OXER1 antagonists and uses thereof

Abstract

Disclosed are compounds of formula (I), wherein ring A is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms, compositions thereof, wherein L1, L2, R1-R4 and m are as defined in claim 1, and methods of their use, for antagonism of the G protein-coupled receptor OXER1 and treatment of OXER1-mediated disorders, such as asthma or cancer. [Formula 1] TIFF2025503491000394.tif43164

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 291,555, filed December 20, 2021, the contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to compounds and methods useful for antagonizing the G protein-coupled receptor OXER1. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Arachidonic acid is an important biological intermediate that is converted into numerous eicosanoids with potent biological activities. Metabolism of arachidonic acid via the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotrienes, such as LTB4, LTC4, and LTD4, as well as 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE). 5-HETE is oxidized to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) by the action of 5-hydroxyeicosanoid dehydrogenase, a microsomal enzyme found in leukocytes and platelets, as well as endothelial and epithelial cells.

[0004] 5-oxo-ETE is a potent chemoattractant for eosinophils and neutrophils, eliciting a variety of rapid responses in these cells. Examples of responses in these cells include actin polymerization, calcium mobilization, integrin expression, L-selectin release, degranulation, and superoxide production, as well as cell migration and tissue infiltration. 5-oxo-ETE's primary target is likely eosinophils, and it is the most potent chemoattractant for these cells among lipid mediators. 5-oxo-ETE has been shown to induce transendothelial migration of eosinophils and induce infiltration of both eosinophils and neutrophils into the skin. 5-oxo-ETE also promotes the survival of eosinophils and other potential types of inflammatory cells, for example, by inducing GM-CSF release from monocytes. 5-oxo-ETE is also a monocyte chemoattractant and has been shown to stimulate the proliferation of prostate tumor cells. Eosinophil migration to body sites, including the skin, lungs, and intestine, is mediated by eosinophil chemoattractants such as 5-oxo-ETE and plays an important role in type 2 inflammation-induced diseases, including skin, respiratory, and gastrointestinal diseases such as asthma, allergic rhinitis, chronic obstructive pulmonary disorder, atopic dermatitis, psoriasis, and acne. Eosinophil migration has also been shown to be involved in certain cancers, such as prostate cancer.

[0005] OXER1 is a G protein-coupled receptor (GPCR) that is highly selective for 5-oxo-ETE. It is also known as G protein-coupled receptor 170 (GPR170), hGPCR48, HGPCR48, and R527. The interaction of 5-oxo-ETE with OXER1 is an important mediator of eosinophil migration. Selective OXER1 antagonists may serve as therapeutic or prophylactic agents for the above diseases. Summary of the Invention

[0006] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as antagonists of OXER1. In certain embodiments, the present invention provides compounds of the formulae presented herein.

[0007] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with OXER1, including those described herein.

[0008] The solvent is evaporated under reduced pressure, and the compounds provided by the present invention are also useful for studying OXER1 in biological and pathological phenomena; studying eosinophil migration to body sites including the skin, lungs, and intestines; and for the in vitro or in vivo comparative evaluation of new OXER1 inhibitors or other eosinophil migration modulators. DETAILED DESCRIPTION OF THE INVENTION

[0009] 1. Details of Specific Embodiments of the Invention: In certain embodiments, the present invention provides a compound of formula I: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, 1 , L 2 , R 1 , R 2 , R 3 , R 4 Each of and m, both alone and in combination, is as defined below and described in the embodiments herein.

[0010] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0011] In some embodiments, the present invention provides a method for treating an OXER1-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula I or an N-oxide or a pharmaceutically acceptable salt thereof.

[0012] 2. Compounds and Definitions: The compounds of the present invention include those compounds generally described herein and further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Further, general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0013] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation; or a monocyclic or bicyclic hydrocarbon (also referred to herein as a "carbocycle," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. According to the IUPAC definition, a "bridge" is an unbranched chain of atoms, atom, or valence bond connecting two bridgeheads, where a "bridgehead" refers to any skeletal atom of the ring system that is attached to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, the substitutable nitrogen of a bridged bicyclic group is optionally substituted. Examples of bridged bicyclic groups include: [ka]

[0015] The term "lower alkyl" refers to C 1~4 Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1~4 refers to a straight or branched chain alkyl group.

[0017] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (in the case of N-substituted pyrrolidinyl)).

[0018] As used herein, the term "unsaturated" means that any moiety has one or more units of unsaturation.

[0019] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0020] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0021] The term "alkenylene" refers to a divalent 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 substituted aliphatic groups.

[0022] The term "halogen" means F, Cl, Br, or I.

[0023] The term "oxo" refers to an "=O" substituent. For example, a cyclopentane substituted with an oxo group is a cyclopentanone.

[0024] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which 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 invention, "aryl" refers to an aromatic ring system, such as, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl" as used herein.

[0025] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, for example, "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, in which 6, 10, or 14 π electrons are shared in a cyclic arrangement, and in addition to carbon atoms, have 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0026] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety, either saturated or partially unsaturated, having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in saturated or partially unsaturated rings having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (e.g., 3,4-dihydro-2H-pyrrolyl), NH (e.g., pyrrolidinyl), or +NR (e.g., N-substituted pyrrolidinyl).

[0027] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocycle groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0028] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0029] A partially aromatic bicyclic ring refers to a bicyclic ring in which one ring of the bicyclic ring is aromatic and the other ring of the bicyclic ring is not aromatic.

[0030] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogen atoms of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure can be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph (which may be substituted by R°); -(CH2) 0-4 O(CH2)0-1 Ph (which may be substituted with R°); -CH=CHPh (which may be substituted with R°); -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which may be substituted by R°); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-N(R°)C(NR°)N(R°) 2; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4(linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) are each independently halogen, —(CH2), 0-2 R · ,-(Halo R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · , -(CH2) 0-2 CH(OR · )2;-O(HaloR · ), -CN, -N3, -(CH2) 0-2 C(O)R · , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · , -(CH2) 0-2 SR · , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · , -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · , -(C 1~4 Linear or branched alkylene)C(O)OR · , or -SSR· where each R · is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph is independently selected from a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0033] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, wherein R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below 1~6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] R * Suitable substituents on the aliphatic group include halogen, -R · ,-(Halo R ·), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2, or -NO2, where each R · is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] R †Suitable substituents on the aliphatic group are independently halogen, —R · ,-(Halo R · ), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2, or -NO2, where each R · is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the normal scope of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et 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 the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of salts include phosphate, 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, and valerate.

[0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+ (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0039] 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 of each asymmetric center, Z and E double bond isomers, Z and E structural isomers, etc. Accordingly, single stereochemical isomers of the present compounds, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures, are within the scope of the invention. Unless otherwise stated, all tautomers of the present compounds are within the scope of the invention. Furthermore, 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, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, including the replacement of carbons with C-rich carbohydrates, are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0040] In certain embodiments, R of the provided compounds 1 contains one or more deuterium atoms. In certain embodiments, R of provided compounds 2 contains one or more deuterium atoms. In certain embodiments, R of provided compounds 3 contains one or more deuterium atoms. In certain embodiments, R of provided compounds 4contains one or more deuterium atoms. In certain embodiments, R of provided compounds 5 contains one or more deuterium atoms. In certain embodiments, L of provided compounds 1 contains one or more deuterium atoms. In certain embodiments, L of provided compounds 2 contains one or more deuterium atoms. In certain embodiments, L of provided compounds 3 contains one or more deuterium atoms. In certain embodiments, ring A of provided compounds contains one or more deuterium atoms. In certain embodiments, ring B of provided compounds contains one or more deuterium atoms. In certain embodiments, ring C of provided compounds contains one or more deuterium atoms. In certain embodiments, R of provided compounds can be substituted with one or more deuterium atoms. In certain embodiments, R of provided compounds can be substituted with one or more deuterium atoms. z may be substituted with one or more deuterium atoms.

