disclosure provides a compound of formula I-a-6, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0144] In certain embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, -C 1 ralkyl, -Ci-4haloalkyl, =CR ₂ , =0, -COR, -(CR ₂ )o-6C0 ₂ R, -(CR ₂ )o- f _i CONR ₂ , -OR, -(CR ₂ )!-4OR, -NR ₂ , -(CR ₂ )I^NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , - SR, -SO ₂ R, -S(O)R, -(CR ₂ ) _{O 6} SO ₃ R, -(CR ₂ ) _{O 6} SO ₂ NR ₂ , -(CR ₂ )O ₆ OSO ₂ NR ₂ , -(CR ₂ ) _{O 6} NRSO ₂ R, - (CR ₂ ) ₍ wNRSO ₂ OR, -(CR ₂ )^OP(OR)2, -(CR ₂ ) _0-fi OP(O)(OR) ₂ , -(CR ₂ ) _0-fi P(O)(OR) ₂ , -(CR ₂ )o-

₆ OP(O)(H)OR, or -B(OR) ₂ ; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0145] In particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, -C i ₄ al ky I . -Ci. ₄ haloalkyl, =CH ₂ , =0, -(CH ₂ )o-4C0 ₂ H, -(CH ₂ X ₄ CO ₂ CI 4alkyl, -(CH ₂ )o^C0 ₂ Ci ₄ haloalkyl, -(CH ₂ )„ ₄ CONH ₂ , -(CH ₂ )o_4CONHCi- ₄ alkyl, -(CH ₂ )O^CON(CI. 4alkyl) ₂ , -(CH ₂ )O- ₄ CO(/V-prolinc), -(CH ₂ )O- ^CO(/V-pyrrolidine- 3 -carboxylic acid), -(CH ₂ )<> ₄ (/V- pyrazole)-(CH ₂ )t ₄ 4CO ₂ H, -(CH ₂ )o- ^CO(/V-pyrazole)-(CH ₂ )o. ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )D ₄ (/V-pyrrolc)- (CH ₂ )O- ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(/V-pyrrole)-(CH ₂ ) ₍₄ 4C0 ₂ Ci 4alkyl, -(CH ₂ )(M-O(phenyl)-(CH ₂ )^ 4CO ₂ H, -(CH ₂ )o-4-0(phenyl)-(CH ₂ )o-4C0 ₂ Cr ₄ alkyl, -(CH ₂ )o-4-0(cycloalkane)-(CH ₂ )o- ₄ C0 ₂ H, - (CH ₂ )o-4-0(cycloalkane)-(CH ₂ )(MC0 ₂ Ci.4alkyl, -(CH ₂ )o^C(0)NR ^a (CH ₂ )i ₄ CO ₂ H, -(CH ₂ )o- 4C(O)NR ^a -CH(C _M alkyl)-CO ₂ H, -(CH ₂ )^ ₄ C(O)NR ^a (CH ₂ )i ₄ CONH ₂ , -(CH ₂ )o^ ₄ C(0)NR ^a (CH ₂ )i 4CONHCi. ₄ alkyl, -(CH ₂ )o ₄ C(0)NR7CH ₂ ), ₄ CON(C, ₄ alkyl) ₂ , -OH, -(CH ₂ ), ₄ OH. -(CH^OCi- 4alkyl, -(CH ₂ )(MO(CH ₂ )I_ ₅ CO ₂ H, -(CH ₂ )o- ₄ 0(CH ₂ )i_5C0 ₂ Cr ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CHFCO ₂ H, -(CH ₂ ) _M 0(CH ₂ )I ₄ CHFCO ₂ CI ₄ alkyl, -(CH ₂ ) _M OCH(CH ₃ )(CH ₂ ) i ₄ CC) ₂ H . -(CH ₂ ) i 4OCH(CH ₃ )(CH ₂ )I ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ ) _M O(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -( CH ₂ ) I ₄ OfCH ₂ )i 4CH(CH ₃ )CO ₂ Ci ₄ alkyl, -CHOH(CH ₂ )i ₄ O(CH ₂ )I ₅ CO ₂ H, -CHOH(CH ₂ )^O(CH ₂ )I _S CO ₂ CI 4alkyl, -CHCF ₃ (CH ₂ ) _1-4 O(CH ₂ ) _1-5 CO ₂ H, -CHCF ₃ (CH ₂ ) _M O-(CH ₂ ) _1-5 CO ₂ Ci- ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ )I ₅ CONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I ₅ C0NR ^a 0H, -(CH ₂ )I ₄ O(CH ₂ )I ₅ C0NR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -NH ₂ , -(CH ₂ )O ₄ NR7CH ₂ ) I ₄ CO ₂ H, -(CH ₂ )O ₄ NR7CH ₂ ) I ₄ CO ₂ Ci 4alkyl, -(CH ₂ ) ₄ NH ₂ . -(CH ₂ )o^NHCi- ₄ alkyl, -(CH ₂ ) _{0 4} NR ^a C(O)Ci ₄ alkyl. -(CH ₂ )o- ₄ NR ^a C(0)Ph, - tCH ₂ ) _{0 4} NR ^;i COtCH ₂ )i ₄ OH, -(CH ₂ )^ ₄ N(CI ₄ alkyl) ₂ , -(CH ₂ ) _{0 4} SO ₃ H. -(CH ₂ )o^S0 ₂ NH ₂ , -(CH ₂ ) _{0 4} SO ₂ NR ^a Ci. ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ Ci. ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ Ph, -(CH ₂ )o_ ₄ NR ^a S0 ₂ (CH ₂ )v 4CO ₂ H, -(CH ₂ )O_ ₄ OP(OH) ₂ , -(CH ₂ )o_40P(OH)(OCi. ₄ alkyl), or -(CR ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci^alkyl; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring. [0146] In further particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, C i ₄ al ky 1 , -Ci- ₄ haloalkyl, =CH2, (CkhJo 4CO2H, -iCPPto 4CO2C 1 4alkyl, -(CI >2)0 4CO2C1 4haloalkyl, -(CI 12)0 4CO(/V-prolinc), -(O [2)0 4COGV-pyrrolidinc-3- carboxylic acid), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i- ₄ C0 ₂ H, -(CH ₂ )o- ₄ C(O)NR ^a -CH(Ci ₄ alkyl)-CO ₂ H, -OH, -(CH ₂ )MOH, -(CH ₂ )o-40Ci- ₄ alkyl, -(CH ₂ )^O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )^O(CH ₂ )i_ ₅ CO ₂ Ci.4alkyl, - (CH ₂ )o-4NR ^a C(0)Ci ₄ alkyl, -(CH ₂ )o- ₄ NR ^a C(0)Ph, -(CH ₂ )o^NR ^a CO(CH ₂ )i ₄ OH, -(CH ₂ )o-4S0 ₃ H, - (CH ₂ )O-4S0 ₂ NH2, -(CH ₂ )(44NRGSO2C1 ₄ alkyl, -(CH ₂ )o ^NR ^a SO ₂ Ph, -(CH ₂ )o-4NR ^a S0 ₂ (CH ₂ )i- 4CO ₂ H, -(CH ₂ )Q-4OP(OH) ₂ , or -(CR ₂ )o-40P(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl; m is 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0147] In particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, C 1 ₄ al ky 1 , -Ci- ₄ haloalkyl, -C3 ecycloalkyl, =CH ₂ , =0, -iCkbto 4CO2H, - (CH ₂ )o- ₄ C0 ₂ Ci. ₄ alkyl, -(CH ₂ )^ ₄ CO ₂ Ci ₄ haloalkyl, -(CH ₂ )(MO(CH ₂ )I_ ₅ CO ₂ H, -(CH ₂ ) _{O 4} O(CH ₂ ) I 5CO ₂ Ci- ₄ alkyl, -(CH ₂ )I. ₄ O(CH ₂ )I ₄ CHHCO ₂ H, -(CH ₂ )i_ ₄ O(CH ₂ )i^CHFCO ₂ Ci ₄ alkyl, -(CH ₂ )I- 4OCH(CH ₃ )(CH ₂ )I ₄ CO ₂ H, -(CH ₂ ) _M OCH(CH3)(CH ₂ )i^CO ₂ Ci 4alkyl, -(CH ₂ )I ₄ O(CH ₂ )I 4CH(CH ₃ )CO ₂ H, -(CH ₂ )1^O(CH ₂ )1 ₄ CH(CH ₃ )CO ₂ CI ₄ alkyk -CH0H(CH ₂ )I ₄ O(CH ₂ )I -5CO2H, - CHOH(CH ₂ )MO(CH ₂ )I ₅ CO ₂ Ci ₄ alkyl, -CHCF3(CH ₂ )I^O(CH ₂ )I 5CO2H, -CHCF ₃ (CH ₂ )MO- (CH ₂ )I 5CO2C1 ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a ₂ , -(CH ₂ )MO(CH ₂ )I ₅ C0NR ^a 0H, -(CH ₂ )I 4O(CH ₂ )I _s C0NR ^a CN, -(CH ₂ )I_4O(CH ₂ )I_ ₅ P(O)OH ₂ , -(CH ₂ )O ₄ CONH ₂ , -(CH ₂ )(MCONHCi- ₄ alkyl, -(CH ₂ )o ₄ CON(C I ₄ alkyl) ₂ . -(CH ₂ )o- ₄ CO(/V-proline), -(CH ₂ )o-4CO(7V-pyrrolidine-3-carboxylic acid), -(CH ₂ )o- ₄ (/V-pyrazole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )Q. ₄ CO(/V-pyrazolc)-(CH ₂ )o 4CO2C1 ₄ alkyl, - (CH ₂ )o-4(/V-pyrrole)-(CH ₂ )(MC02H, -(CH2)o^CO(^-pyn-ole)-(CH ₂ )o^C02Cb4alkyl, -(CH ₂ )<> I- 0(phenyl)-(CH ₂ )o- ₄ C02H, -(CH ₂ )o- ^-O(phenyl)-(CH ₂ )( ₄₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o 4-0(cycloalkanc)- (CH ₂ )o-4C0 ₂ H, -(CH ₂ )o- ₄ -0(cycloalkanc)-(CH ₂ ) ₀ _4C02Ci 4alkyl, -(CH ₂ )o^C(0)NR ^a (CH ₂ )i_ 4CO ₂ H, -(CH ₂ )o- ₄ C(0)NR ^a -CH(Ci- ₄ alkyl)-C0 ₂ H, -(CH ₂ )o ₄ C(O)NR ^I (CH ₂ )I ₄ CONH ₂ , -(CH ₂ ) _{0 4} C(O)NR"(CH ₂ )I 4CONHC 1 ₄ alkyl, -(CH ₂ )o ₄ C( O)NR"(CH ₂ )I ₄ CON(C I _ ₄ alkyl) ₂ , -OH, -(CH ₂ )I_ 4OH, -(CH ₂ )o_ ₄ OCi- ₄ alkyl, -(CH ₂ )o_ ₄ OC(0)Ci ₄ alkyl, -NH ₂ , -(CH ₂ )o- ₄ NR ^a (CH ₂ )i_ ₄ C0 ₂ H, -(CH ₂ )o_ 4NR ^a (CH ₂ )i-4CO2Ci ₄ alkyl, -(CH ₂ ) I INH ₂ . -(CH ₂ )o^NHCi. ₄ alkyl, -(CH ₂ )o- ₄ NR ^a C(0)Ci. ₄ alkyl, - (CH ₂ )o- ₄ NR ^a C(0)Ph, -(CH ₂ )<> ₄ NR ^a CO(CH ₂ )i 4OH, -(CH ₂ )(wN(Ci.4alkyl)2, -(CH ₂ )<> 4SO3H, - (CH ₂ )o^ ₄ S0 ₂ NH ₂ , -(CH ₂ )(X ^SO ₂ NR ^a Ci ₄ alkyl, -(CH ₂ )o ₄ NR\SO,C I . ₄ alkyl, -(CH ₂ )o_ ₄ NR ^a S0 ₂ Ph, - rCH ₂ )o ₄ NR\SO ₂ (CH ₂ )I 4CO2H, -(CH ₂ )o- ₄ OP(OH) ₂ , -(CH ₂ )o-40P(OH)(OCi- ₄ alkyl), or -(CR ₂ )^ 4OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0148] In further particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, -Ci ₄ alkyk -Ci- ₄ haloalkyl, -C3 gcycloalkyl, =CH ₂ , -(CH ₂ )o- ₄ C0 ₂ H, - (CH ₂ )O- ₄ 0(CH ₂ )I-5C0 ₂ H, -(CH ₂ )o^O(CH ₂ ) _1-5 C0 ₂ Ci ₄ alkyl, -(CH ₂ )o^CO(W-proline), -(CH ₂ )o- 4CO(/V-pyrrolidine-3-carboxylic acid), -(CH ₂ )o- ₄ C(O)NR ^a (CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o ₄ C(O)NR ^a - CH(Cr ₄ alkyl)-CO ₂ H, -OH, -(CH ₂ )r ₄ OH. -(CH ₂ )o^OCi ₄ alkyl, -(CH ₂ )o^OC(0)Ci ₄ alkyl, -(CH ₂ )o- 4NR ^a C(O)Ci- ₄ alkyl, -(CH ₂ )o->NR ^a C(0)Ph, -(CH ₂ ) _i: . ₄ NR ^; 'CO(CH ₂ ) I ₄ OH. -(CH ₂ )o ₄ SO ₃ H. -(CH ₂ )o- 4SO ₂ NH ₂ , -1CH ₂ )O ₄ NR\SO ₂ C I ₄ alkyl. -(CH ₂ )o- ₄ NR\SO ₂ Ph. -1CH ₂ ) _{4 4} NR 'SO ₂ (CH ₂ ), ₄ CO ₂ H. - (CH ₂ )O- ₄ OP(OH) ₂ , or -(CR ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; m is 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0149] In further particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -methoxy, -OtBu, -CF3, -(CH ₂ )I_SCO ₂ H, - (CH ₂ )i_ ₅ CO ₂ Ci. ₄ alkyl, -(CH ₂ )o. ₄ O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )o_ ₄ 0(CH ₂ )i_ ₅ C0 ₂ Ci- ₄ alkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0150] In particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, -Ci- ₄ alkyl, -Ci- ₄ haloalkyl, -C3 gcycloalkyl, =CH ₂ , =0, -(CH ₂ )o- ₄ C0 ₂ H, - (CH ₂ )o- ₄ C0 ₂ Cr ₄ alkyl, -(CH ₂ )^ ₄ O(CH ₂ )I 5CO2H, -(CH ₂ )o- ₄ 0(CH2)i-5C0 ₂ Ci. ₄ alkyl, -(CH ₂ )o- 4CONH ₂ , -(CH ₂ )o- ₄ CONHCi. ₄ alkyl, -(CH ₂ )o- ₄ CON(Cr ₄ alkyl) ₂ , -(CH ₂ )o- ₄ CO(W-proline), -(CH ₂ )o_ 4CO(/V-pyrrolidine-3-carboxylic acid), -(CH ₂ )o- ₄ C(O)NR ^; '(CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o^C(0)NR ^a - CH(Ci ₄ alkyl)-CO ₂ H, -(CH ₂ )<> ₄ C7O)NR '(CH ₂ ), ₄ CONH ₂ . (CH ₂ )o^C(0)NR ^a (CH ₂ )i ₄ CONHCI 4alkyl, -(Cl I ₂ )o ₄ CJ O)NR7C1 I ₂ )i ₄ CON(C I ₄ alkyl) ₂ . -OH, -(CH ₂ )I- ₄ OH, -(CH ₂ )o- ₄ OCr ₄ alkyl, -NH ₂ , -(CH ₂ )I- ₄ M~K -(CH ₂ )(wNHCwalkyl, -(CH ₂ )^NR ^a C(O)Cr ₄ alkyl, -(CH ₂ )o_ 4NR ^a C(O)Ph, -(CH ₂ )(wNRW(CH ₂ ) _M OH, -(CH ₂ )(wN(Ci- _4a lkyl) ₂ , -(CH ₂ )(wSO ₃ H, -(CH ₂ )o_ 4SO ₂ NH ₂ , -(CH ₂ )o^S0 ₂ NR ^a Ci- ₄ alkyl, 4CH ₂ ) _{() 4} NR ^a SO ₂ C, ₄ alkyl. -(CH ₂ )o- ₄ NR ^a S0 ₂ Ph, -(CH ₂ )o- 4NR ^a SO ₂ (CH ₂ )i ₄ CO ₂ H, -(CH ₂ )O^OP(OH) ₂ , -(CI I ₂ )o ₄ OP(O1 I)( OCi ₄ alkyl), or -(CR ₂ )o- 4OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Cr ₄ alkyl; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0151] In further particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ^fi is independently halogen, -Ci- ₄ alkyl, -Ci- ₄ haloalkyl, -C ₃ gcycloalkyl, =CH ₂ , -(CH ₂ )o~ ₄ C0 ₂ H, - (CH ₂ )I_4O(CH ₂ )I_5CO ₂ H, -(CH ₂ ) _M O(CH ₂ )i_5CO ₂ Cr ₄ alkyl, -(CH ₂ )(MCO(7V-proline), -(CH ₂ )o- 4CO(/V-pyrrolidine-3-carboxylic acid), -(CH ₂ )o- ₄ C(O)NR ^a (CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o ₄ C(O)NR ^a - CH(Ci ₄ alkyl)-CO ₂ H, -OH, -(CH ₂ )I ₄ C)H. -(CH ₂ )o^OCi. ₄ alkyl, -( CH ₂ ) _{0 4} NR ^a C(O)C, _ ₄ alkyl, - (CH ₂ )o_ ₄ NR ^a C(0)Ph, -(CH ₂ )„ ₄ NR ^a CO(CH ₂ ), ₄ OH. -(CH ₂ j„ ₄ SO ₃ H. -(CH ₂ )„ ₄ SO ₂ NH ₂ . -(CH ₂ )o- 4NR ^a SO ₂ Ci- ₄ alkyl, -(CH ₂ )o- ₄ NR\SO ₂ Ph. -(CH ₂ )o- ₄ NR ^a SO ₂ (CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o- ₄ OP(OH) ₂ , or - (CR ₂ )O- ₄ OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl, m is 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0152] In certain embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, =0, -COR, -(CR ₂ )o-eC0 ₂ R, -(CR ₂ )o-eCONR ₂ , -OR, -(CR ₂ ) I ₄ OR. -NR ₂ , -(CR ₂ )I- ₄ NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO ₂ R, -S(O)R, -(CR ₂ )O- ₆ S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, or -B(OR) ₂ ; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted Ci 6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0153] In particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, =0, -(CH ₂ )o. rCO-H, -(CH ₂ )o rCCX'i -4alkyl, -(CH2)o-4CONH2, -(CH ₂ )o_ 4CONHCi-4alkyl, -(CH2)o-4CON(Ci-4alkyl)2, -(CH ₂ )o-4CO(/V-proline), -(CH2)o^CO(A/-pyrrolidine- 3-carboxylic acid), -(CH ₂ V 4C(O)NR ^a (CH ₂ )i ₄ CO ₂ H. -(CH ₂ )o. ^C(O)NR ^a -CH(Ci ₄ alkyl)-CO ₂ H, -(CI I2)0 4C(O)NR\CI I ₂ )I 4CONI I2, -(CH ₂ )o^C(0)NR ^a (CH2)i-4CONHCi-4alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CON(Ci- ₄ alkyl)2, -OH, -(CH ₂ )I- ₄ OH, -(CH ₂ )o-40Ci- ₄ alkyl, -NH ₂ , -(CH ₂ )I-4NH ₂ , -(CH ₂ )o-4NHCi- ₄ alkyl, -(CH ₂ )o-4NR ^a C(0)Ci ₄ alkyl, -(CH ₂ )o^NR ^a C(0)Ph, -(CH ₂ )o^NR ^a CO(CH ₂ )i- 4OH, -(CH ₂ )o-4N(Ci 4alkyl)2, -(CH ₂ )o ^SO ₃ H, -(CH ₂ )o ^SO ₂ NH ₂ , -(CHjo 4SO ₂ NR ^a Ci ₄ alkyl. - (CH ₂ )o- ₄ NR ^a S0 ₂ Ci-4alkyl, -(CH ₂ )o^NR ^a S0 ₂ Ph, -(CH ₂ )o-4NR ^a S02(CH2)i 4C0 ₂ H, -(CH ₂ )o- 4OP(OH) ₂ , -(CH ₂ )o-40P(OH)(OCi ₄ alkyl), or (CR ₂ )O^IOP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0154] In further particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein: each R ⁶ is independently halogen, -(CH ₂ )Q_4CO ₂ H, -(CH ₂ )O- ^CO(iV-proline), -(CH ₂ )O ₄ COGV-pyrrolidinc-3- carboxylic acid), -(CH ₂ )o-4C(0)NR ^a (CH ₂ )i-4C0 ₂ H, -tCH _{2j() 4} C(O)NR ^a -CH(Ci ₄ alkyl)-CO ₂ H. -OH, -(CH ₂ )I 4OH, -(CH ₂ )o-tNR ^a C(0)Ci. ₄ alkyl, -(CH ₂ )o. ^NR ^a C(O)Ph, -(CH ₂ )o- ₄ NR ^a CO(CH ₂ )i^OH, - (CH2)O- ₄ S0 ₃ H, -(CH ₂ )O-4S0 ₂ NH ₂ , -(CH ₂ )O 4NR ^a SO ₂ Ci ₄ alkyl, -(CH ₂ )o-4NR ^a S0 ₂ Ph, -(CH ₂ )o- 4NR ^a SO ₂ (CH ₂ )i 4CO2H, -(CH ₂ )O-40P(OH) ₂ , or -(CR ₂ )o-40P(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; m is 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0155] In particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein, m is 1;