[0041] Drawn structures represent relative configuration unless indicated as absolute configuration. The present invention contemplates individual enantiomers and racemic mixtures. Diastereomeric mixtures are also contemplated.

[0042] As used herein, an "OXER1 antagonist" or "OXER1 inhibitor" refers to a molecule that reduces, inhibits, or otherwise decreases one or more of the biological activities of OXER1 (e.g., Gαi signaling, increased immune cell migration, and secretion of pro-inflammatory cytokines). Antagonism using an OXER1 antagonist does not necessarily indicate complete elimination of OXER1 activity. Instead, activity may be reduced by a statistically significant amount, such as at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in OXER1 activity compared to an appropriate control. In some embodiments, an OXER1 antagonist reduces, inhibits, or otherwise decreases OXER1 activity. The compounds disclosed herein bind directly to OXER1 and inhibit its activity.

[0043] By "specific antagonist" is meant an agent that reduces, inhibits, or decreases the activity of a defined target to a greater extent than the activity of an unrelated target. For example, an OXER1-specific antagonist reduces at least one biological activity of OXER1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCR). In some embodiments, the IC of the antagonist for the target is 50 is the IC of the antagonist against the non-target 50The IC of the OXER1 antagonist is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or less. The compounds disclosed herein may or may not be specific OXER1 antagonists. A particular OXER1 antagonist reduces the biological activity of OXER1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCR). In certain embodiments, the OXER1 antagonist specifically inhibits the activity of OXER1. In some of these embodiments, the IC of the OXER1 antagonist for OXER1 is 50 The IC of OXER1 antagonists on closely related GPCRs (e.g., free fatty acid receptors (FFARs) such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other types of GPCRs (e.g., class A GPCRs) 50 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the

[0044] The compounds of the present invention may be tethered to a detectable moiety. It will be understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that the detectable moiety can be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to the detectable moiety. Such moieties are well known to those skilled in the art and include groups containing carboxylate, amino, thiol, or hydroxyl moieties, to name just a few. It will be understood that such moieties can be attached directly to the provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57. In some embodiments, such moieties may be attached via strained alkynes. Methods using strained alkynes to enable rapid Cu-free click chemistry are known in the art and include those described by Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

[0045] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that is detectable, such as primary labels and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0046] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to produce a detectable signal. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. In the case of antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), which then generates a detectable signal.

[0047] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, the Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPYFL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591), BODIPY630 / 650, BODIPY650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2 ',7'-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0048] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Patent Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A variety of neutral and charged organic molecules (biomolecules or synthetic compounds) in the appropriate mass range (100-2000 daltons) can also be used as mass tags.

[0049] The compounds of the present invention can be tethered to E3 ligase binding moieties.It will be understood that such compounds are useful as decomposition agents (see, for example, Kostic and Jones, Trends Pharmacol. Sci., 2020, 41(5), 305-31; Ottis and Crews, ACS Chem. Biol. 2017, 12(4), 892-898).Those skilled in the art will recognize that E3 ligase binding moieties can be attached to provided compounds via suitable substituents as defined above.Such decomposition agents have been found to be useful for targeting degradation of G protein-coupled receptors (Li et al.Acta Pharm. Sin. B. 2020, 10(9), 1669-1679).

[0050] As used herein, the term "E3 ligase binding moiety" is used interchangeably with the term "E3 ligase binder" and relates to any moiety that is capable of binding to and / or recruiting an E3 ligase (e.g., cIAP1, MDM2, cereblon, VHL, APC / C) for targeted degradation.

[0051] The compounds of the present invention can be tethered to lysosome targeting moieties. It will be understood that such compounds are useful as degraders (see, for example, Banik et al. 2020. Nature 584, 291-297). Those skilled in the art will recognize that lysosome targeting moieties can be attached to the provided compounds via suitable substituents as defined above. Such degraders have been found to be useful for targeted degradation of secretory proteins and membrane proteins (Banik et al. 2020).

[0052] As used herein, the term "lysosome targeting moiety" is used interchangeably with the term "lysosome binding moiety" and relates to any moiety that is capable of binding to and / or recruiting a cell surface lysosome targeting receptor (e.g., cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

[0053] As used herein, the terms "measurable affinity" and "measurable inhibition" refer to a measurable change in OXER1 activity between a sample containing a compound of the present invention or a composition thereof and OXER1 GPCR and an equivalent sample containing OXER1 GPCR in the absence of the compound or composition thereof.

[0054] As used herein, the words "a" and "an" mean "one or more" and include the plural forms unless the context requires otherwise.

[0055] Throughout this specification, when compositions are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is further contemplated that compositions of the present invention consist essentially of, or consist of, the recited components, and processes and methods according to the present invention consist essentially of, or consist of, the recited processing steps.

[0056] As a general matter, compositions specifying percentages are by weight unless otherwise specified.

[0057] 3. Description of Exemplary Embodiments As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein: Ring A is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; L 1 is one of the following: (a) a C1-5 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) Covalent bonding; each R is independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally join together to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is independently an optionally substituted divalent ring selected from a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, or a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2 is one of the following: (a) a C1-7 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -CH(F)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) Covalent bonding; R 1 is (i) —C(O)OR, —C(O)N(R)S(O)R, —C(O)N(R)OR, —C(O)NR, —CN, —OH, and hydrogen; (ii) 5-6 membered partially unsaturated oxo-heterocyclyl (n R 5and (iii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (n instances of R 5 (replaced with instances of ); R 2 is one of the following: (a) phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered saturated or partially unsaturated spirocycle having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered aromatic or partially aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (each of which is selected from p R 6 replaced with instances of ); or (b) C1-7 aliphatic, -C≡CR, -C(O)OR, or -C(O)R (each of which has p R 6 replaced with instances of ); or (c) hydrogen; R 3 is one of the following: (a) a C1-6 aliphatic group optionally substituted with one or more -OH or -N(R)2; (b)-CD3; (c) hydrogen; or (d) Absence; R 4 Each instance of is independently hydrogen, deuterium, or R z, -C≡CR, halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2 (CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N( -R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or The Two R's 4 the groups optionally taken together form =O; or The Two R's 4 groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 and R 6 Each instance of is independently hydrogen, deuterium, or R z , halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C (O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or The Two R's5 the groups optionally taken together form =O; The Two R's 6 the groups optionally taken together form =O; The Two R's 5 groups, optionally taken together with their intervening atoms, form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's 6 groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z each instance is independently selected from an optionally substituted group selected from C1-6 aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; However, L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is n-hexyl, [ka] rather than; L 1-R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is not n-hexyl).

[0058] As generally defined above, Ring A is an 8- to 10-membered aromatic or partially aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl.

[0059] In some embodiments, ring A is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl.

[0060] In some embodiments, R 4 , R 3 , -C(O)-L 1 -R 1 , and -L 2 -R 2 Ring A substituted with [ka] [ka] is.

[0061] In some embodiments, ring A is selected from those shown in Table 1 below.

[0062] As generally defined above, L 1 is any one of the following: (a) a C1-5 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) a covalent bond.

[0063] In some embodiments, L 1 is a C1-5 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0064] In some embodiments, L 1 is a C1-5 divalent straight or branched saturated hydrocarbon chain. 1 teeth, [ka] is.

[0065] In some embodiments, L 1 is a C1-5 divalent linear or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is replaced with -Cy-, where Cy is a divalent ring selected from a 4-7 membered saturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 teeth, [ka] is.

[0066] In some embodiments, L 1 is a covalent bond.

[0067] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] is.

[0068] In some embodiments, L 1 is selected from those shown in Table 1 below.

[0069] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from C aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0070] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C1-6 aliphatic. In some embodiments, R is phenyl. In some embodiments, R is an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocycle. In some embodiments, R is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0071] Two R groups on the same nitrogen, as generally defined above, can optionally be joined together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0072] In some embodiments, two R groups on the same nitrogen are optionally joined together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0073] In some embodiments, R is selected from those shown in Table 1 below.

[0074] As generally defined above, each -Cy- is independently an optionally substituted divalent ring selected from a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, or a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0075] In some embodiments, -Cy- is an optionally substituted divalent ring selected from a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] In some embodiments, -Cy- is phenylenyl.

[0077] In some embodiments, -Cy- is a 3- to 7-membered saturated or partially unsaturated carbocyclyl or a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, -Cy- is selected from those shown in Table 1 below.

[0079] As generally defined above, L 2 is any one of the following: (a) a C1-7 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -CH(F)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) a covalent bond.

[0080] In some embodiments, L 2is a C1-7 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -CH(F)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0081] In some embodiments, L 2 is a C1-7 divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is replaced with -O-. 2 is -(CH2) 3-4 -O-(CH2) 1-2 In some embodiments, L 2 is -(CH2) 3-4 In some embodiments, L 2 is a C1-7 divalent straight or branched unsaturated hydrocarbon chain. 2 is a C1 divalent linear unsaturated hydrocarbon chain.

[0082] In some embodiments, L 2 is a covalent bond.

[0083] In some embodiments, L 2 teeth, [ka] [ka] is.

[0084] In some embodiments, L 2 is selected from those shown in Table 1 below.

[0085] As generally defined above, R 1is (i) —C(O)OR, —C(O)N(R)S(O)R, —C(O)N(R)OR, —C(O)NR, —CN, —OH, and hydrogen; (ii) 5-6 membered partially unsaturated oxo-heterocyclyl (n R 5 and (iii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (n instances of R 5 are selected from the

[0086] In some embodiments, R 1 is selected from (i) —C(O)OR, —C(O)N(R)S(O)R, —C(O)N(R)OR, —C(O)NR, —CN, —OH, and hydrogen. 1 is a 5-6 membered partially unsaturated oxo-heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and n R 5 In some embodiments, R 1 is a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and n R 5 is replaced with an instance of

[0087] In some embodiments, R 1 is (i) —C(O)OR, —C(O)N(R)S(O)R, and —C(O)N(R)OR; and (ii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (n R 5 are selected from the

[0088] In some embodiments, R 1 is —C(O)OR. In some embodiments, R 1 is —C(O)N(R)S(O)R. In some embodiments, R 1is —C(O)N(R)OR. In some embodiments, R 1 is a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and n R 5 is replaced with an instance of In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is —C(O)NR. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is -CN. In some embodiments, R 1 is —OH. In some embodiments, R 1 is hydrogen.

[0089] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0090] As generally defined above, R 2 is one of the following: (a) phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered saturated or partially unsaturated spirocycle having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered aromatic or partially aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (each of which is selected from p R 6 replaced with instances of ); or (b) C1-7 aliphatic, -C≡CR, -C(O)OR, or -C(O)R (each of which has p R 6 replaced with instances of ); or (c) Hydrogen.

[0091] In some embodiments, R 2 is phenyl and p R 6 In some embodiments, R 2 is a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and p R 6 In some embodiments, R 2 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, and p R 6 In some embodiments, R 2 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and p R 6 In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and p R 6In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated spiro ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and p R 6 In some embodiments, R 2 is an 8- to 10-membered aromatic or partially aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and p R 6 In some embodiments, R 2 is a C1-7 aliphatic and p R 6 In some embodiments, R 2 is -C≡CR. In some embodiments, R 2 is —C(O)OR. In some embodiments, R 2 is —C(O)R. In some embodiments, R 2 is hydrogen.

[0092] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0093] In some embodiments, R 2 is -C≡CR. In some embodiments, R 2 is -C≡C- (a 3- to 7-membered saturated monocyclic carbocyclic ring substituted with 1 or 2 halo groups). In some embodiments, R 2 is -C≡C- (cyclobutyl substituted with one or two halo groups).

[0094] In some embodiments, R 2is selected from those shown in Table 1 below.

[0095] As generally defined above, R 3 is any one of the following: (a) a C1-6 aliphatic group optionally substituted with one or more -OH or -N(R)2; (b) -CD3; (c) hydrogen; or (d) absent.

[0096] In some embodiments, R 3 is a C aliphatic group optionally substituted with one or more -OH or -N(R). In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CD3. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 is absent.

[0097] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0098] As generally defined above, R 4 Each instance of is independently hydrogen, deuterium, or R z, -C≡CR, halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR 2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N= S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0099] In some embodiments, R 4 is hydrogen, deuterium, R z , -C≡CR, halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR 2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N= S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0100] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -CF3. In some embodiments, R 4 is —OCH. In some embodiments, R 4is -OCF3. In some embodiments, R 4 is -CN. In some embodiments, R 4 teeth, [ka] is.

[0101] As generally defined above, the two R 4 The groups optionally taken together form =O.

[0102] In some embodiments, two R 4 The groups optionally taken together form =O.

[0103] As generally defined above, the two R 4 The groups optionally together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] In some embodiments, two R 4 The groups optionally together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0106] As generally defined above, R 5 and R 6 Each instance of is independently hydrogen, deuterium, or R z, Halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN ), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N( R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S( O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0107] In some embodiments, R 5 is hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN ), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N( R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S( O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0108] As generally defined above, the two R 5 The groups optionally taken together form =O.

[0109] In some embodiments, two R 5 The groups optionally taken together form =O.

[0110] As generally defined above, the two R 5 The groups optionally together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0111] In some embodiments, two R 5 The groups optionally together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0113] In some embodiments, R 6 is hydrogen, deuterium, R z , Halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN ), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N( R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S( O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0114] As generally defined above, the two R 6 The groups optionally taken together form =O.

[0115] In some embodiments, two R 6The groups optionally taken together form =O.

[0116] As generally defined above, the two R 6 The groups optionally together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0117] In some embodiments, R 4 and R 6 each independently for each occurrence represents hydrogen, halogen, or C1-6 aliphatic.

[0118] In some embodiments, two R 6 The groups optionally together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0119] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0120] As generally defined above, R z is independently selected from an optionally substituted group selected from C aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments, R zare independently selected from optionally substituted groups selected from C aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0122] In some embodiments, R z is selected from those shown in Table 1 below.

[0123] As generally defined above, m is 0, 1, 2, 3, or 4.

[0124] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0125] In some embodiments, m is selected from those shown in Table 1 below.

[0126] As generally defined above, n is 0, 1, 2, 3, or 4.

[0127] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0128] In some embodiments, n is selected from those shown in Table 1 below.

[0129] As generally defined above, p is 0, 1, 2, 3, or 4.

[0130] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0131] In some embodiments, p is selected from those shown in Table 1 below.

[0132] In some embodiments, L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is C 3-6 Alkyl, [ka] rather than; However, L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is C 3-6 Not alkyl.

[0133] In some embodiments, L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is C 3-8 Alkyl, [ka] rather than; However, L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is C 3-8 Not alkyl.