R ⁶ is -(CH ₂ )O- ₄ 0(CH ₂ )I-5C0 ₂ H, such as -(CH ₂ )I 2CXCH2)2 3CO ₂ H. including -CH ₂ O(CH ₂ ) ₂ CO ₂ H; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring. [0156] In certain embodiments, for the above disclosed compounds of formula I-a-6, m is 1 or 2, and at least one R ⁶ includes a terminal -CO2H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )O.4CO2H or (CH ₂ )(MO(CH2)I 5CO2H.

[0157] In particular embodiments, the present disclosure provides a compound of formula I-a-6, wherein n is 2, R ³ is chloro at the 7- and 8 -positions with respect to the quinoline ring and one instance of R ⁶ is - (CH2)o-40(CH ₂ )i-5C0 ₂ H. In certain of such embodiments, the compound of formula I-a-6 is a compound of formula I-a-6*: or a pharmaceutically acceptable salt thereof, wherein: each of Ring A, R ⁶ , and m is as defined above and described in embodiments herein, both singly and in combination. In particular embodiments, m is preferably zero.

[0158] In certain embodiments, the present disclosure provides a compound of formula I-a-6*, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-6,* wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-6*, wherein Ring A is an optionally HetAr.

[0159] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is thereby forming a compound of formula I-a-7: or a pharmaceutically acceptable salt thereof, wherein:

Ring B2 is phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; each R ^c is independently halogen, -COR, -(CR2)o-6C0 ₂ R, -(CR2)o~6CONR ₂ , -OR, -(CR ₂ )I-4OR, -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )O-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR2, -(CR2)O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR) ₂ , -(CR ₂ )O- ₆ P(0)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 0, 1, 2, 3, or 4, particularly 1, 2, 3, or 4; q is 0, 1, or 2; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0160] In certain embodiments, the present disclosure provides a compound of formula I-a-7, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-7, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-7, wherein Ring A is an optionally HetAr.

[0161] In certain embodiments, the present disclosure provides a compound of formula I-a-7, wherein Ring B2 is phenyl, particularly substituted phenyl. In other embodiments, Ring B2 is not phenyl. For example, Ring B2 may be a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, Ring B2 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.

[0162] In some embodiments, the present disclosure provides a compound of formula I-a-7, wherein R ⁶ is not R ^B .

[0163] In some embodiments, the present disclosure provides a compound of formula I-a-7, wherein R which is H or Ci-6alkyl.

[0164] In certain embodiments, the present disclosure provides a compound of formula I-a-7, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0165] In certain embodiments, for the above disclosed compounds of formula I-a-7, m is 1 or 2, and at least one R ⁶ includes a terminal -CO2H group. For example, in certain instances, at least one R ⁶ is -(CH ₂ )O- 4CO2H or (CH ₂ )(MO(CH2)I 5CO2H.

[0166] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is or a pharmaceutically acceptable salt thereof, wherein: each R ⁶ is independently hydrogen (only on N), halogen (not on N), -COR, -(CR ₂ )o-6C0 ₂ R, -(CR ₂ )o- 6CONR ₂ , -OR, -(CR ₂ )I- ₄ OR, -NR ₂ , -(CR ₂ )MNR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )O-6S0 ₃ R, -(CR2K6SO2NR2, -(CR ₂ )O-60S0 ₂ NR2, -(CR ₂ )(«NRSO ₂ R, -(CR ₂ )O- ₆ NRS020R, -(CR ₂ )O- ₆ OP(OR)2, -(CR ₂ )O- ₆ OP(0)(OR)2, -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O- 6OP(O)(H)OR, -B(OR) ₂ , or R ^B ;

X is absent (i.e., a bond in the ring), -CR ₂ -, -NR-, -O-, -S-, or -SO2-, particularly -CR2-, -NR-, or -O, m is 1, 2, 3, or 4; q is 0, 1, or 2; and each of Ring A, R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0167] In certain embodiments, the present disclosure provides a compound of formula La-8 or formula La-8*, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula La-8 or formula La-8*, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula La-8 or formula La-8*, wherein Ring A is an optionally HetAr. [0168] In some embodiments, the present disclosure provides a compound of formula La-8 or formula I- a-8*, wherein R ⁶ is not R ^B .

[0169] In some embodiments, the present disclosure provides a compound of formula La-8 or formula I- a-8*. wherein which is H or Ci galkyl.