[0134] In some embodiments, the invention provides a compound of formula I, wherein ring A is indolyl, azaindolyl, benzothiophenyl, or benzofuranyl, and a compound of formula Ia-1, Ia-2, Ia-3, or Ia-4: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0135] In some embodiments, the present invention provides compounds of formula I, wherein L 1 is 2-methylpropylene, and a compound of formula Ib-1, Ib-2, or Ib-3: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 2 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0136] In some embodiments, the present invention provides compounds of formula I, wherein L 1 is pyrrolidinyl, piperidinyl, or azetidinyl, and provides a compound of formula Ib-4, Ib-5, or Ib-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 2 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0137] In some embodiments, the present invention provides compounds of formula I, wherein L 2 is a C alkylene optionally substituted with one —OH or —F, and is a compound of formula Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Ic-8, Ic-9, or Ic-10: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L1 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0138] In some embodiments, the present invention provides compounds of formula I, wherein L 2 teeth, [ka] and a compound of formula Ic-11, Ic-12, Ic-13, or Ic-14: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 1 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0139] In some embodiments, the present invention provides compounds of formula I, wherein L 1 is hexylene, and one methylene unit of the chain is independently replaced with —O—, to form a compound of formula Ic-15, Ic-16, Ic-17, Ic-18, or Ic-19: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 1 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0140] In some embodiments, the present invention provides compounds of formula I, wherein L 1 teeth, [ka] and a compound of formula Ic-20, Ic-21, or Ic-22: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 1 , R 1 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0141] In some embodiments, the present invention provides compounds of formula I, wherein R 1 is carboxyl, tetrazolyl, or [ka] and a compound of formula Id-1, Id-2, or Id-3: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 1 , L 2 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0142] In some embodiments, the present invention provides compounds of formula I, wherein R 2 is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is selected from p R 6and a compound of formula Ie-1, Ie-2, Ie-3, or Ie-4, substituted with an instance of: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 1 , L 2 , R 1 , R 3 , R 4 , R 6 Each of m, p, and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0143] In some embodiments, the present invention provides compounds of formula I, wherein R 2 is methyl, ethyl, isopropyl, tert-butyl, -CF3, or [ka] and a compound of formula Ie-5, Ie-6, Ie-7, Ie-8, Ie-9, or Ie-10: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein rings A, L 1 , L 2 , R 1 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0144] In some embodiments, the present invention provides a compound of Formula I, wherein the compound has formula If-1, If-2, If-3, If-4, If-5, or If-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R 4 , R6 Each of p, and p, both alone and in combination, is as defined above and described in the embodiments herein.

[0145] In some embodiments, the invention provides a compound of Formula I, wherein the compound has formula Ig-1, Ig-2, Ig-3, Ig-4, Ig-5, or Ig-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 6 Each of p, and p, both alone and in combination, is as defined above and described in the embodiments herein.

[0146] In some embodiments, the invention provides a compound of Formula I, wherein the compound has formula Ih-1, Ih-2, Ih-3, Ih-4, Ih-5, or Ih-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 6 Each of p, and p, both alone and in combination, is as defined above and described in the embodiments herein.

[0147] In some embodiments, the present invention provides a compound of Formula I, wherein the compound has formula Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, or Ii-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R, R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0148] In some embodiments, the invention provides a compound of Formula I, wherein the compound has formula Ij-1, Ij-2, Ij-3, Ij-4, Ij-5, or Ij-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , R 6 Each of m, p, and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0149] In some embodiments, the invention provides a compound of Formula I, wherein the compound has formula Ij-7, Ij-8, Ij-9, Ij-10, Ij-11, or Ij-12: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , R 6 Each of m, p, and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0150] In some embodiments, the invention provides a compound of Formula I, wherein the compound has formula Ik-1, Ik-2, Ik-3, Ik-4, Ik-5, or Ik-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , R 6 Each of m, p, and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0151] In some embodiments, the present invention provides a compound of Formula I, wherein the compound has formula Iq-1, Iq-2, Iq-3, Iq-4, Iq-5, or Iq-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 2 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0152] In some embodiments, the present invention provides a compound of Formula I, wherein the compound has any one of formulas Iq-7, Iq-8, Iq-9, or Iq-10: [ka] or a pharmaceutically acceptable salt thereof, wherein L 2 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0153] In some embodiments, the present invention provides a compound of Formula I, wherein the compound has the formula Iq-11: [ka] or a pharmaceutically acceptable salt thereof, wherein L 2 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0154] In some embodiments, the present invention provides a compound of Formula I, wherein the compound has formula Ir-1, Ir-2, Ir-3, Ir-4, Ir-5, or Ir-6: [ka] or N-oxide, or a pharmaceutically acceptable salt thereof, wherein L 2 , R 2 , R 3 , R 4 Each of , and m, both alone and in combination, is as defined above and described in the embodiments herein.

[0155] In some embodiments, the present invention provides a compound of formula I, wherein the compound has any one of formulas Ir-7, Ir-8, Ir-9: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above and described in the embodiments herein.

[0156] In some embodiments, the present invention provides a compound of formula I, wherein the compound has formula Ir-10: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above and described in the embodiments herein.

[0157] Another aspect of the present invention provides a compound of formula I-1: [ka] or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein: Ring A is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; L 1 is one of the following: (a) a C1-5 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) Covalent bonding; each R is independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally join together to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is independently an optionally substituted divalent ring selected from a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, or a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2is one of the following: (a) a C1-7 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -Cy-, -C(R)2-, -CH(R)-, -CH(OR)-, -CH(F)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) Covalent bonding; R 1 is (i) —C(O)OR, —C(O)N(R)S(O)R, and —C(O)N(R)OR; and (ii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (n R 5 (replaced with instances of ); R 2 is one of the following: (a) phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered saturated or partially unsaturated spirocycle having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered aromatic or partially aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (each of which is selected from p R 6 replaced with instances of ); or (b) C1-7 aliphatic, -C≡CR, -C(O)OR, or -C(O)R (each of which has p R 6 replaced with instances of ); or (c) hydrogen; R 3 is one of the following: (a) a C1-6 aliphatic group optionally substituted with one or more -OH or -N(R)2; (b)-CD3; (c) hydrogen; or (d) Absence; R 4 Each instance of is independently hydrogen, deuterium, or R z , -C≡CR, halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2 (CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N( -R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or The Two R's 4 the groups optionally taken together form =O; or The Two R's 4 groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 and R 6 Each instance of is independently hydrogen, deuterium, or R z, halogen, -CN, -NO2, -OR, -OCF3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C (O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or The Two R's 5 the groups optionally taken together form =O; The Two R's 6 the groups optionally taken together form =O; The Two R's 5 groups, optionally taken together with their intervening atoms, form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's 6 groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R z each instance is independently selected from an optionally substituted group selected from C1-6 aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; However, L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is n-hexyl, [ka] rather than; L 1 -R 1 but [ka] and R 3 and R 4 Ring A containing the substituent of [ka] If L 2 -R 2 is not n-hexyl).

[0158] In certain embodiments, the variable moiety R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , ring A, or m is one of the embodiments described above in connection with formula I.

[0159] In certain embodiments, the compound has the advantage of having low binding affinity to plasma proteins in a subject. Low binding affinity to plasma proteins allows for a high concentration of free compound in the subject, resulting in a superior therapeutic effect. The binding of the compound to plasma proteins can be analyzed according to procedures described in the literature for assessing the binding of compounds to plasma proteins.

[0160] Exemplary compounds of the present invention are set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

[0161] In some embodiments, the present invention provides a compound shown in Table 1 above, or an N-oxide, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound shown in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound shown in Table 1 above, or an N-oxide, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0162] In some embodiments, the present invention provides a compound selected from compounds I-13 to I-304 shown in Table 1 above. In some embodiments, the present invention provides a compound selected from compounds I-305 to I-467 shown in Table 1 above. In some embodiments, the present invention provides a compound selected from compounds I-13 to I-304 shown in Table 1 above, or an N-oxide, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound selected from compounds I-305 to I-467 shown in Table 1 above, or an N-oxide, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound selected from compounds I-13 to I-304 shown in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound selected from compounds I-305 to I-467 shown in Table 1 above, or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound selected from compounds I-13 to I-304 shown in Table 1 above, or an N-oxide, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides pharmaceutical compositions comprising a compound selected from compounds I-305 to I-467 shown in Table 1 above, or an N-oxide, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0164] In some embodiments, the present invention provides a compound of formula I, or an N-oxide, or a pharmaceutically acceptable salt thereof, as defined above, or a pharmaceutical composition comprising a compound of formula I, or an N-oxide, or a pharmaceutically acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for use as a medicament, as defined above.

[0165] In the chemical structures in Table 1 above and in the Examples below, stereocenters are described according to the Enhanced Stereo Representation format (MDL / Biovia, e.g., using the labels "or1", "or2", "abs", "and1").

[0166] Additional exemplary compounds include those set forth in the table below: In certain embodiments, the compound may be a compound in the table below, or an N-oxide, or a pharmaceutically acceptable salt thereof. [ka] [ka]

[0167] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound shown in the table above, or an N-oxide, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0168] In some embodiments, the present invention provides a compound of the table above, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the table above, or an N-oxide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for use as a medicament.

[0169] In some embodiments, the present invention also provides a compound of formula I as described herein, or a pharmaceutical composition as described herein, for use in a method for inhibiting OXER1 as described herein, a method for regulating an immune response in a subject in need thereof as described herein, and / or a method for treating an OXER1-dependent disorder as described herein.

[0170] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method for inhibiting OXER1 as described herein.

[0171] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method for modulating an immune response in a subject in need thereof, as described herein.

[0172] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method for treating an OXER1-dependent disorder as described herein.

[0173] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for inhibiting OXER1, for modulating an immune response in a subject in need thereof, and / or for treating an OXER1-dependent disorder.

[0174] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for inhibiting OXER1.

[0175] In some embodiments, the present invention also provides the use of a compound of Formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for modulating an immune response in a subject in need thereof.

[0176] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for treating an OXER1-dependent disorder.

[0177] In some embodiments, the present invention also provides the use of a compound of formula I as described herein, or a pharmaceutical composition as described herein, in a method for inhibiting OXER1 as described herein, a method for regulating an immune response in a subject in need thereof as described herein, and / or a method for treating an OXER1-dependent disorder as described herein.

[0178] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for inhibiting OXER1 as described herein.

[0179] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for modulating an immune response in a subject in need thereof.

[0180] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for treating an OXER1-dependent disorder as described herein.

[0181] General Methods for Providing Compounds of the Invention The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds, and as described in detail in the Examples herein.

[0182] 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to measurably inhibit OXER1 or a mutant thereof in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably inhibit OXER1 or a mutant thereof in a biological sample or a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0183] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0184] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0185] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention, or an inhibitory active metabolite or residue thereof.

[0186] As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of OXER1 or a mutant thereof.

[0187] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of the present invention. Thus, metabolites include compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce its metabolic product. When the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, etc. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Specific examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0188] The compounds of the present invention may be in the form of a "prodrug," which includes compounds having moieties that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted to esters by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkylamino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In some embodiments, the compounds of the present invention are prodrugs of any of the formulas described herein.

[0189] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0190] For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0191] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings, or coloring agents can also be added.

[0192] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0193] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0194] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0195] For topical application, pharmaceutically acceptable compositions can be formulated into a suitable ointment, containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, pharmaceutically acceptable compositions can be formulated into a suitable lotion or cream, containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0196] For ophthalmic use, pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions may be formulated into an ointment, such as petrolatum.

[0197] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0198] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0199] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, the provided compositions are formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0200] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the patient's age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular compound in the composition.

[0201] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for inhibiting the signaling activity of one or more GPCRs. In some embodiments, the GPCR inhibited by the compounds and methods of the invention is OXER1.

[0202] The compounds disclosed herein find use in inhibiting the activity of OXER1, a G protein-coupled receptor (GPCR) that is highly selective for 5-oxo-ETE.

[0203] Arachidonic acid metabolites, such as 5-oxo-ETE and other eicosanoids, are potent chemoattractants for eosinophils and neutrophils. The effects of these eicosanoids are mediated by approximately 20 G protein-coupled receptors, exerting a variety of both harmful and beneficial effects on airway smooth muscle and inflammatory cells, making them strongly implicated in the pathophysiology of asthma (Powell, Clinical Science (2021), 135, 1945-1980). Eicosanoids stimulate various responses in these cells, including actin polymerization, calcium mobilization, integrin expression, and degranulation (Powell and Rokach, Progress in Lipid Research 52:651-665 (2013)). The biological effects of 5-oxo-ETE are mediated by highly selective OXE receptors, such as OXER1, which are expressed on various inflammatory and tumor cells. Eicosanoids acting through OXE receptors, such as OXER1, induce the migration of eosinophils and neutrophils. Eosinophils are the primary effector cells in the immune system and are part of the innate immune system. Upon activation, eosinophils release a cocktail of cytotoxic proteins and cytokines from eosinophil granules. Eosinophils play an important role in type 2 proinflammatory diseases, likely helping to control the type of immune response that occurs. Cytokines such as IL-4, IL-13, and IL-25 are found within eosinophil granules. These induce Th2-polarized responses associated with asthma and other allergic and inflammatory diseases. Activated eosinophils also release lipid mediators, which can cause airway smooth muscle contraction and contribute to airway hyperresponsiveness.Abnormally activated eosinophils are known to be present in patients with severe asthma and other eosinophil-related diseases (Klion, AD, Ackerman, SJ & Bochner, BS Contributions of Eosinophils to Human Health and Disease. Annu. Rev. Pathol. Mech. Dis. 15, 179-209 (2020); Ramirez, GA et al. Eosinophils from Physiology to Disease: A Comprehensive Review. Biomed Res Int 2018, e9095275 (2018)).

[0204] The 5-oxo-ETE / OXER1 axis plays an important role in both cell migration and cell survival, and in the development of diseases involving eosinophils and neutrophils, including various inflammatory diseases and cancers. In one embodiment, the present invention provides compounds, combinations, compositions, and methods as defined herein that can inhibit eosinophil and neutrophil migration. Accordingly, the present invention also encompasses the treatment or prevention of disease states that can be alleviated by inhibiting eosinophil or neutrophil migration.

[0205] 5-oxo-ETE has been shown to play an important role in allergen-induced eosinophilia. Blocking its action with the OXER1 antagonist S-Y048 may provide a novel therapeutic approach for eosinophilic disorders (Inhibition of allergen-induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non-human primates; Miller et al., Br J Pharmacol, (2020), 177(2), 360-371). In one embodiment, the present invention provides compounds, combinations, compositions, and methods defined herein that can provide treatment for eosinophilic disorders.

[0206] Metabolomic studies have identified 5-oxo-ETE as a key metabolite, and its receptor OXER1 was significantly increased in the plasma of patients with acute myocardial infarction (AMI). 5-oxo-ETE and OXER1 appear to play essential roles in the induction of myocardial ischemic injury via branched-chain amino acid transaminase 1 (BCAT1), and overexpression of BCAT1 / BCAT2 (branched-chain amino acid transaminase 2) in the heart may ameliorate myocardial ischemic injury. Therefore, therapeutic agents targeting OXER1 and BCAT1 / BCAT2 are promising strategies for the clinical management of AMI (Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1, Lai et al., Basic Research in Cardiology, (2021), 116:3, 1-25). In one embodiment, the present invention provides compounds, combinations, compositions, and methods defined herein that may provide promising treatments for the clinical management of AMI.

[0207] Eosinophil infiltration into the lungs of asthmatics via 5-oxo-ETE / OXER1 has been shown to be involved in late-onset inflammatory asthma. OXER1 antagonists may be a promising therapeutic approach for the treatment of late-onset inflammatory asthma by preventing eosinophils from migrating into the lungs during asthma attacks, thereby alleviating asthma symptoms (Gore et al., J. Med. Chem., (2013), 56, 3725-3732). In one embodiment, the present invention provides compounds, combinations, compositions, and methods defined herein that may provide a promising treatment for late-onset inflammatory asthma.

[0208] A selective OXER1 antagonist has been shown to inhibit allergen-induced eosinophil infiltration into the skin of experimentally sensitized rhesus monkeys to house dust mites and to inhibit lung inflammation resulting from aerosolized allergen challenge (Powell WS, Rokach J., Targeting the OXE Receptor as a Potential Novel Therapy for Asthma, Biochem. Pharmacol., (2020), 179, 113930). These results provide the first evidence for the pathophysiological role of 5-oxo-ETE in mammals and suggest that selective OXE receptor antagonists can be used alone or in combination with current asthma medications, and that combining them with glucocorticoids or cysLT1 antagonists, which act via different mechanisms, may result in synergistic effects between these drugs. In one embodiment, the present invention provides compounds, combinations, compositions and methods defined herein that, alone or in combination with current asthma medications, may provide promising treatments for asthma and other eosinophilic disorders.