[0170] In certain embodiments, the present disclosure provides a compound of formula La-8 or formula La-8*, wherein R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0171] In certain embodiments, the present disclosure provides a compound of formula La-8 or formula La-8*, wherein: each R ⁶ is independently halogen, =0, -COR, -(CR ₂ )o <>CO ₂ R. -(CR Jo (,CONR ₂ , -OR, -(CR Ji 4OR. -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR2)O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- f _i OP(OR) ₂ , -(CR ₂ )o_ _fi OP(0)(OR) ₂ , -(CR ₂ )o- _fi P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, or -B(OR) ₂ ; m is 1, 2, 3, or 4, particularly 1 or 2; q is 1 or 2; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0172] In particular embodiments, the present disclosure provides a compound of formula La-8 or formula La-8*, wherein: each R ⁶ is independently halogen, =0, -(CH ₂ )o 4CO2H. -tCH ₂ )o 4CO2C 1 4alkyl. -(CH ₂ )o-4CONH ₂ , -(CH ₂ )o- 4CONHCi. ₄ alkyl, -(CH ₂ )o-4CON(Cwalkyl) ₂ , -fCH ₂ ) _{0 4} CO(/V-proline), -(CH ₂ )o^C(0)NR ^a (CH ₂ )i- 4CO ₂ H, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ ) _M CONH ₂ , -(CH ₂ )o^C(0)NR ^a (CH ₂ ) _M CONHCi. ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH Ji ₄ CON(CI _ ₄ alkyl) ₂ , -OH, -(CH ₂ )I- ₄ OH, -(CH ₂ )o-40Ci- ₄ alkyl, -NH ₂ , -(CH ₂ )I-4NH ₂ , -(CH ₂ )o-4NHCi- ₄ alkyl, -(CH ₂ )o-4N(Ci. ₄ alkyl)2, -(CH2X4SO3H, -(CH ₂ )(MSO ₂ NH2, -(CH ₂ )o- 4SO ₂ NHCi- ₄ alkyl, -(CH ₂ ) _{() 4} NR ^a SO ₂ Ci ₄ alkyl. -(CH ₂ )o- ₄ OP(OH) ₂ . -(CH ₂ )o-tOP(OH)(OCi. ₄ alkyl), or -(CR ₂ )Q-4OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl; m is 1, 2, 3, or 4, particularly 1 or 2; q is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0173] In further particular embodiments, the present disclosure provides a compound of formula I-a-8 or formula I-a-8*, wherein: each R ⁶ is independently halogen, -(CIF jo 4CO2H. dCH2)o rCOi/V-prolinc), -(CH2)o^C(0)NR ^a (CH ₂ )i- 4CO2H, -OH, -(CH ₂ )r rOH, -(CH ₂ )o 4SO3H, -(CH ₂ )o 4SO2NH2. -(CH ₂ )o ₄ NR'SO ₂ CI ₄ alkyl, - (CH ₂ )O-40P(OH) ₂ , or -(CR ₂ )O-40P(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; m is 1 or 2; q is 1; and each R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0174] In certain embodiments, for the above disclosed compounds of formula I-a-8 or I-a-8*, m is 1 or 2, and at least one R ⁶ includes a terminal -CO ₂ H group. For example, in certain instances, at least one R ⁶ is -1CH ₂ )O 4CO2H or -(CH ₂ )<MO(CH ₂ )I 5CO2H.

[0175] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is

N \"^N' H thereby forming a compound of formula I-a-9:

I-a-9 or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0176] In certain embodiments, the present disclosure provides a compound of formula I-a-9, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-9, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-9, wherein Ring A is an optionally HetAr. [0177] In certain embodiments, the present disclosure provides a compound of formula La-9, wherein R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0178] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is p/ c \(R ⁶ )m

' , thereby forming a compound of formula I-a-10:

La-10 or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR ₂ )o 6CO2R, -(CICjo 6CONR2. -OR, -(CR ₂ ) I 4OR. -NR2, -(CR ₂ )I-4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR2)O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )0-6OP(O)(OR)2, -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of Ring A, R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0179] In certain embodiments, the present disclosure provides a compound of formula I-a-10, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-a-10, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-a-10, wherein Ring A is an optionally HetAr.

[0180] In some embodiments, the present disclosure provides a compound of formula I-a-10, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole.

[0181] In particular embodiments, the present disclosure provides a compound of formula I-a-10, wherein Ring C is pyrrolyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane, 5- azaspiro[2.4]heptanyl, or octahydrocyclopenta[b]pyrrolyl.

[0182] In particular embodiments, the present disclosure provides a compound of formula I-a-10, wherein Ring C is 3-hydroxyproline, Ci galkyl 3-hydroxyproline ester, or Ci-ghaloalkyl 3-hydroxyproline ester.

[0183] In some embodiments, the present disclosure provides a compound of formula I-a-10, wherein: each R ⁶ is independently fluoro, -CN, methyl, -C ₃ gcycloalkyl, -CF3, -CO2H, -NH2, -OH, -OCi- ₄ alkyl, =CH ₂ , =O, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i_4OCi- ₄ alkyl, -(CH ₂ )I_4O(CH2)I-5CO ₂ H, -(CH ₂ )i- ₄ O(CH2)i- ₅ CO ₂ Ci. ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ )I 4CHFCO2H. -(CH ₂ )I 4O(CH ₂ )i^CHFCO ₂ Ci 4alkyl, -(CH ₂ )I ^OCH(CH ₃ )(CH ₂ )I ₄ CO ₂ H. -(CH ₂ )I ₄ OCH(CH ₃ )(CH ₂ )I 4CO2C1 ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -(CH ₂ ) _M O(CH ₂ )I- 4CH(CH3)CO ₂ CI ₄ alkyl, -CHOH(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH-(CH ₂ )MO(CH ₂ )I 5CO2C1 4alkyl, -CHCF ₃ (CH ₂ ) I ^O(CH ₂ )I 5CO2H, -CHCF ₃ (CH2)i^O(CH2)i-5CO ₂ Ci. ₄ alkyl, -(CH ₂ )o- 4O(CH ₂ )I sCONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I sCONR ^a OH, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )I 5CO2H, -(CH ₂ )I 5CO2C1 ₄ alkyl, 4CH ₂ )o 4CHCHCO2H, -(CH2)o- ₄ CHCHC0 ₂ Ci ₄ alkyl, -CO ₂ Ci. ₄ alkyl, -C0 ₂ Ci. ₄ haloalkyl, -OCOCi. ₄ alkyl, - O(CH ₂ )I ₄ CO ₂ H, -O(CH ₂ )I ₄ CO ₂ Ci ₄ alkyl, -OCONR4CH ₂ )<> ₄ CO ₂ H, -OCONR4CH ₂ )<> ₄ CO ₂ C, 4alkyl, -OCO-(/\'-morpholinc). -CONH ₂ , -CONHOH, -CONHOCi ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CO ₂ H, -(CH ₂ )(r4C(O)NR ^a (CH2)i- ₄ CO2Ci. ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH2)i- 4(pyrrolid-2-one), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i- ₄ (piperidin-2-one), -(CH ₂ )o- ^C(O)NR ^a (CH ₂ )i- 4C(OH)(CF ₃ ) ₂ , -(CH2)o- ₄ C(0)NR ^a (CH2)i_ ₄ CONH2, 4CH ₄ ) _{(1 4} CONR ^;I SOCI ₄ haloalkyl, -(CH ₂ )o- 4CO(2V-pyrrolidine)-(CH ₂ )o 4CO2H, -(CH ₂ )o 4CO(A^-pyrrolidine)-(CH ₂ )o 4CO2C1 ₄ alkyl, -(CH ₂ )o 4(A^-pyrazole)-(CH2)o- ₄ C02H, -(CH ₂ )o. ₄ CO(/V-pyrazolc)-(CH2jo ₄ CO2Ci ₄ alkyl, -(CH ₂ )o- ₄ (iV- pyrrole)-(CH ₂ )o- ₄ C0 ₂ H, -(Cl I ₂ )o ₄ CO(/V-pyrrole)-(CI I ₂ )( ₄ CO ₂ Ci ₄ alkyk -(CH ₂ )o-4-0-(phenyl)- (CH ₂ )O- ₄ C0 ₂ H, -(CH ₂ )O ₄ -0-(phcnyl)-(CH ₂ )o ₄ CO ₂ CI ₄ alkyl, -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- 4CO2H, -(CH2)o-4-0(cycloalkane)-(CH2)o- ₄ C02Ci- ₄ alkyl, -(CH ₂ )o. - ₄ CO(2V-pyrrolidine)-(CH ₂ )o- 4SO2NH2, -(CH ₂ )o ₄ CO(.'V-pyrrolidinc )-(tcti'azolc). -(CH ₂ )(> ₄ CO(/V-pipei idine)-(CH ₄ )o ₄ COIH. - (CH2)o- ₄ CO(iV-piperidine)-(CH2)o- ₄ C02Ci ₄ alkyl, -(CH ₂ )o- ₄ CO(/V-morpholine)-(CH2)o - ₄ CO2H, - CONR ^a (bicyclo[l.l.l]pentane)-(CH ₂ )o- ₄ C0 ₂ H, -NH ₂ , -(CH ₂ )o- ₄ NR ^a (CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o- 4NR ^a (CH2)i- ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o_ ₄ N[(CH2)i- ₄ C02Ci- ₄ alkyl] ₂ , -(CH ₂ )o->NR ^a CO(isoxazole)-OH, - (CH2)o-4NR ^a S02(benzene)-C02H, -(CH ₂ k 4NR ^a SO7CH, )i 4CO2H, -(CH2)o-4NR ^a S02(CH2)i- 4CO ₂ Ci-4alkyl, -(CH ₂ )o^iNR ^a S0 ₂ (CH ₂ )i^(imidazolidine-2, 4-dione), -1CH ₂ )O 40P(0)(H)0H, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl; and m is 1, 2, 3, or 4.

[0184] In particular embodiments, the present disclosure provides a compound of formula I-a-10, wherein each R ^fi is independently fluoro, -methyl, cyclohexyl, -CF3, -CO2H, -CChCwalkyl, -CO2C1 4haloalkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0185] In particular' embodiments, the present disclosure provides a compound of formula I-a-10, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF3, -methoxy, -(CH2)I 5CO2H, -(CH2)I- ₅ CO ₂ Ci- ₄ alkyl, -(CH ₂ )o ^O(CH ₂ )I 5CO2H, -(CH2)(MO(CH ₂ )i-5CO ₂ CMalkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0186] In certain embodiments, the present disclosure provides a compound of formula I-a-10, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0187] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is

La-11 or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR2)o-eC02R, -(CR2)o-eCONR2, -OR, -(CR ₂ ) I 4OR, -NR2, -(CR ₂ )I_4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )O-6S0 ₃ R, -(CR ₂ )o-6S0 ₂ NR2, -(CR2)O-60S0 ₂ NR2, -(CR ₂ )O-6NRS0 ₂ R, -(CR2)O- _C NRS0 ₂ OR, -(CR ₂ )O- _fi OP(OR) ₂ , -(CR2)O-60P(0)(OR)2, -(CR2)O-6P(0)(OR)2, -(CR ₂ )O-60P(0)(H)OR, -B(0R)2, or R ^B ; m is 0, 1, 2, or 3; and each of Ring A, R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0188] In certain embodiments, the present disclosure provides a compound of formula I-a-11, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl.

[0189] In certain embodiments, the present disclosure provides a compound of formula I-a-11, wherein Ring A is optionally substituted HetCy. For example, in certain embodiments, Ring A is optionally substituted HetCy, and HetCy is selected from optionally substituted tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, tetrahydroquinolinyl 4H- quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. In further such embodiments, Ring A is optionally substituted HetCy, and HetCy is selected from optionally substituted morpholinyl, piperazinyl, 2,5-dihydro-lH-pyrrole and 2,3-dihydro-lH-pyrrole.

[0190] In certain embodiments, the present disclosure provides a compound of formula I-a-11, wherein Ring A is an optionally HetAr. For example, in certain embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted thienyl, furanyl, pyrrolyl, triazolyl. tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibcnzofuranyl, indazolyl, bcnzimidazolyl, bcnzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. In further such embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted thienyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, and pyrimidinyl. In preferred embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted triazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.

[0191] In some embodiments, the present disclosure provides a compound of formula I-a-11, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole. [0192] In particular embodiments, the present disclosure provides a compound of formula I-a-11, wherein each R ⁶ is independently fluoro, -methyl, =0, =CH ₂ , -cyclohexyl, phenyl, morpholinyl, -OMe, - OtBu, -CF3, -CO2H, -CChCi ^alkyl, -CChCi rhaloalkyl, or -OH; and m is 0 or 1, or 2, particularly 0 or 1.

[0193] In certain embodiments, the present disclosure provides a compound of formula I-a-11, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0194] In some embodiments, the present disclosure provides a compound of formula I, wherein at least one R ³ is halogen, such as chloro at the 8-position, thereby forming a compound of formula I-b-1:

I-b-1 or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ² , and R ³ is as defined above and described in embodiments herein, and n is 0, 1, 2, or 3, both singly and in combination.

[0195] In certain embodiments, the present disclosure provides a compound of formula I-b-1, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-b-1, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-b-1, wherein Ring A is an optionally HetAr.

[0196] In certain embodiments, the present disclosure provides a compound of formula I-b-1, wherein R ² is R ^B , wherein R ^B is an optionally substituted C1-6 aliphatic, preferably a substituted C1-6 aliphatic, such as -(CR ₂ )I 4NR(CR ₂ )O 6CO2R, -(CR ₂ )I-40(CR2)O-4C0 ₂ R, -(CR ₂ )I-4CO ₂ R, -(CR ₂ )I- rOH. -(CR ₂ )I-4NH ₂ , -(CR ₂ )MC(O)NH ₂ , -(CR ₂ )i-4C(O)NHCi ₄ alkyl, or -(CR ₂ )MC(O)N(C _M alkyl) ₂ , particularly -(CR ₂ )I- 4NR(CR ₂ )o rCCFR or -(CR2)I-4CC>2R,. In some embodiments, R ² is -(CH2)i-4NR ^a (CH ₂ )o-4C02R ^a , such as -(CH ₂ )i-4NR ^a (CH ₂ )o-4C0 ₂ H, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl. In other embodiments, R ² is -<CH ₂ )I 4N(SO ₂ CI 4alkylkCH ₂ )o 4CO2R' ¹ . such as is -(CH ₂ )i-4N(S0 ₂ Ci-4alkyl)(CH2)o- 4CO2H, wherein R ^a , independently for each occurrence, is H or Ci 4alkyl. In other embodiments, R ² is -fC R 2) 1 4CO2R, such as -f C R 2) 1 4CO2H, including -(CTDi^CChH. In certain embodiments, R ² includes a terminal -CO2H group. For example, in certain instances, R ² includes a terminal -(CH2)o-4C02H group. [0197] In some embodiments, the present disclosure provides a compound of formula I, wherein n is 2 and R ³ is chloro at the 7- and 8-positions, thereby forming a compound of formula I-b-2:

I-b-2 or a pharmaceutically acceptable salt thereof, wherein each of Ring A and R ² is as defined above and described in embodiments herein, both singly and in combination.

[0198] In certain embodiments, the present disclosure provides a compound of formula I-b-2, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-b-2, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-b-2, wherein Ring A is an optionally HetAr.

[0199] In certain embodiments, the present disclosure provides a compound of formula I-b-2, wherein R ² is R ^B , wherein R ^B is an optionally substituted Ci-6 aliphatic, preferably a substituted Ci-6 aliphatic, such as -(CR2)I^NR(CR ₂ )^ ₆ CO2R, -(CR ₂ )I- ₄ 0(CR ₂ )O- ₆ C0 ₂ R, -(CR ₂ )I- ₄ CO ₂ R, -(CR ₂ )I- ₄ OH. -(CR ₂ )I- ₄ NH ₂ , -(CR ₂ )MC(O)NH ₂ , -(CR ₂ )i- ₄ C(O)NHCi ₄ alkyl, or -(CR ₂ ) _M C(O)N(Ci ₄ alkyl) ₂ , particularly -(CR ₂ )i- ₄ NR(CR ₂ )O-6C0 ₂ R or -(CR ₂ )I- ₄ CC>2R,. In some embodiments, R ² is -(CH ₂ )i_ ₄ NR ^a (CH ₂ )o- ₄ C0 ₂ R ^a , such as -(CH ₂ )i_ ₄ NR ^a (CH ₂ )o- ₄ C0 ₂ H, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl. In other embodiments, R ² is -(CH ₂ )i^N(S0 ₂ Ci- ₄ alkyl)(CH ₂ )o- ₄ C0 ₂ R ^a , such as is -(CH ₂ )i_ ₄ N(S0 ₂ Ci_ ₄ alkyl)(CH ₂ )o- ₄ CO ₂ H, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl. In other embodiments, R ² is -(CR ₂ )I ₄ CO ₂ R. such as -(CR ₂ )i ₄ CO ₂ H, including -(CH ₂ )I ₄ CO ₂ H. In certain embodiments, R ² includes a terminal -CO ₂ H group. For example, in certain instances, R ² includes a terminal -(CH ₂ )O- ₄ C0 ₂ H group.

[0200] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is , and R is chloro at the 7- and 8 -positions thereby forming a compound of formula I-c-1:

I-c-1 or a pharmaceutically acceptable salt thereof, wherein: each R ⁶ is independently halogen, =0, -COR, -(CR2)o-eC02R, -(CR2)o-eCONR2, -OR, -(CR?)! 4OR. -NR2, -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o- ₆ S02NR2, -(CR ₂ )O- ₆ OS02NR2, -(CR2)O-6NRS0 ₂ R, -(CR2)O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O-60P(0)(OR)2, -(CR ₂ )(WP(O)(OR)2, -(CR ₂ )(MOP(O)(H)OR, -B(0R) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of Ring A, R and R ^B is as defined above and described in embodiments herein, both singly and in combination.

[0201] In certain embodiments, the present disclosure provides a compound of formula I-c-1, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl.

[0202] In certain embodiments, the present disclosure provides a compound of formula I-c-1, wherein Ring A is optionally substituted HetCy. For example, in certain embodiments, Ring A is optionally substituted HetCy, and HetCy is selected from optionally substituted tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, tetrahydroquinolinyl 4H- quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. In further such embodiments, Ring A is optionally substituted HetCy, and HetCy is selected from optionally substituted morpholinyl, piperazinyl, 2,5-dihydro-lH-pyrrole and 2,3-dihydro-lH-pyrrole.

[0203] In certain embodiments, the present disclosure provides a compound of formula I-c-1, wherein Ring A is an optionally HetAr. For example, in certain embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted thienyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. In further such embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted thienyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, and pyrimidinyl. In preferred embodiments, Ring A is optionally substituted HetAr, and HetAr is selected from optionally substituted triazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.

[0204] In some embodiments, the present disclosure provides a compound of formula I-c-1, wherein: each R ⁶ is independently fluoro, -CN, methyl, =0, =CH2, -C3 ecycloalkyl, -CF3, -CO2H, -NH2, -OH, -OCi

4alkyl, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i-4OCi- ₄ alkyl, -(CH ₂ )o^ ₄ 0(CH ₂ )i ₅ CO ₂ H, -(CH ₂ )o- ₄ 0(CH ₂ )i_ ₅ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ ) I ₄ CHFCO ₂ H, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CHFCO ₂ CI _ ₄ alkyl, -(CH ₂ ) I ₄ OCH(CH ₃ XCH ₂ )I ₄ CO ₂ H, -(CH ₂ )I 4OCH(CH ₃ )(CH ₂ )I 4CO2C1 ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -(CH ₂ )I^O(CH ₂ )I 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CHOH(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH(CH ₂ ) _M O(CH ₂ )I 5CO2C1 4alkyl, -CHCF3(CH ₂ )MO(CH ₂ )I-5CO ₂ H, -CHCF3(CH2)MO-(CH ₂ )i-5CO ₂ Ci- ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ )I ₅ CONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I ₅ C0NR ^a 0H, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )I ₅ CO ₂ CI ₄ alkyl, -(CH ₂ ) _{0 4} CHCHCO ₂ H, -I CH ₂ )O ₄ CHCHCO ₂ C I ₄ alkyl, -CO ₂ C _M alkyl, -CO ₂ Ci- ₄ haloalkyl, -OCOCi- ₄ alkyl, - 0(CH ₂ )I ₄ CO ₂ H, -O(CH ₂ )1 ₄ CO ₂ C1 ₄ alkyl, -OCONR ^a (CH ₂ )o^C0 ₂ H, -OCONR ^a (CH ₂ )o ₄ CO ₂ C, 4alkyl, -OCO-(A-morpholine), -CONH ₂ , -C0NH0H, -CONHOCi ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CO ₂ H, -(CH ₂ )o^C(0)NR ^a (CH ₂ )i- ₄ C02Ci- ₄ alkyl, -(CH2)o- ₄ C(0)NR ^a (CH ₂ )i- 4(pyrrolid-2-one), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ ₄ (piperidin-2-one), -(CH ₂ )o ₄ C(O)NR '(CH ₂ )I 4C(OH)(CF ₃ ) ₂ , -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i_ ₄ CONH ₂ , -(CH ₂ ) _{0 4} CONR ^a SO ₂ Ci ₄ haloalkyl, -(CH ₂ ) _{4 4} CO(A-pyrrolidine)-(CH ₂ )o-4C0 ₂ H, -1CH ₂ )O ₄ CO(/V-pyri'olidinc)-(CH ₂ )o ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o- 4(Af-pyrazole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o ₄ CO(/V-pyrazolc)-(CH ₂ )o ₄ CO ₂ CI ₄ ;ilkyl, -(CH ₂ ) _{4 4} (/V- pyrrole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o- - ₄ CO(A-pyrrole)-(CH2)o- ₄ C0 ₂ Ci _ ₄ alkyl, -(CH ₂ )o-4-0(phenyl)- (CH ₂ )O_ ₄ C02H, -(CH ₂ )O ₄ -0(phcnyl)-(CH ₂ )o ₄ CO ₂ CI ₄ alkyl, -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- 4CO ₂ H, -(CH ₂ )o-4-0(cycloalkane)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o- ₄ CO(A-pyrrolidine)-(CH ₂ )o- 4SO ₂ NH ₂ , -(CH ₂ )o-4CO(A^-pyrrolidine)-(tetrazole), -(CH ₂ )o ₄ CO(/V-pipei idine)-(CH ₂ )o ₄ CO ₂ H, - (CH ₂ )o- ₄ CO-(A-piperidine)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o- ₄ CO(A-morpholine)-(CH ₂ )o- ₄ C0 ₂ H, - CONR ^a (bicyclo[l.l.l]pentane)-(CH ₂ )o- ₄ C0 ₂ H, -NH ₂ , -(CH2)o^NR ^a (CH2) _M C0 ₂ H, -(CH ₂ )o- 4NR'(CH ₂ )I ₄ CO ₂ C, ₄ alkyl, -(CH ₂ )o- ₄ N[(CH2)i- ₄ C0 ₂ Ci- ₄ alkyl]2, -(CH ₂ )o^NR ^a CO(isoxazole)OH, - (CH ₂ )o- ₄ NR ^a S0 ₂ (phcnyl)-C0 ₂ H, -(CH ₂ )o .NRkSOziCHj, ₄ CO ₂ H, -(CH .) _{() 4} NR ^a SO ₂ i'CH ₂ ) 4CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ (CH ₂ )i^(imidazolidine-2, 4-dione), -(CH ₂ )o~ ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and m is 1. 2, 3, or 4. [0205] In particular embodiments, the present disclosure provides a compound of formula I-c-1, wherein each R ⁶ is independently fluoro, =0, =CH ₂ , -methyl, cyclohexyl, -CF3, -CO2H, -CCFCi ^alkyl, -CO2C1- ₄ haloalkyl, or -OH; m is 1, 2, or 3, particularly 1 or 2.

[0206] In particular embodiments, the present disclosure provides a compound of formula I-c-1, wherein each R ⁶ is independently fluoro, =O, =CH2, -methyl, cyclohexyl, -CF3, -methoxy, -OtBu, -(CH2)I-5CO2H, -(CH ₂ )i-5CO ₂ Ci-4alkyl, -(CH ₂ ) _0-4 O(CH ₂ ) _1-5 CO ₂ H, -(CH^o^OCCH^i-sCOzCi ^alkyl, -(CH^OCCH,)] sCONR ^a ₂ , or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0207] In particular' embodiments, the present disclosure provides a compound of formula I-c-1, wherein, m is 1; and R ⁶ is -(CH ₂ )O-40(CH ₂ )I-5C0 ₂ H, such as -(CH ₂ )I ₂ O(CH ₂ ) ₂ aCChH, including - CH ₂ O(CH ₂ ) ₂ CO ₂ H.

[0208] In some embodiments, the present disclosure provides a compound of formula I, wherein R ² is - NRR ⁵ , and R ³ is chloro at the 7- and 8-positions thereby forming a compound of formula I-c-2:

I-c-2 or a pharmaceutically acceptable salt thereof, wherein:

R ⁵ is -(CR ₂ ) ₂ ^OR, -(CR ₂ )O- ₆ C0 ₂ R, -(CR ₂ )O- ₆ CONR ₂ , -(CR ₂ )O- ₆ C(0)NR(CR ₂ )O-6C0 ₂ R, -(CR ₂ )O- 6C(0)NR(CR ₂ )O-6CONR ₂ , -(CR ₂ )O- ₆ NRCOR, -(CR ₂ )o- ₄ NR ^a C(0)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o- 6SO2NR2, -(CR ₂ )O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , - (CR ₂ )0- ₆ OP(O)(OR)2, -(CR ₂ )(WP(O)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, or R ^B ; and each of Ring A, R and R ^B is as defined above and described in embodiments herein, both singly and in combination.

[0209] In certain embodiments, the present disclosure provides a compound of formula I-c-2, wherein Ring A is an optionally substituted phenyl, preferably substituted phenyl. In certain embodiments, the present disclosure provides a compound of formula I-c-2, wherein Ring A is optionally substituted HetCy. In certain embodiments, the present disclosure provides a compound of formula I-c-2, wherein Ring A is an optionally HetAr.