[0209] High expression of OXER1 is associated with triple-negative breast cancer and ER - It has been shown to be a major cause of poor prognosis in breast cancer (Masi et al., Oncogenesis, (2020), 9, 105). In one embodiment, the present invention provides a method for the treatment of triple-negative breast cancer and ER tumors by inhibiting OXER1. - The compounds, combinations, compositions and methods defined herein are provided as potential and rational agents for the personalized treatment of breast cancer.

[0210] 5-oxo-ETE induces a strong migration response, and LTB4 has been shown to induce degranulation of basophils (Iikura et al., J Allergy Clin Imminol, (2005), 116, 578-585), suggesting that 5-oxo-ETE may be a therapeutic target for allergic inflammation. In one embodiment, the present invention provides compounds, combinations, compositions and methods defined herein that may provide a promising treatment for allergic inflammation by inhibiting OXER1.

[0211] 5-oxo-ETE can prolong the survival of eosinophils by stimulating monocytes to release granulocyte / macrophage colony-stimulating factor (GM-CSF), a potent survival factor (Stamatiou et al., J. Biol. Chem., (2004), 279, 28159-28164). The interaction of 5-oxo-ETE with monocytes / macrophages to release GM-CSF is known to be crucial for eosinophil survival after reaching the lungs, and this may be important in diseases such as asthma. Furthermore, because GM-CSF has a potent effect on neutrophils and monocytes, 5-oxo-ETE may also be involved in diseases such as arthritis and atherosclerosis, which are characterized by the accumulation of neutrophils and monocytes in joints and arteries, respectively. 5-oxo-ETE has potent effects on eosinophil, neutrophil, and monocyte migration and also promotes their survival, suggesting that this substance may be an important mediator of various inflammatory diseases. In one embodiment, the present invention provides compounds, combinations, compositions, and methods defined herein that may provide promising treatments for various inflammatory diseases, such as asthma, arthritis, and atherosclerosis, through OXER1 inhibition.

[0212] 5-oxo-ETE has been shown to stimulate the proliferation of prostate tumor cells, and OXE receptors are expressed on prostate tumor cells. Arachidonic acid metabolites, including HETE and oxo-ETE, have been shown to increase the growth and promote survival of various cancers, including lung cancer, pancreatic cancer, and prostate cancer. Furthermore, 5-hydroxyeicosatetraenoides are the major arachidonic acid metabolites in prostate cancer cells (see, for example, WO2007 / 025254 and US2005 / 0106603 for a review of the role of G protein-coupled eicosanoid receptors in cancer). These findings suggest the potential role of the compounds defined herein as 5-oxo-ETE receptor antagonists in the treatment or prevention of certain cancers and in inducing apoptosis in these cancer cells. Thus, in one embodiment, compounds, combinations, compositions, and methods defined herein are provided that may be useful for the treatment or prevention of cancer, including lung cancer, pancreatic cancer, and / or prostate cancer. In one aspect, provided herein are methods that may be useful for treating or preventing lung cancer, pancreatic cancer, and / or prostate cancer. In another aspect, provided are methods that may be useful for inducing apoptosis in cancer cells, e.g., lung cancer, pancreatic cancer, and / or prostate cancer cells.

[0213] Thus, the compounds, combinations, and compositions provided herein are useful for treating or preventing diseases or conditions involving 5-oxo-ETE.Thus, compounds, combinations, compositions, and methods defined herein are provided that can provide treatment or prevention of eosinophilic and inflammatory conditions.

[0214] There are many diseases or conditions that are inflammatory in nature. For example, inflammatory diseases affecting the population include asthma, severe eosinophilic asthma, chronic obstructive pulmonary disease (COPD), hypereosinophilic syndrome (HES), nasal polyps, allergic rhinitis, atopic dermatitis, chronic idiopathic urticaria, psoriasis, acne, idiopathic pulmonary fibrosis, eosinophilic gastritis, eosinophilic esophagitis (EoE), and eosinophilic gastroenteritis. Inflammation is also a common cause of pain. Inflammatory pain can arise for many reasons, such as infection, surgery, or other trauma. Those skilled in the art will understand that the term "inflammation" includes any condition characterized by a local or systemic defensive response that may be elicited by physical trauma, infection, chronic disease, such as those described herein above, and / or a chemical and / or physiological response to an external stimulus (e.g., as part of an allergic reaction). Any such response may function to destroy, attenuate, or isolate both the injurious agent and the damaged tissue, but may manifest itself as, for example, heat, swelling, pain, redness, vasodilation and / or increased blood flow, infiltration of the affected area by leukocytes, loss of function, and / or any other symptom known to be associated with an inflammatory condition. Thus, the term "inflammation" is also understood to include any inflammatory disease, disorder, or condition itself, any condition having an inflammatory component associated therewith, and / or any condition characterized by inflammation as a symptom, including, insofar as it relates to a respiratory disease or condition, acute inflammation, chronic inflammation, ulcerative inflammation, specific inflammation, allergic inflammation, and necrotizing inflammation, as well as other forms of inflammation known to those skilled in the art. Thus, for purposes of the present invention, the term also includes inflammatory pain, pain in general, and / or fever.

[0215] In one aspect, there are provided compounds, combinations, compositions and methods as defined herein that may provide treatment or prevention of respiratory diseases or conditions, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic rhinitis, rhinitis, and any other respiratory disease or condition that is characterized by inflammation or has an inflammatory component characterized by eosinophilia.

[0216] In one embodiment, there are provided compounds, combinations, compositions and methods as defined herein that may provide treatment or prevention of asthma, the methods comprising administration of a compound or composition of the disclosure to a subject.

[0217] Asthma is a complex, common, chronic disorder of the airways characterized by variable and relapsing symptoms, including airway obstruction, bronchoconstriction, and underlying inflammation. Treatment regimens for asthma vary depending on the severity of the condition.

[0218] As used herein, the term "asthma" includes all types of asthma, including, but not limited to, mild, moderate, and severe asthma; exercise-induced asthma; aspirin-induced asthma; extrinsic or allergic asthma; intrinsic or non-allergic asthma; occupational asthma; cough variant asthma; nocturnal asthma; childhood-onset asthma; and adult-onset asthma.

[0219] In one embodiment, the compounds, combinations, compositions and methods defined herein are provided that can treat or prevent chronic obstructive pulmonary disease (COPD). COPD refers to a group of lung diseases that typically result in narrowing of the airways due to an abnormal inflammatory response in the lungs. Non-limiting examples of COPD include bronchitis and emphysema. Idiopathic pulmonary fibrosis (IPF) is another lung disease in which eicosanoids are involved.

[0220] In one embodiment, the compounds, combinations, compositions and methods defined herein are provided that may provide treatment or prevention of allergic rhinitis. Allergic rhinitis is an inflammation of the nasal passages, usually accompanied by watery rhinorrhea and itchy nose and eyes. Allergies occur when the immune system overreacts to airborne particles, causing an allergic reaction.

[0221] According to another aspect, there are provided compounds, combinations, compositions and methods as defined herein which may provide treatment or prevention of diseases or conditions in which eicosanoids such as 5-oxo-ETE and 5-HETE are implicated.

[0222] According to another aspect, there are provided compounds, combinations, compositions and methods as defined herein that may be useful for inhibiting the effects of eicosanoids such as 5-oxo-ETE and 5-HETE and 5-oxo-15-HETE.

[0223] According to another aspect, there are provided compounds, combinations, compositions and methods as defined herein that may be useful for antagonizing 5-oxo-ETE receptors, such as OXE receptors.