[0210] In some embodiments, the present disclosure provides a compound of formula I-c-2, wherein R ⁵ is not R ^B . [0211] In particular embodiments, the present disclosure provides a compound of formula I-c-2, wherein R ⁵ is -(CH ₂ ) _{2 4} OH, -(CH ₂ ) ₂ 4O(CH ₂ )! ₅ CO ₂ H, -(CH ₂ )2-JO(CH ₂ )I _ ₅ CO ₂ CI . ₄ alkyl, -(CH ₂ )^ ₃ CH(CH ₂ OH) ₂ , - (CH ₂ ) ₂ _4OCi- ₄ alkyl, (CH ₂ ), ₄ CO ₂ H. -(CH ₂ )i_ ₄ CO ₂ C _{] 4} alkyl, -1CH ₂ ), ₄ CONH ₂ . -(CH ₂ ) _M CONHCi ₄ alkyl, - (CH ₂ )i_ ₄ CON(Ci- ₄ alkyl) ₂ , -(CH ₂ ) _M C(O)NR ^a (CH ₂ )i ₄ CO ₂ H, -(CH ₂ ) _M C(O)NR ^a (CHMe)CO ₂ H, -(CH ₂ )I- ₄ C(O)NR ^a (CH ₂ )i ₄ CONH ₂ . -(CH ₂ )i^C(O)NR ^a (CH ₂ )i_ ₄ CONHCr ₄ alkyl, -(CH ₂ )i_ ₄ C(O)NR ^a (CH ₂ )i_ ₄ CON(Ci. ₄ alkyl) ₂ , -(CH ₂ )o- ₄ NR ^a C(0)(CH ₂ )i_ ₅ C0 ₂ H, -(CH ₂ )^ ₄ NR ^a C(O)(CH ₂ )i_ ₅ CO ₂ Cr ₄ alkyl, -(CH ₂ ) _{2 4} SO ₃ H, -(CH ₂ ) ₂ ^SO ₃ Ci- ₄ alkyl, -(CH ₂ ) _{2 4} SO ₂ NH ₂ , -(CH ₂ )i^C(O)NR ^a (CH ₂ ) _2-4 SO ₂ NH ₂ , -(CH ₂ )i_ ₄ CO(A- pyrrolidine)-SO ₂ NH ₂ ,-(CH ₂ ) _2-4 SO ₂ NHCwalkyl, -(CH ₂ ) _2-4 SO ₂ N(Ci ₄ alkyl) ₂ , -(CH ₂ ) _{2 4} OSO ₂ NH ₂ , -(CH ₂ ) _{2 4} NR'(CH ₂ ) _{2 4} CO ₂ H. (CH ₂ ) _{2 4} NR ^a CO(CH ₂ ) _M CO ₂ H, -(CH ₂ ) _2-4 NR ^a CO(cyclopentane)-CO ₂ H, -(CH ₂ ) ₂ _ ₄ NR ^a CO(benzene)-OH, -(CH ₂ ) ₂ ^NR ^a CO(benzene)-CO ₂ H, -(CH ₂ ) _{2 4} NR ^a SO ₃ H, -(CH ₂ ) _2.4 NR 'SO ₂ C I ₄ alkyl, -(CH ₂ ) _{2 4} NR ^a SO ₂ (CH ₂ ) _{2 4} OH, -(CH ₂ ) _2-4 NR ^a SO ₂ (CH ₂ ) _2-4 OCr ₄ alkyl, -1CH ₂ ) _{2 4} NR ^a SO ₂ (CH ₂ ) _{2 4} CO ₂ H, - (CH ₂ ) _2-4 NR ^a SO ₂ (benzene)-CO ₂ H, -(CH ₂ ) _{2 4} NR ^a SO ₂ ( bcnzenc)-CO ₂ Ci _ ₄ alkyl, -(CH ₂ ) _2-4 SO ₂ NR ^a (CH ₂ ) ₂ _ ₄ OH, -(CH ₂ ) ₂ . A/V-saccharin). -(CH ₂ ) _{2 4} SO ₂ NR ^a (CH ₂ ) _{2 4} CO ₂ H, -(CH ₂ ) _2-4 SO ₂ NR ^a (cyclopentane)-CO ₂ H, - (CH ₂ ) _2-4 NR ^a (cyclohexane)-CO ₂ Ci ₄ alkyl, -(CH ₂ ) _2.4 S0 ₂ (A-pyi rolidine)-C0 ₂ H, -(CH ₂ ) _2-4 SO ₂ (A- piperidine)-CO ₂ H, (CH ₂ )I ₄ OP(OH) ₂ , -(CH ₂ ) _M P(O)(OH) ₂ , -(CH ₂ ) _M P(O)(OH)(OCi ₄ alkyl), or (CH ₂ ) _{2 4} OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H, Cr ₄ alkyl, or -SO ₂ Ci- ₄ alkyl.

[0212] In some embodiments, the present disclosure provides a compound of formula I-c-2, wherein R in -NRR ⁵ is R ^a , which is H or Ci galkyl, particularly methyl.

[0213] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A thereby forming a compound of formula I-d-1:

I-d-1 or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0214] In certain embodiments, the present disclosure provides a compound of formula I-d-1, wherein

R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0215] In certain embodiments, the present disclosure provides a compound of formula I-d-1, wherein R ² is R ^B , wherein R ^B is an optionally substituted Ci-6 aliphatic, preferably a substituted Ci-6 aliphatic, such as -(CR ₂ )MNR(CR ₂ )O-6C0 ₂ R, -(CR ₂ )I- ₄ 0(CR ₂ )O- ₆ C0 ₂ R, -(CR ₂ )I- ₄ CO ₂ R, -(CR ₂ )I- ₄ OH. -(CR ₂ )I- ₄ NH ₂ , -(CR ₂ )I^C(O)NH ₂ , -(CR ₂ )i- ₄ C(O)NHCi 4alkyl, or -(CR ₂ )i^C(O)N(Ci. ₄ alkyl)2, particularly -(CR ₂ )I- 4NR(CR ₂ )O-6C0 ₂ R or -(CR2)I- ₄ CO ₂ R,. In some embodiments, R ² is -(CH2)i- ₄ NR ^a (CH ₂ )o-4C02R ^a , such as - (CH ₂ )i-4NR ^a (CH2)o- ₄ C02H, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl. In other embodiments, R ² is -(CH ₂ )i^N(S0 ₂ Ci. ₄ alkyl)(CH ₂ )o-4C0 ₂ R ^a , such as is -(CH ₂ )i- ₄ N(S0 ₂ Ci- ₄ alkyl)(CH ₂ )o- 4CO ₂ H, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl. In other embodiments, R ² is - (CR ₂ )MCO ₂ R, such as -(CR ₂ )i- ₄ CO ₂ H, including -(CH ₂ )I-4CO ₂ H. In certain embodiments, R ² includes a terminal -CO ₂ H group. For example, in certain instances, R ² includes a terminal -(CH2)o- ₄ C0 ₂ H group.

[0216] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A

N=N thereby forming a compound of formula I-d-2:

I-d-2 or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0217] In certain embodiments, the present disclosure provides a compound of formula I-d-2, wherein R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0218] In certain embodiments, the present disclosure provides a compound of formula I-d-2, wherein R ² is R ^B , wherein R ^B is an optionally substituted Ci-6 aliphatic, preferably a substituted Ci-6 aliphatic, such as -(CR2)MNR(CR2)O-6C0 ₂ R, -(CR ₂ )I-40(CR2)O-6C0 ₂ R, -(CR ₂ )I-4CO ₂ R, -(CR ₂ )I- rOH. -(CR ₂ )I-4NH ₂ , -(CR ₂ )I^C(O)NH ₂ , -(CR ₂ )i-4C(O)NHCi ₄ alkyl, or -(CR ₂ )i^C(O)N(Cwalkyl) ₂ , particularly -(CR ₂ )I- 4NR(CR ₂ )O-6C0 ₂ R or -(CR ₂ )I- ₄ CO ₂ R,. In some embodiments, R ² is -(CH ₂ )i-4NR ^a (CH2)o-4C0 ₂ R ^a , such as - (CH ₂ )i- ₄ NR ^a (CH ₂ )o- ₄ C0 ₂ H, wherein R ^a , independently for each occurrence, is H or Cr ₄ alkyl. In other embodiments, R ² is -1CH ₂ )I ₄ N(SO ₂ CI ₄ alkyl)(CH ₂ )o ₄ CO ₂ R\ such as is -(CH2)i- ₄ N(S02Ci- ₄ alkyl)(CH2)o- ₄ CO ₂ H, wherein R ^a , independently for each occurrence, is H or Ci ₄ alkyl. In other embodiments, R ² is - (CR ₂ ) I ₄ CO ₂ R, such as -(CR ₂ )r ₄ CO ₂ I I, including -(CH ₂ )I ₄ CO ₂ H. In certain embodiments, R ² includes a terminal -CO ₂ H group. For example, in certain instances, R ² includes a terminal -(CH ₂ )O_ ₄ C0 ₂ H group.

[0219] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A thereby forming a compound of formula I-d-3:

I-d-3 or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0220] In certain embodiments, the present disclosure provides a compound of formula I-d-3, wherein R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0221] In certain embodiments, the present disclosure provides a compound of formula I-d-3 wherein R ² is R ^B , wherein R ^B is an optionally substituted Ci-6 aliphatic, preferably a substituted Ci-6 aliphatic, such as -(CR ₂ )I- -iNRlCFbl. -eCChR, -(CR2)I-40(CR2)O-6C0 ₂ R, -(CR ₂ )I- ₄ CO ₂ R, -(CR ₂ )I-4OH, -(CR ₂ )L 4NH2. - (CR ₂ ) _M C(O)NH ₂ , -(CR2) _M C(O)NHCi- ₄ alkyl, or -(CR ₂ )i- ₄ C(O)N(Ci- ₄ alkyl)2, particularly -(CR ₂ )I- ₄ NR(CR ₂ )o-6C02R or -(CR ₂ )i- ₄ CO ₂ R,. In some embodiments, R ² is -(CH ₂ )i- ₄ NR ^a (CH2)o-4C0 ₂ R ^a , such as - (CH ₂ )i- ₄ NR ^a (CH2)o- ₄ C0 ₂ H, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl. In other embodiments, R ² is -1CH ₂ )I ₄ N(SO ₂ CI ₄ alkyl)(CH ₂ )o ₄ CO ₂ R''. such as is -(CH ₂ )i_ ₄ N(S0 ₂ Ci- ₄ alkyl)(CH ₂ )o_ ₄ CO ₂ H, wherein R ^a , independently for each occurrence, is H or Cr ₄ alkyl. In other embodiments, R ² is - (CR ₂ ) I -1CO2R. such as -(CR ₂ )I- ₄ CO ₂ H. including -(CH2)I- ₄ CO ₂ H. In certain embodiments, R ² includes a terminal -CO ₂ H group. For example, in certain instances, R ² includes a terminal -(CH ₂ )O- ₄ C0 ₂ H group. [0222] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A thereby forming a compound of formula I-d-4 or I-d-4*, respectively: or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0223] In certain embodiments, the present disclosure provides a compound of formula I-d-4 or formula I-d-4*, wherein R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0224] In certain embodiments, the present disclosure provides a compound of formula I-d-4 or I-d-4*„ wherein R ² is R ^B , wherein R ^B is an optionally substituted Ci-6 aliphatic, preferably a substituted Ci-6 aliphatic, such as -(CR2)i-4NR(CR2)o-eC02R, -(CR2)r 40(CR2)o 6CO2R, -(CR2)r 4CO2R, -(CR2) I 4OI I, - (CR ₂ )MNH ₂ , -(CR ₂ )I-4C(O)NH ₂ , -(CR ₂ )i^C(O)NHCi- ₄ alkyl, or -(CR ₂ )i^C(O)N(Ci. ₄ alkyl)2, particularly - (CR2)MNR(CR2)O-6CC>2R or -(CR2) 1 rCChR.- In some embodiments, R ² is -(CH2)i- ₄ NR ^a (CH2)o~ ₄ C02R ^a , such as -ICHili 4NR ^a (CH2)o 4CC)IH. wherein R ^a , independently for each occurrence, is H or Ci. ₄ alkyl. In other embodiments, R ² is -(CH2)i-4N(S02Ci ₄ alkyl)(CH2)o- ₄ C02R ^a , such as is -(CEbh^tbKSChCi ₄ alkyl)(CH2)o-4C02H, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl. In other embodiments, R ² is -(CR2)I-4CC>2R, such as -(CR2) I 4CO2H, including -(CH 2) 1 4CO2H. In certain embodiments, R ² includes a terminal -CO2H group. For example, in certain instances, R ² includes a terminal -(CPFk rCChH group.

[0225] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A thereby forming a compound of formula I-d-5 or I-d-5*, respectively: or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0226] In certain embodiments, the present disclosure provides a compound of formula I-d-5 or formula I-d-5*, wherein R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0227] In certain embodiments, the present disclosure provides a compound of formula I-d-5 or I-d-5*, wherein R ² is R ^B , wherein R ^B is an optionally substituted Ci-6 aliphatic, preferably a substituted Ci-6 aliphatic, such as -(CR2)I-4NR(CR2)O-CCC>2R, dCR:)! rCXCR:/) 4CO2R. -(CR2I1 4CO2R. -(CR2)I 4OH, - (CR ₂ )MNH ₂ , -(CR ₂ )MC(O)NH ₂ , -(CR ₂ )i-4C(O)NHCi-4alkyl, or -(CR2)i-4C(O)N(Ci- ₄ alkyl) ₂ , particularly - (CR2)MNR(CR2)O-6CC>2R or -(CR2) 1 4CO2R,. In some embodiments, R ² is -(CH2)i-4NR ^a (CH2)o-4C02R ^a , such as -(CH2) I 4NR '(CH2)o 4CO2H, wherein R ^a , independently for each occurrence, is H or Ci-4alkyl. In other embodiments, R ² is -(CH2)i- ₄ N(S02Ci ₄ alkyl)(CH2)o-4C02R ^a , such as is -(CH2)i^N(SC>2Ci- ₄ alkyl)(CH2)o 4CO2H, wherein R ^a , independently for each occurrence, is H or Ci 4alkyl. In other embodiments, R ² is -(CR2)I-4CC>2R, such as -fC R2) 1 4CO2H, including (CH 2) 1 4CO2H. In certain embodiments, R ² includes a terminal -CO2H group. For example, in certain instances, R ² includes a terminal -(CH2F 4CO2H group.

[0228] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR ₂ )o-6C0 ₂ R, -(CR ₂ )o-6CONR ₂ , -OR, -(CR ₂ ) I ₄ OR. -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o-6S02NR ₂ , -(CR ₂ )O-60S0 ₂ NR2, -(CR2)O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, -B(0R) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0229] In some embodiments, the present disclosure provides a compound of formula I-e-1, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole.

[0230] In particular embodiments, the present disclosure provides a compound of formula I-e-1 , wherein Ring C is pyrrolyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptanyl, or oct ahy dr ocy clopent a [b ] pyrrolyl .

[0231] In particular embodiments, the present disclosure provides a compound of formula I-e-1, wherein Ring C is 3-hydroxyprolinc, Ci-galkyl 3-hydroxyprolinc ester, or C 1 ghaloalkyl 3-hydroxyprolinc ester.

[0232] In some embodiments, the present disclosure provides a compound of formula I-e-1, wherein: each R ⁶ is independently fluoro, -CN, methyl, -C ₃ gcycloalkyl, -CF ₃ , -CO2H, -NH2, -OH, -OCi-4alkyl,

=CH ₂ , =O, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i-4OCi- ₄ alkyl, -(CH ₂ )I-4O(CH ₂ )I_5CO ₂ H, -(CH ₂ )i_4O(CH ₂ )i-5CO ₂ Ci- ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ )MCHFCO ₂ H, -(CH ₂ )1 ₄ O(CH2)I^CHFCO ₂ CI ₄ alkyl, -(CH ₂ )I ^OCH(CH ₃ )(CH ₂ )I ₄ CO,H.