[0224] It should also be understood that the compounds and compositions of the present invention, in addition to blocking the biological response to 5-oxo-ETE, 5-oxo-15-HETE, and 5-HETE, can also block the biological response to other related eicosanoids that can similarly act as ligands for OXE receptors. Thus, as used herein, "eicosanoid" refers to a substance derived from a fatty acid having 20 carbon atoms, such as eicosanoic acid, and in one embodiment, a fatty acid that is unsaturated at the 8th position. Non-limiting examples of eicosanoids encompassed by the methods provided herein include 5-oxo-ETE, 5-HETE, 5-HPETE, arachidonic acid, 5-oxo-ETrE (5-oxo-6E,8Z,11Z-eicosatrienoic acid), 5-HETrE (5-hydroxy-6E,8Z,11Z-eicosatrienoic acid), eicosa-5Z,8Z,11Z-trienoic acid, 5-oxo-EDE (5-oxo-6E,8Z-eicosadienoic acid), and eicosa-5Z,8Z-dienoic acid. Additionally, certain 18-carbon polyunsaturated fatty acids are included, such as 5-oxo-ODE (5-oxo-6E,8Z-octadecadienoic acid), 5-HODE (5-hydroxy-6E,8Z-octadecadienoic acid), and sebalaic acid (5Z,8Z-octadecadienoic acid).

[0225] In one aspect, there are provided compounds, combinations, compositions and methods defined herein that may be useful for the treatment or prevention of viral infections (e.g., influenza, cold).

[0226] In one aspect, there are provided compounds, combinations, compositions and methods as defined herein that may be useful for the treatment or prevention of atopic dermatitis, psoriasis and / or acne.

[0227] 5-LO products are thought to contribute to the development of tissue inflammation. The synthesis of leukotrienes and 5-oxo-ETEs is regulated by the enzyme 5-lipoxygenase.

[0228] The pharmacological role of 5-LO products has been studied in psoriasis.It has been suggested that inhibiting 5-LO products may be useful in the treatment of psoriasis.Tissue inflammation is a component of the acne process.Therefore, inhibitors of 5-lipoxygenase products may be useful compounds in the treatment of acne vulgaris.

[0229] Atopic dermatitis is a chronic, recurrent skin condition. Its pathophysiology is thought to involve the release of inflammatory mediators. 5-LO products are thought to contribute to inflammatory and atopic conditions. Therefore, modulators of 5-LO products may be useful for the treatment of atopic dermatitis.

[0230] In one embodiment, the presently disclosed subject matter relates to a method of inhibiting OXER1, comprising contacting OXER1 with an effective amount of a compound of the present invention or a pharmaceutical composition described herein.

[0231] In certain embodiments, the subject matter disclosed herein relates to a method for modulating an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0232] The compounds disclosed herein directly bind to OXER1 and inhibit its signaling activity. In some embodiments, the compounds disclosed herein reduce, inhibit, or otherwise alleviate OXER1-mediated inflammatory responses.

[0233] The compounds disclosed herein may or may not be specific OXER1 antagonists. A particular OXER1 antagonist reduces the biological activity of OXER1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In certain embodiments, the compounds disclosed herein specifically inhibit the signaling activity of OXER1. In some of these embodiments, the IC of the OXER1 antagonist for OXER1 is 50 The IC of OXER1 antagonists against another GPCR activated by free fatty acids (FFAs) or other types of GPCRs (e.g., class A GPCRs) 50 Approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, and 0.001% lower.

[0234] The compounds disclosed herein can be used in methods for inhibiting OXER1. Such methods include contacting OXER1 with an effective amount of a compound of the present disclosure. "Contacting" means bringing the compound sufficiently close to isolated OXER1 GPCR or cells expressing OXER1 so that the compound can bind to OXER1 and inhibit its activity. The compound can be contacted with OXER1 in vitro or in vivo via administration of the compound to a subject.

[0235] Any method known in the art for measuring OXER1 signaling activity, such as in vitro assays or measuring downstream biological effects of OXER1 signaling activity, may be used to determine whether OXER1 is inhibited.

[0236] The compounds disclosed herein can be used to treat OXER1-dependent disorders. As used herein, "OXER1-dependent disorders" refer to pathological conditions in which OXER1 activity is required for the development or maintenance of the pathological condition. In some embodiments, the OXER1-dependent disorder is an inflammatory condition.

[0237] The compounds of the present disclosure also find use in modulating the immune response in a subject in need thereof. Such a method comprises administering an effective amount of a compound of the present invention.

[0238] As used herein, "modulating an immune response" refers to modulating any immunogenic response to an antigen.

[0239] In another aspect of the invention, the invention provides novel compounds of the invention for use in therapy.

[0240] In a further aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic protocols and routes disclosed herein.

[0241] Therefore, a primary object of the present invention is to provide compounds of the present invention that are capable of modifying the activity of OXER1 and thereby preventing or treating any condition that may be causally linked to it.

[0242] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description.

[0243] The present disclosure provides a method for treating an OXER1-mediated disorder, disease, or condition in a patient, comprising administering to the patient in need thereof a compound described herein (e.g., a compound of Formula I) or a pharmaceutical composition comprising the compound. In some embodiments, the disease, disorder, or condition is asthma, severe eosinophilic asthma, late-onset inflammatory asthma, chronic obstructive pulmonary disease (COPD), hypereosinophilic syndrome (HES), nasal polyps, allergic inflammation, allergic rhinitis, atopic dermatitis, chronic idiopathic urticaria, psoriasis, acne, idiopathic pulmonary fibrosis, eosinophilic gastritis, eosinophilic esophagitis (EoE), eosinophilic gastroenteritis, arthritis, atherosclerosis, or acute myocardial infarction. In some embodiments, the disease, disorder, or condition is asthma.

[0244] The present disclosure provides a method for modulating (e.g., inhibiting) OXER1 activity, the method comprising administering to a patient a compound provided herein, or an N-oxide, or a pharmaceutically acceptable salt thereof.

[0245] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0246] In the methods described herein, a compound of the present invention or a pharmaceutical composition thereof is administered to a subject with cancer.

[0247] In certain embodiments, the subject matter disclosed herein relates to a method for treating an OXER1-dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the OXER1-dependent disorder is cancer.

[0248] In some embodiments, the subject matter disclosed herein relates to a method for treating a chronic viral infection. In some embodiments, the subject matter disclosed herein relates to the use of an OXER1 inhibitor as an adjuvant treatment to improve the efficacy of vaccination.

[0249] In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0250] In certain aspects, the present invention provides methods of treating cell proliferation disorders, such as cancer.

[0251] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0252] In certain embodiments, the cell proliferative disorder is cancer.

[0253] Examples of cancers that can be treated using the compounds of the present disclosure include, but are not limited to, chronic or acute leukemia, such as acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, and combinations of these cancers.

[0254] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, hematological cancers (e.g., lymphoma, leukemia, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of these cancers.

[0255] In certain embodiments, the cancer is leukemia, hi another embodiment, the cancer is selected from the group consisting of acute myeloid leukemia and chronic myeloid leukemia.

[0256] In certain embodiments, the cancer is selected from leukemia and blood cancer. In certain embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In certain embodiments, the cancer is AIDS-related.

[0257] In certain embodiments, the cancer is selected from leukemia and hematological cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blastic phase chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms, such as plasmacytoma and multiple myeloma. The leukemias referred to herein can be acute or chronic.

[0258] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers.

[0259] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0260] The term "inflammatory condition(s)" as used herein refers to a group of conditions such as inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, pulmonary diseases (e.g., chronic obstructive pulmonary disease (COPD) and pulmonary interstitial diseases (e.g., idiopathic pulmonary fibrosis (IPF))), psoriasis, gout, allergic airway diseases (e.g., asthma, rhinitis), and endotoxin-induced conditions (e.g., complications following bypass surgery or chronic endotoxin states contributing to, for example, chronic heart failure). In particular, the term refers to rheumatoid arthritis, allergic airway diseases (e.g., asthma), and inflammatory bowel disease. In more particular aspects, the term refers to uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and inflammation of the skin and / or colon caused by tumor treatments aimed at activating the immune response.