-(CH ₂ )I 4OCH(CH ₃ )(CH ₂ )I 4CO2C1 ₄ alkyl, -(CH ₂ )I 4O(CH ₂ )I 4CH(CH ₃ )CO ₂ H, -(CH ₂ )I^O(CH ₂ )I- 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CHOH(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH-(CH ₂ )MO(CH ₂ )I 5CO2C1 4alkyl, -C1 ICI' ₃ (C11 ₂ )i ₄ O(C11 ₂ )i ₃ CO ₂ l I. -CHCF ₃ (CH ₂ ) _M O(CH ₂ )i_5CO ₂ CMalkyl, -(CH ₂ )o- 4O(CH ₂ )I -sCONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a OH, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )I 5CO2H, -(CH ₂ )I 5CO2C1 ₄ alkyl, -(CH ₂ )^ 4CHCHCO2H, -(CH ₂ )(V4CHCHCO ₂ CI ₄ alkyl, -CO ₂ Ci. ₄ alkyl, -CO ₂ Ci. ₄ haloalkyl, -OCOCi- ₄ alkyl, -

O(CH ₂ )I 4CO2H, -O(CH ₂ )I 4CO2C1 ₄ alkyl, -OCONR ^a (CH ₂ ) ₍₄₄ CO ₂ H, -OCONR ^a (CH ₂ )o ₄ CO ₂ Ci ₄ alkyl, -OCO-(A-morpholine), -CONH ₂ , -CONHOH, -CONHOC1 ₄ alkyl, -(CH ₂ )o- 4C(O)NRCH ₂ )I 4CO2H, -(CH ₂ )<, ₄ C(O)NR4CH ₂ )I ₄ CO ₂ Ci ₄ alkyl. -(CH2) _0-4 C(O)NR ^a (CH ₂ )i- 4(pyrrolid-2-one), -(CH2)o- ₄ C(0)NR ^a (CH2)i- ₄ (piperidin-2-one), -(CH ₂ )o ^C(O)NR ^a (CH ₂ )i- 4C(OH)(CF ₃ ) ₂ , -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i- ₄ CONH ₂ , -(Cl l ₂ ) _{0 4} CONR\SO ₂ CI ₄ haloalkyl. (CI 1 ₂ ) ₍ , 4CO(/V-pyrrolidmc)-(CH ₂ )o ₄ CO ₂ H, -(CH ₂ )O ₄ CC)(/V-pyri'olidinc)-(CH ₂ )o ₄ CO ₂ C I ₄ alkyl, -(CH ₂ )o- 4(/V-pyrazolc)-(CH ₂ )o ₄ CO ₂ H, -(CH ₂ ) _{O 4} CO(/V-pyraz<>lc)-(CH ₂ )o ₄ CO ₂ CI ₄ alkyl, -(CH ₂ )o- ₄ (/V- pyrrole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o ₄ CO(/V-pyrrolc)-(CH ₂ )( ₄ CO ₂ Ci ₄ alkyl. -(CH ₂ )o-4-0-(phenyl)- (CH ₂ )o ₄ CO ₂ H, -(CH ₂ ) _O 4-0-(phcnyl)-(CH ₂ )o ₄ CO ₂ CI ₄ alkyk -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- 4CO ₂ H, -(CH ₂ )o-4-0(cycloalkane)-(CH ₂ )o_ ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o- ₄ CO(A-pyrrolidine)-(CH ₂ )o_ 4SO ₂ NH ₂ , -(CH ₂ )O ₄ CO(.'V-pyrrolidincj-(tctrazole), -(CH ₂ )o ₄ CO(/V-pipci idinc)-(CH ₂ )() ₄ CO ₂ H, - (CH ₂ )o- ₄ CO((V-piperidine)-(CH ₂ )o-4C0 ₂ Ci ₄ alkyl, -(CH ₂ ) _{() 4} CO(/V-morpholinc)-(CH ₂ )o ₄ CO ₂ H. - CONR ^a (bicycloLl.l.l]pentane)-(CH ₂ )o- ₄ C0 ₂ H, -NH ₂ , -(CH ₂ )o^NR ^a (CH ₂ )i^C0 ₂ H, -(CH ₂ )o- 4NR ^a (CH ₂ )i- ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ N[(CH2)i- ₄ C0 ₂ Ci. ₄ alkyl]2, -(CH ₂ )o^NR ^a CO(isoxazole)-OH, - (CH ₂ )o- ₄ NR ^a S02(benzene)-C0 ₂ H, -(CH ₂ )o^NR ^a S0 ₂ (CH ₂ )i ₄ CO ₂ H, -(CH ₂ )„ ₄ NR ^a SO ₂ (CH ₂ ), 4CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ (CH ₂ ) _M (imidazolidine-2, 4-dione), -(CH ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or C i ₄ alkyl; and m is 1, 2, 3, or 4.

[0233] In particular' embodiments, the present disclosure provides a compound of formula I-e-1, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF3, -CO ₂ H, -CO ₂ C 1 ₄ alkyl, -CO ₂ Ci- ₄ haloalkyl, or - OH; and m is 1, 2, or 3, particularly 1 or 2.

[0234] In particular embodiments, the present disclosure provides a compound of formula I-e-1, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF3, -methoxy, -(CH ₂ )I sCO ₂ H, -(CH ₂ )I sCChCi ₄ alkyl, -(CH ₂ )O- ^O(CH ₂ )I ₅ CO ₂ H, -(CHzlo^OCCHzh-sCCFCi ralkyl, or -OH; and m is 1 , 2, or 3, particularly 1 or 2.

[0235] In certain embodiments, the present disclosure provides a compound of formula I-e-1, wherein R ³ is independently optionally substituted Ci-e aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0236] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A

N=N

^ ?NH

Y is zvwvwv and R ² is , thereby forming a compound of formula I-e-2:

I-e-2 or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR ₂ )o-gC0 ₂ R, -(CR ₂ )o-gCONR ₂ , -OR, -(CR ₂ )I 4OR. -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR2, -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O- ₆ NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ ) _M OP(O)(H)OR, -B(0R) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0237] In some embodiments, the present disclosure provides a compound of formula I-e-2, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole.

[0238] In particular embodiments, the present disclosure provides a compound of formula I-e-2, wherein Ring C is pyrrolyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptanyl, or oct ahy dr ocy clopent a [b ] pyrrolyl .

[0239] In particular embodiments, the present disclosure provides a compound of formula I-e-2, wherein Ring C is 3-hydroxyproline, Ci ealkyl 3-hydroxyproline ester, or Ci-ghaloalkyl 3-hydroxyproline ester.

[0240] In some embodiments, the present disclosure provides a compound of formula I-e-2, wherein: each R ⁶ is independently fluoro, -CN, methyl, -C3 gcycloalkyl, -CF3, -CO2H, -NH2, -OH, -OCi-4alkyl, =CH ₂ , =O, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i-4OCi- ₄ alkyl, -(CH ₂ )I-4O(CH ₂ )I_ ₅ CO ₂ H, -(CH ₂ )i_ ₄ O(CH ₂ )i_ ₅ CO ₂ Ci. ₄ alkyl, -(CH ₂ )I- 4O(CH ₂ ) I 4CHFCO2H, -(CH ₂ )I ₄ O(CH ₂ )I 4CHFCO2C1 _ ₄ alkyl, -(CH ₂ )I ^OCH(CH ₃ )(CH ₂ )I ₄ CO ₂ H, -(CH ₂ )I ₄ OCH(CH ₃ )(CH ₂ )I -4CO2C1 _ ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I 4CHfCH _; )C0.H, -(CH ₂ )wO(CH ₂ ),_ 4CH(CH ₃ )CO ₂ C1 _ ₄ alkyl, -CHOH(CH ₂ )I ₄ O(CH ₂ )I ₅ CO ₂ H, -CHOH-(CH ₂ )MO(CH ₂ )I_ ₅ CO ₂ C ₁ - 4alkyl, -CHCF ₃ (CH ₂ )MO(CH ₂ )I_5CO ₂ H, -CHCF ₃ (CH ₂ ) _M O(CH ₂ )i_ ₅ CO ₂ Cwalkyl, -(CH ₂ )o_ 4O(CH ₂ )I ₅ CONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a OH, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )I ₅ CO ₂ CI ₄ alkyl, -(CH ₂ ) _{0 4} CHCHCO ₂ H, -(CH ₂ )o_ ₄ CHCHC0 ₂ Ci ₄ alkyl, -CO ₂ C _M alkyl, -CO ₂ Cn ₄ haloalkyl, -OCOCi- ₄ alkyl, - O(CH ₂ )1 ₄ CO ₂ H, -O(CH ₂ )I ₄ CO ₂ C| _ ₄ alkyl, -OCONR ^a (CH ₂ )o^C0 ₂ H, -OCONR ^a (CH ₂ )o ₄ CO ₂ C, 4alkyl, -OCO-(iV-morpholine), -CONH ₂ , -CONHOH, -CONHOCi ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CO ₂ H, -(CH ₂ )O 4C(0)NR ^;I (CH ₂ )I ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ 4(pyrrolid-2-one), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ ₄ (piperidin-2-one), -(CH ₂ )o^tC(0)NR ^a (CH ₂ )i- 4C(OH)(CF ₃ ) ₂ , -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i_ ₄ CONH ₂ , -(CH ₂ ) _{0 4} CONR 'SO ₂ CI ₄ haloalkyl, -(CH ₂ )o_ 4CO(/V-pyiT<>lidinc)-(CH ₂ )o ₄ CO ₂ H, -(CH ₂ )o- ₄ CO(A'-pyrrolidine)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o- 4(Af-pyrazole)-(CH ₂ )o_ ₄ C0 ₂ H, -iCH ₂ )o ₄ C06V-pyrazolcHCH ₂ )o ₄ CO ₂ Ci ₄ alkyl. -(CH ₂ )o- ₄ (2V- pyrrole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o- ₄ COOV-pyrrolc)-(CH ₂ ) ₍ . ₄ CO ₂ Ci _ ₄ alkyl, -(CH ₂ )o-4-0-(phenyl)- (CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o^-0-(phenyl)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- 4CO ₂ H, -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- ₄ C0 ₂ Ci_ ₄ alkyl, -(CH ₂ )o- - ₄ CO(2V-pyrrolidine)-(CH ₂ )o- 4SO ₂ NH ₂ , -(CH ₂ )o- ₄ CO(A^-pyrrolidine)-(tetrazole), -(CH ₂ )o ₄ CO(/V-pipei idinc)-(CH ₂ )o ₄ CO ₂ H, - (CH ₂ )o- ₄ CO(A'-piperidine)-(CH ₂ )o- ₄ C0 ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ CO(A'-morpholine)-(CH ₂ )o- ₄ C0 ₂ H, - CONR ^a (bicyclo[l.l.l]pentane)-(CH ₂ )o- ₄ C0 ₂ H, -NH ₂ , -(CH ₂ )o^NR ^a (CH ₂ )i^C0 ₂ H, -(CH ₂ )o- 4NR ^a (CH ₂ )i_ ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o_ ₄ N[(CH ₂ )i_ ₄ C0 ₂ Ci- ₄ alkyl] ₂ , -(CH ₂ )o^NR ^a CO(isoxazole)-OH, - (CH ₂ )o- ₄ NR ^a S0 ₂ (benzene)-C0 ₂ H, -(CH ₂ )<> ₄ NR ^a SO ₂ (CH ₂ ), ₄ CO ₂ H, -(CH ₂ )o- ₄ NR'SO ₂ (CH ₂ ), 4CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ (CH ₂ )i^(imidazolidine-2, 4-dione), -(CH ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and m is 1, 2, 3, or 4.

[0241] In particular embodiments, the present disclosure provides a compound of formula I-e-2, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF ₃ , -CO ₂ H, -CO ₂ C 1 ₄ alkyl, -CO ₂ Ci- ₄ haloalkyl, or - OH; and m is 1, 2, or 3, particularly 1 or 2.

[0242] In particular embodiments, the present disclosure provides a compound of formula I-e-2, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF ₃ , -methoxy, -(CH ₂ )i sCO ₂ H, -(CH ₂ )i sCO ₂ Ci ₄ alkyl, -(CH ₂ ) _{(t 4} O(CH ₂ )i 5CO ₂ H, -(CH ₂ )o^O(CH ₂ )i- ₅ C0 ₂ Ci- ₄ alkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0243] In certain embodiments, the present disclosure provides a compound of I-e-2, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0244] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A , thereby forming a compound of formula I-e-3:

I-e-3 or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR2)o-eC02R, -(CR2)o-eCONR2, -OR, -(C2 R2) i rOR. -NR2, -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )O-6S0 ₃ R, -(CR2)O-6S0 ₂ NR2, -(CR2)<WOSO ₂ NR2, -(CR ₂ )O-6NRS0 ₂ R, -(CR2)O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR)2, -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0245] In some embodiments, the present disclosure provides a compound of formula I-e-3, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole.

[0246] In particular embodiments, the present disclosure provides a compound of formula I-e-3, wherein Ring C is pyrrolyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptanyl, or oct ahy dr ocy clopent a [b ] pyrroly 1. [0247] In particular embodiments, the present disclosure provides a compound of formula I-e-3, wherein Ring C is 3-hydroxyproline, Ci ealkyl 3-hydroxyproline ester, or Ci r, haloalky I 3-hydroxyproline ester.

[0248] In some embodiments, the present disclosure provides a compound of formula I-e-3, wherein: each R ⁶ is independently fluoro, -CN, methyl, -Cs ecycloalkyl, -CF ₃ , -CO2H, -NH2, -OH, -OCi- ₄ alkyl, =CH ₂ , =O, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i-4OCi- ₄ alkyl, -(CH2)I-4O(CH ₂ )I-5CO ₂ H, -(CH ₂ )i_4O(CH ₂ )i_5CO ₂ Ci- ₄ alkyl, -(CH ₂ )I 4O(CH ₂ ) _M CHFCO ₂ H, -(CH ₂ )I ₄ O(CH ₂ )I 4CHFCO2C1 _ ₄ alkyl, -(CH ₂ ) _M OCH(CH ₃ )(CH ₂ )I^CO ₂ H, -(CH ₂ )I ₄ OCH(CH ₃ )(CH ₂ )I ₄ CO ₂ C1 ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -(CH ₂ )^O(CH ₂ )I 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CHOH(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH-(CH ₂ )MO(CH ₂ )I ₅ CO ₂ Ci 4alkyl, -CHCF ₃ (CH ₂ ) _M O(CH ₂ ) _1-5 CO ₂ H, -CHCF ₃ (CH ₂ ) _M O(CH ₂ ) _1-5 CO ₂ Cwalkyl, -(CH ₂ )o- 4O(CH ₂ )I ₅ CONR ^a ₂ , (CH ₂ )i ₄ O(CH ₂ )I ₅ CONR ^a OH, -(CH ₂ )I -4O(CH ₂ )I ₅ CONR ^a CN, (CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )I ₅ CO ₂ CI ₄ alkyl, -(CH ₂ h 4CHCHCO ₂ H, -(CH ₂ )o_ ₄ CHCHC0 ₂ Ci. ₄ alkyl, -CO ₂ Ci ₄ alkyl, -CO ₂ Ci- ₄ haloalkyl, -OCOCi- ₄ alkyl, - O(CH ₂ )I ₄ CO ₂ H, -O(CH ₂ )I ₄ CO ₂ CI ₄ alkyl, -OCONR ^a (CH ₂ )o^C0 ₂ H, -OCONR ^; '(CH ₂ )o ₄ CO ₂ Ci 4alkyl, -OCO-OV-morpholinc). -CONH ₂ , -CONHOH, -CONHOCi ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CO ₂ H, -(CH2)<> ₄ C(O)NR4CH ₂ )I ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ 4(pyrrolid-2-one), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ ₄ (piperidin-2-one), (CH ₂ )o ₄ C(O)NR ^;I (CH ₂ )I 4C(OH)(CF ₃ ) ₂ , -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i_ ₄ CONH ₂ , -(CH ₂ ) _{0 4} CONR 'SO ₂ CI ₄ haloalkyl, -(CH ₂ )o 4CO(2V-pyrrolidine)-(CH ₂ )t ₄ 4CO ₂ H, -(CH ₂ )o ₄ CO(/V-pyri'olidinc)-(CH ₂ )o ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o- 4(7V-pyrazole)-(CH ₂ )o_ ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(^-pyrazole)-(CH ₂ )o- ₄ C0 ₂ Ci ₄ alkyl, -(CH ₂ )O_ ₄ (1V- pyrrole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(/V-pyrrolc)-(CH ₂ ) _{( 4} CO ₂ Ci _ ₄ alkyl, -(CH ₂ )o-4-0-(phenyl)- (CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ ) _{O 4} -0-(phenyl)-(CH ₂ )o ₄ CO ₂ CI ₄ alkyl, -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- 4CO ₂ H, -(CH ₂ )o-4-0(cycloalkane)-(CH ₂ )o_ ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o- ₄ COO\'-pyiTolidine)-(CH ₂ )o 4SO ₂ NH ₂ , -(CH ₂ )o- ₄ CO(A^-pyrrolidine)-(tetrazole), -(CH ₂ )o ₄ CO(/V-pipci idiiie)-(CH ₂ )o ₄ CO ₂ H, - (CH ₂ )o- ₄ CO(iV-piperidine)-(CH ₂ )o- ₄ C0 ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ CO(W-morpholine)-(CH ₂ )o- ₄ C0 ₂ H, - CONR ^a (bicyclo[l.l.l]pentane)-(CH ₂ )o_ ₄ C0 ₂ H, -NH ₂ , -(CH ₂ )o ₄ NR ^a (CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o_ 4NR ^a (CH ₂ )i_ ₄ CO ₂ Ci 4alkyl, -(CH ₂ )o- ₄ N[(CH ₂ )i_ ₄ C0 ₂ Ci-4alkyl] ₂ , -(CH ₂ )o^NR ^a CO(isoxazole)-OH, - (CH ₂ )o- ₄ NR ^a S0 ₂ (benzene)-C0 ₂ H, -iCH ₂ ) _{() 4} NR ^a SO ₂ (CH ₂ ), ₄ CO ₂ H, -(CH ₂ )o- ₄ NR ^a S0 ₂ (CH ₂ )i- 4CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ (CH ₂ ) _M (imidazolidinc-2,4-dionc), -(CH ₂ )Q_ ₄ OP(O)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and m is 1, 2, 3, or 4. [0249] In particular embodiments, the present disclosure provides a compound of formula I-e-3, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF ₃ , -CO ₂ H, -CO ₂ Ci^alkyl, -CO ₂ Ci-4haloalkyl, or - OH; and m is 1, 2, or 3, particularly 1 or 2.

[0250] In particular embodiments, the present disclosure provides a compound of formula I-e-3, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF ₃ , -methoxy, (CH ₂ )i 5CO ₂ H, (CH ₂ )I sCO ₂ Ci ₄ alkyl, -(CH ₂ )CMO(CH ₂ )I 5CO2H, -(CH ₂ )o^O(CH2)i-5C02Ci 4alkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0251] In certain embodiments, the present disclosure provides a compound of formula I-e-3, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0252] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A

I-e-4 I-e-4* or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitr ogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR2)o-6C0 ₂ R, -(CR ₂ )o-6CONR2, -OR, -(CR ₂ ) I rOR. -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o-6S0 ₂ NR2, -(CR2)O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR) ₂ , -(CR ₂ )O- ₆ P(0)(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(H)OR, -B(0R) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0253] In some embodiments, the present disclosure provides a compound of formula I-e-4 or formula I- e-4*, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole.

[0254] In particular' embodiments, the present disclosure provides a compound of formula I-e-4 or formula I-e-4*, wherein Ring C is pyrrolyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane, 5- azaspiro[2.4]heptanyl, or octahydrocyclopenta[b]pyrrolyl.

[0255] In particular embodiments, the present disclosure provides a compound of formula I-e-4 or formula I-e-4*, wherein Ring C is 3-hydroxyproline, Ci galkyl 3-hydroxyproline ester, or Ci ghaloalkyl 3- bydroxyproline ester.

[0256] In some embodiments, the present disclosure provides a compound of formula I-e-4 or formula I- e-4*, wherein: each R ⁶ is independently fluoro, -CN, methyl, -C3 ccycloalkyl, -CF3, -CO2H, -NH2, -OH, -OCi- ₄ alkyl, =CH ₂ , =O, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i-4OCi- ₄ alkyl, -(CH2)I-4O(CH ₂ )I-5CO ₂ H, -(CH ₂ )i-4O(CH ₂ )i-5CO2Ci-4alkyl, -(CH ₂ )I 4O(CH ₂ ) _M CHFCO ₂ H, -(CH ₂ )I ₄ O(CH ₂ )I 4CHFCO2C1 galkyl, -(CH ₂ ) _M OCH(CH ₃ )(CH ₂ )I^CO ₂ H, -(CH ₂ )1 ₄ OCH(CH3)(CH ₂ )I ₄ CO ₂ C1 ₄ alkyl, -(CH ₂ )wO(CH ₂ )wCH(CH ₃ )CO ₂ H, -(CH ₂ )wO(CH ₂ ),_ 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CHOH(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH-(CH ₂ )I ₄ O(CH ₂ )I 5CO2C1 4alkyl, -CHCF ₃ (CH ₂ )I^O(CH ₂ )I 5CO2H, -CHCF ₃ (CH ₂ ) _M O(CH ₂ )i-5CO ₂ Cwalkyl, -(CH ₂ )o- 4O(CH ₂ )I ₅ CONR ^a 2, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a OH, -(CH ₂ )I ₄ O(CH ₂ )I ₅ CONR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )I 5CO2H, -(CH ₂ )I 5CO2C1 ₄ alkyl, -(CH ₂ ) _{0 4} CHCHCO ₂ H, -(CH ₂ )o_ ₄ CHCHC0 ₂ Ci. ₄ alkyl, -CO ₂ Ci ₄ alkyl, -CO ₂ Ci- ₄ haloalkyl, -OCOCi- ₄ alkyl, - O(CH ₂ )1 ₄ CO ₂ H, -O(CH ₂ )1 ₄ CO ₂ C1 ₄ alkyl, -OCONR ^a (CH ₂ )o^C0 ₂ H, -OCONR^CHJ^COJCI 4alkyl, -OCO-(lV-morpholine), -CONH ₂ , -CONHOH, -CONHOCi ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )i^CO ₂ H, -(CH2)<> 4C(O)NR4CH2)I ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ 4(pyrrolid-2-one), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ ₄ (piperidin-2-one), -(CH ₂ )o ^C(O)NR ^a (CI I ₂ )i- 4C(OH)(CF ₃ ) ₂ , -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i_ ₄ CONH ₂ , -(CH ₂ ) _{0 4} CONR 'SO ₂ CI ₄ haloalkyl, -(CH ₂ )o_ 4CO(/V-pyrrolidmc)-(CH ₂ )o 4CO ₂ H. -(CH ₂ )O- ₄ CO(/V-pyi i'olidinc)-(CH ₂ )o 4CO2C1 ₄ alkyl, -(CH ₂ )o- 4(A^-pyrazole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(A^-pyrazole)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )O- ₄ (1V- pyrrole)-(CH2)o- ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(A^-pyrrole)-(CH ₂ )o- ₄ C02Ci- ₄ alkyl, -(CH ₂ )o-4-0-(phenyl)- (CH ₂ )(v ₄ CO ₂ H, -(CH ₂ )O- ^-0-(phenyl)-(CH ₂ )o- ₄ CO:Ci ₄ alkyl. -(CH ₂ )o-4-0(cycloalkane)-(CH ₂ )o- 4CO2H, -(CH2)o-4-0(cycloalkane)-(CH2)o-4C02Ci-4alkyl, -(CH ₂ )o- -4CO(7V-pyrrolidine)-(CH ₂ )o- 4SO2NH2, -(CH ₂ )o-4CO(A^-pyrrolidine)-(tetrazole), -(CH ₂ )o ₄ CO(/V-pipci idine)-(CH2)o 4CO2H, - Kd [2)0 rCOi/V-pipcridincHCI bJo 4CO2C1 ralkyl, -(CI F lo ₄ CO(/V-moi'pholine)-(Cl l2)o 4CO2I I, - CONR ^a (bicyclo[l.l.l]pentane)-(CH ₂ )o-4C0 ₂ H, -NH ₂ , -(CH ₂ )o- ₄ NRdCH ₂ ) 4CO2H, -(CH ₂ )o- 4NR ^a (CH2)i-4CO ₂ Ci 4alkyl, -(CH ₂ )o_4N[(CH ₂ )i_4C0 ₂ Ci-4alkyl]2, -(CH ₂ )o->NR ^a CO(isoxazole)-OH, - (CH2)o-4NR ^a S0 ₂ (benzene)-C0 ₂ H, -(CH ₂ ) _{(J 4} NR ^a SOdCH ₂ )i ₄ CO ₂ H. -(CH ₂ )<r - ₄ NR ^a SO ₂ (CH ₂ )i_ 4CO ₂ Ci- ₄ alkyl, -(CHjo 4NR\SO ₂ (CH ₂ )i ₄ (imidazolidine-2, 4-dione), -(CH ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and m is 1, 2, 3, or 4.

[0257] In particular embodiments, the present disclosure provides a compound of formula I-e-4 or formula I-e-4*, wherein each R ^fi is independently fluoro, -methyl, cyclohexyl, -CF3, -CO2H, -CO2C1 4alkyl, -CO2C1 rhaloalkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0258] In particular' embodiments, the present disclosure provides a compound of formula I-e-4 or formula I-e-4*, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF3, -methoxy, -(CH ₂ )I 5CO2H, -(CH ₂ )i-5CO ₂ Ci ₄ alkyl, -(CH ₂ )O^O(CH ₂ )I 5CO2H, -(CH2)o^O(CH ₂ )i-5C0 ₂ Cr4alkyl, or -OH; and m is 1 , 2, or 3, particularly 1 or 2.

[0259] In certain embodiments, the present disclosure provides a compound of I-e-4 or formula I-e-4*, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring.

[0260] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A or a pharmaceutically acceptable salt thereof, wherein:

Ring C is pyrrolyl or a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring C) independently selected from nitrogen, oxygen, and sulfur; each R ⁶ is independently halogen, =0, -COR, -(CR2)o-6C0 ₂ R, -(CR ₂ )o-6CONR2, -OR, -(CR ₂ ) I ₄ 0R. -NRz, -(CR ₂ )I-4NR ₂ , -NRC(0)0R, -NRC(0)R, -NRC(0)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o- ₆ S0 ₂ NR ₂ , -(CR ₂ )O- ₆ OS0 ₂ NR ₂ , -(CR ₂ )O- ₆ NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR) ₂ , -(CR ₂ )O-60P(0)(H)OR, -B(0R) ₂ , or R ^B ; m is 1, 2, 3, or 4; and each of R, R ^B , R ³ , and n is as defined above and described in embodiments herein, both singly and in combination.

[0261] In some embodiments, the present disclosure provides a compound of formula I-e-5 or formula I- e-5*, wherein Ring C is azetidinyl, pyrrolyl, 2,3-dihydro-lH-pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiazolidinyl, indolinyl, isoindolinyl, octahydroindolyl, azepanyl, an oxazepane, an azabicyclohexane, an azabicycloheptane, an azabicyclooctane, an azabicyclononane, an azaspiroheptane, or an octahydrocyclicpentapyrrole.

[0262] In particular embodiments, the present disclosure provides a compound of formula I-e-5 or formula I-e-5*, wherein Ring C is pyrrolyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane, 5- azaspiro[2.4]heptanyl, or octahydrocyclopenta[b]pyrrolyl.

[0263] In particular embodiments, the present disclosure provides a compound of formula I-e-5 or formula I-e-5*, wherein Ring C is 3-hydroxyprolinc, Ci ealkyl 3-hydroxyprolinc ester, or Ci ehaloalkyl 3- hydroxyproline ester.

[0264] In some embodiments, the present disclosure provides a compound of formula I-e-5 or I-e-5*, wherein: each R ⁶ is independently fluoro, -CN, methyl, -C3 r, cycloalkyl, -CF3, -CO2H, -NH2, -OH, -OCi- ₄ alkyl, =CH ₂ , =0, tetrazolyl, imidazoyl, thiophenyl, l,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, - (CH ₂ )i-4OCi-4alkyl, -(CH ₂ )I-4O(CH ₂ ) ₁ -5CO ₂ H, -(CHz)i^O(CH ₂ )i-5CO ₂ Ci-4alkyl, -(CH ₂ )I- 4O(CH ₂ )MCHFCO ₂ H, -(CH ₂ )I ₄ O(CH ₂ )I 4CHFCO2C1 _ ₄ alkyl, (CHz^OCHCOHKCHz^COzH, -(CH ₂ )I ₄ OCH(CH ₃ )(CH ₂ )I 4CO2C1 ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -(CH ₂ )I^O(CH ₂ )I 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CH0H(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH-(CH ₂ )MO(CH ₂ )I 5CO2C1 4alkyl, -CHCFdCHji ₄ O(CH2)i 5CO ₂ H. -CHCF ₃ (CH ₂ ) _M O(CHz)i-5COzCMalkyl, -(CH ₂ )o- 4O(CH ₂ )I sCONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I sCONR ^a OH, -(CH ₂ )I ₄ O(CH ₂ )I _s C0NR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -CH(OH)CF ₃ , -COH(CF ₃ ) ₂ , -(CH ₂ )! ₅ CO ₂ H, -(CH ₂ )I _ ₅ CO ₂ CI _ ₄ alkyl, -iCH ₂ ) ₍₎ 4alkyl, -OCO-(N-morpholine), -CONH ₂ , -CONHOH, -CONHOCi ₄ alkyl, -(CH ₂ )o- 4C(O)NR ^a (CH ₂ )^CO ₂ H, -(CH ₂ )o-4C(0)NR ^a (CH ₂ )i- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i_ 4(pyrrolid-2-one), -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ )i_ ₄ (piperidin-2-one), -(CH ₂ )o ₄ C(O)NR ^I (CH ₂ )I 4C(OH)(CF ₃ ) ₂ , -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i_ ₄ CONH ₂ , -(CH ₂ )o- ₄ CONR ^a S0 ₂ Ci ₄ haloalkyl, -(CH ₂ ) _{4 4} COOV-pyrrolidhicHCH ₂ )o ₄ CO ₂ H. -(CH ₂ )O ₄ CC)(/V-pyri'olidinc)-(CH ₂ )o ₄ CC) ₂ C I ₄ alkyl. -(CH ₂ )o- 4(A^pyrazole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(Af-pyrazole)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -('CH ₂ ) ₁ > ₄ (/V- pyrrole)-(CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )o- ₄ CO(/V-pyrrolc)-(CH ₂ ) _{(1 4} CO ₂ Ci _ ₄ alkyl, -(CH ₂ )o-4-0-(phenyl)- (CH ₂ )o- ₄ C0 ₂ H, -(CH ₂ )O ₄ -0-(phcnyl)-(CH ₂ )o ₄ CO ₂ CI ₄ alkyl, -(CH ₂ )o- ₄ -0(cycloalkane)-(CH ₂ )o- 4CO ₂ H, -(CH ₂ )o-4-0(cycloalkane)-(CH ₂ )o- ₄ C0 ₂ Ci- ₄ alkyl, -(CH ₂ )o_ ₄ CO(/V-pyrrolidine)-(CH ₂ )o- 4SO ₂ NH ₂ , -(CH ₂ )o-4CO(A'-pyrrolidine)-(tetrazole), -(CH ₂ )o ₄ CO(/V-pipei idinc)-(CH ₂ )o ₄ CO ₂ H, - (CH ₂ )o- ₄ CO(N-piperidine)-(CH ₂ )o^C0 ₂ Ci ₄ alkyl, -(CH ₂ )o- ₄ CO(Af-morpholine)-(CH ₂ )o- ₄ C0 ₂ H, - CONR ^a (bicyclo[l.l.l]pentane)-(CH ₂ )o- ₄ C0 ₂ H, -NH ₂ , -(CH ₂ )o- ₄ NR ^a (CH ₂ ) ₄ CO ₂ H, -(CH ₂ )o_ 4NR ^a (CH ₂ )i_ ₄ CO ₂ Ci ₄ alkyl, -(CH ₂ ) _0-4 N[(CH ₂ )i_ ₄ CO ₂ Ci- ₄ alkyl] ₂ , -(CH ₂ )o^NR ^a CO(isoxazole)-OH, - (CH ₂ )o- ₄ NR ^a S0 ₂ (benzene)-C0 ₂ H, -(CH ₂ )o. ₄ NR ^a SO ₂ (CH ₂ )i ₄ CO ₂ H. -(CH ₂ )o- ₄ NR ^a SO ₂ (CH ₂ )i 4CO ₂ Ci- ₄ alkyl, -(CH ₂ )o^NR ^a S0 ₂ (CH ₂ )i^(imidazolidine-2, 4-dione), -(CH ₂ )o- ₄ OP(0)(H)OH, wherein R ^a , independently for each occurrence, is H or Ci- ₄ alkyl; and m is 1, 2, 3, or 4.

L0265J In particular embodiments, the present disclosure provides a compound of formula l-e-5 or formula I-e-5*, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF3, -CO ₂ H, -CO ₂ Ci ₄ alkyl, -C0 ₂ Ci- ₄ haloalkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0266] In particular embodiments, the present disclosure provides a compound of formula I-e-5 or formula I-e-5*, wherein each R ⁶ is independently fluoro, -methyl, cyclohexyl, -CF3, -methoxy, -(CH ₂ )I- ₅ CO ₂ H, -(CH ₂ )i- ₅ CO ₂ Ci ₄ alkyl, -(CH ₂ )^O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ ) ₍₄₄ O(CH ₂ )i_5CO ₂ Ci- ₄ alkyl, or -OH; and m is 1, 2, or 3, particularly 1 or 2.

[0267] In certain embodiments, the present disclosure provides a compound of formula I-e-5 or formula I-e-5*, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8- positions with respect to the quinoline ring. [0268] In some embodiments, the present disclosure provides a compound of formula I, wherein Ring A , thereby forming a compound of formula I-f-1 :

I-f-1 or a pharmaceutically acceptable salt thereof, wherein: each R ⁶ is independently halogen, =0, -COR, -(CR2)o-6C0 ₂ R, -(CR ₂ )o-6CONR2, -OR, -(CR ₂ )I rOR. -NR ₂ , -(CR ₂ )I-4NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , -SR, -SO2R, -S(O)R, -(CR ₂ )o-6S0 ₃ R, -(CR ₂ )o-6S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR ₂ , -(CR ₂ )O-6NRS0 ₂ R, -(CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O- 6OP(OR) ₂ , -(CR ₂ )O- ₆ OP(0)(OR)2, -(CR ₂ )O- ₆ P(0)(OR)2, -(CR ₂ )O-60P(0)(H)OR, -B(OR) ₂ , or R ^B ; m is 0, 1, 2, 3, or 4, particularly 1, 2, 3, or 4; and each of R, R ³ , R ^B , and n is as defined above and described in embodiments herein, both singly and in combination.

[0269] In some embodiments, the present disclosure provides a compound of formula I-f-1, wherein R ⁶ is not R ^B .

[0270] In certain embodiments, the present disclosure provides a compound of formula I-f-1, wherein R ³ is independently optionally substituted C1-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0271] In certain embodiments, the present disclosure provides a compound of formula I-f-1, wherein: each R ⁶ is independently halogen, -Ci^alkyl, -Ci-4haloalkyl, =CR ₂ , =0, -COR, -(CR2)o-6C0 ₂ R, -(CR ₂ )O-

₆ CONR ₂ , -OR, -(CR ₂ )I-4OR, -NR ₂ , -(CR ₂ )MNR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)NR ₂ , - SR, -SO2R, -S(O)R, -(CR ₂ )O-6S0 ₃ R, -(CR ₂ )O-6S0 ₂ NR ₂ , -(CR ₂ )O-60S0 ₂ NR2, -(CR ₂ )O-6NRS0 ₂ R, - (CR ₂ )O-6NRS0 ₂ OR, -(CR ₂ )O-60P(OR) ₂ , -(CR ₂ )O-60P(0)(OR) ₂ , -(CR ₂ )O-6P(0)(OR)2, -(CR ₂ )O- 6OP(O)(H)OR, or -B(OR) ₂ ; m is 1, 2, 3, or 4, particularly 1 or 2; and each R ³ is independently optionally substituted Ci-6 aliphatic, such as methyl, or halogen, such as bromo and/or chloro, including dichloro, including wherein n is 2 and R ³ is chloro at the 7- and 8-positions with respect to the quinoline ring.

[0272] In particular embodiments, the present disclosure provides a compound of formula I-f-1, wherein: each R ⁶ is independently halogen, C i ₄ al ky 1 , -Ci- ₄ haloalkyl, =CH2, =0, -tCPbto 4CO2H, (CH2V4CO2C1

₄ alkyl, -(CH ₂ )(MCO2Ci4ialoalkyl, -(CH ₂ )o- ₄ CONH ₂ . -(CH ₂ )o_ ₄ CONHCi ₄ alkyl, -(CH ₂ )<MC0N(CI- 4alkyl) ₂ , -(CH ₂ )o-4CO(A^-proline), -(CH ₂ )o- 4CO(/V-pyrrolidine- 3 -carboxylic acid), -(CH ₂ )o- A(.N- pyrazole)-(CH ₂ )o^C0 ₂ H, -(CH ₂ )o- ₄ CO(A'-pyrazole)-(CH ₂ )o^C0 ₂ Ci- ₄ alkyl, -(CH ₂ ) ₀ ^ _t (A'-pyrrole)- (CH ₂ )O-4C0 ₂ H, -(CH2)o-4CO(/V-pyrrole)-(CH2)o^C0 ₂ Ci 4alkyl, -(CH ₂ WO(phenyl)-(CH ₂ )o- 4CO2H, -(CH ₂ )o-4-0(phenyl)-(CH2)o-4C0 ₂ Ci-4alkyl, -(CH ₂ ) ₀ 4-0<'cycloalkancHCH ₂ )o 4CO2H. - (CH ₂ )o-4-0(cycloalkane)-(CH ₂ )(MC0 ₂ Ci-4alkyl, -(CH ₂ )o^C(0)NR ^a (CH ₂ )i_ ₄ C0 ₂ H, -(CH ₂ )o- 4C(O)NR ^a -CH(C _M alkyl)-CO ₂ H, -(CH ₂ )o_ ₄ C(0)NR ^a (CH ₂ )i ₄ CONH ₂ , -(CH ₂ )o^ ₄ C(0)NR ^a (CH ₂ )i 4CONHCi- ₄ alkyl, -(CH ₂ )o- ₄ C(0)NR ^a (CH ₂ ) _M CON(Ci. ₄ alkyl) ₂ , -OH, -(CH ₂ )i ₄ OH, -(CH ₂ )(MOCI- 4alkyl, -( CH ₂ )O ₄ O(CH ₂ )I ₅ CO ₂ H, -(CH ₂ )^ ₄ O(CH ₂ )I ₅ CO ₂ CI ₄ alkyl, -(CH ₂ )I ₄ O(CH ₂ )I ₄ CHFCO ₂ H, -(CH ₂ ) MO(CH ₂ )I 4CHFCO2C1 ₄ alkyl, -(CH ₂ ) 1.4OC H(C H ₃ )(C H 2) 1 4CO2H . -(CH ₂ ) 1 4OCH(CH ₃ )(CH ₂ )I 4CO2C1 ₄ alkyl, -(CH ₂ ) _M O(CH ₂ )I ₄ CH(CH ₃ )CO ₂ H, -(CH ₂ )MO(CH ₂ )I 4CH(CH ₃ )CO ₂ CI ₄ alkyl, -CH0H(CH ₂ )I ₄ O(CH ₂ )I 5CO2H, -CHOH(CH ₂ )MO(CH ₂ )I 5CO2C1 4alkyl, -CHCF ₃ (CH ₂ )I_4O(CH ₂ )I_ ₅ CO ₂ H, -CHCF ₃ (CH ₂ ) _M O-(CH ₂ )i_5CO ₂ Ci.4alkyl, -(CH ₂ )I_ 4O(CH ₂ )I ₅ CONR ^a ₂ , -(CH ₂ )I ₄ O(CH ₂ )I ₅ C0NR ^a 0H, -(CH ₂ )I ₄ O(CH ₂ )I ₅ C0NR ^a CN, -(CH ₂ )I 4O(CH ₂ )I ₅ P(O)OH ₂ , -NH ₂ , -(CH ₂ ) _{O 4} NR ^a (CH ₂ )i ₄ CO ₂ H, -(CH ₂ )o^NR ^a (CH ₂ ) _M C0 ₂ Ci