[0261] The term "pain," as used herein, refers to a disease or disorder characterized by unpleasant sensations, often caused by intense or noxious stimuli, including, but not limited to, nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration), and neuropathic or dysfunctional pain (caused by damage to or abnormal function of the nervous system), and / or pain associated with or caused by the conditions described herein. Pain can be acute or chronic.

[0262] As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, making the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

[0263] In some embodiments, the compounds of the invention may be useful in preventing or reducing the risk of developing any of the diseases mentioned herein, for example, in preventing or reducing the risk of developing a disease, condition, or disorder in individuals who may be predisposed to the disease, condition, or disorder but who have not yet experienced or exhibited the pathology or symptoms of the disease.

[0264] The compounds disclosed herein can be administered by any suitable method known in the art, hi some embodiments, the compounds of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intracerebroventricularly, intratumorally, or intranasally.

[0265] In some embodiments, the OXER1 antagonist is administered continuously. In other embodiments, the OXER1 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of an OXER1 antagonist can include one treatment or a series of treatments.

[0266] It is understood that the appropriate dose of the active compound depends on several factors within the knowledge of a physician or veterinarian of ordinary skill. The dose(s) of the active compound will vary depending on, for example, the age, weight, general condition, sex, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combinations.

[0267] It will also be understood that the effective dosage of the compounds of the invention or pharmaceutically acceptable salts, prodrugs, metabolites or derivatives thereof used for treatment may increase or decrease during the course of a particular treatment. Variations in dosage may occur and may become apparent from the results of diagnostic assays.

[0268] In some embodiments, the OXER1 antagonist is administered to a subject at a dose of about 0.001 μg / kg to about 1000 mg / kg, for example, but not limited to, about 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0269] In the methods described herein, the method can further include administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject before administration of the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or composition.

[0270] As used herein, the terms "treatment," "treat," and "treating," as described herein, refer to reversing, alleviating, delaying the onset of, or inhibiting progression of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have manifested. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the condition and / or taking into account genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0271] The terms "administration" or "administering" include routes of introducing a compound(s) into a subject to perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0272] The term "effective amount" includes an amount effective at the dosage and duration necessary to achieve the desired result. The effective amount of a compound may vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to induce the desired response in the subject. The dosage regimen may be adjusted to provide the optimal therapeutic response.

[0273] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" mean "administration of a compound(s), drug, or other substance such that it enters the patient's body and is therefore subject to metabolic and other similar processes."

[0274] The phrase "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug may reduce the number of cancer cells, decrease tumor size, inhibit (i.e., slow to some extent and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent a drug can prevent the growth of and / or kill existing cancer cells, the drug may be cytostatic and / or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0275] The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0276] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0277] In certain embodiments, a provided combination or composition thereof is administered in combination with another therapeutic agent.

[0278] The compounds of the present invention can be used as therapeutic agents to treat mammalian conditions causally associated with or resulting from abnormal OXER1 activity and / or abnormal OXER1 expression and / or abnormal OXER1 distribution.

[0279] Accordingly, the compounds and pharmaceutical compositions of the present invention find use as therapeutic agents in mammals, e.g., humans, for the prevention and / or treatment of inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0280] Thus, in one aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use as a medicament.

[0281] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament.

[0282] In yet another aspect, the present invention provides methods of treating a mammal having or at risk of having a disease disclosed herein. In certain aspects, the present invention provides methods of treating a mammal, including a human, having or at risk of having an inflammatory condition, pain, a neuroinflammatory condition, a neurodegenerative condition, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, a cardiovascular disease, leukemia, and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein.

[0283] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of an inflammatory condition. In certain embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory condition is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and inflammation of the skin and / or colon caused by tumor treatments aimed at activating the immune response.

[0284] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for the prevention and / or treatment of an inflammatory condition. In certain embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory condition is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and inflammation of the skin and / or colon caused by tumor therapy aimed at activating the immune response.

[0285] In another aspect, the invention provides a method of treating a mammal having or at risk for a disease selected from an inflammatory condition (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis), a pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD) and pulmonary interstitial disease (e.g., idiopathic pulmonary fibrosis (IPF))), a neuroinflammatory condition, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions described herein.

[0286] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from an inflammatory condition, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory condition is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and inflammation of the skin and / or colon caused by tumor treatments aimed at activating the immune response.

[0287] In one aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the prevention and / or treatment of pain. In certain embodiments, the pain is acute or chronic and selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0288] In another aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the manufacture of a medicament for the prevention and / or treatment of pain. In certain embodiments, the pain is acute or chronic and selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0289] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from pain, the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0290] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prophylaxis and / or treatment of neuroinflammatory conditions, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0291] In another aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the manufacture of a medicament for use in the prevention and / or treatment of neuroinflammatory conditions, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0292] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from a neuroinflammatory condition, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, the method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions described herein.

[0293] In one aspect, the invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the prevention and / or treatment of infectious disease(s). In certain embodiments, the infectious disease(s) is / are selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infectious diseases, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0294] In another aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the manufacture of a medicament for the prevention and / or treatment of infectious disease(s). In certain embodiments, the infectious disease(s) are selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infectious diseases, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0295] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from an infectious disease(s), the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infectious diseases, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0296] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prophylaxis and / or treatment of an autoimmune disease and / or a disease involving impaired immune cell function, hi certain embodiments, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

[0297] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for use in the prevention and / or treatment of an autoimmune disease and / or a disease involving impaired immune cell function. In certain embodiments, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

[0298] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from an autoimmune disease and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the autoimmune disease and / or disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

[0299] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of an endocrine and / or metabolic disorder. In certain embodiments, the endocrine and / or metabolic disorder is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes, diseases of the adrenal gland (such as Cushing's syndrome and Addison's disease), ovarian insufficiency (such as polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0300] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for the prevention and / or treatment of an endocrine and / or metabolic disorder. In certain embodiments, the endocrine and / or metabolic disorder is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes, diseases of the adrenal gland (such as Cushing's syndrome and Addison's disease), ovarian insufficiency (such as polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0301] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from an endocrine and / or metabolic disorder, the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the endocrine and / or metabolic disorder is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes, diseases of the adrenal gland (such as Cushing's syndrome and Addison's disease), ovarian insufficiency (such as polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0302] As a further aspect of the invention, there is provided a compound of the invention for use as a medicament, particularly in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of a compound in the manufacture of a medicament for treating or preventing one of the aforementioned conditions and diseases.

[0303] A particular regimen of this method comprises administering to a subject suffering from an inflammatory condition an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the subject, preferably terminating the processes that cause said inflammation. A particular embodiment of this method comprises administering to a subject suffering from or susceptible to developing an inflammatory condition an effective amount of a compound of the invention for a period of time sufficient to reduce or prevent inflammation in the patient, respectively, and preferably halt the processes that cause inflammation.

[0304] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a human patient weighing 40 to 80 kg.

[0305] Transdermal doses are generally selected to provide blood levels that are similar to or lower than those achieved using injection doses.

[0306] When using the compounds of the invention to prevent the onset of symptoms, the compounds of the invention are typically administered under the advice and supervision of a physician at dosage levels described above to patients at risk of developing the symptoms. Patients at risk of developing a particular condition generally include patients who have a family history of the condition or who have been identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0307] The compounds of the present invention can be administered as the sole active agent or in combination with other therapeutic agents, including other compounds that exhibit the same or similar therapeutic activity and that have been determined to be safe and effective for such combined administration. In certain embodiments, co-administration of two (or more) agents can allow significantly lower dosages of each to be used, thereby reducing the side effects observed.

[0308] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of an inflammatory condition; specific agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0309] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of arthritis (e.g., rheumatoid arthritis); specific agents include, but are not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (e.g., but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporine), and biologic DMARDS (e.g., but not limited to, infliximab, etanercept, adalimumab, rituximab, golimumab, certolizumab pegol, tocilizumab, interleukin-1 blockers, and abatacept).

[0310] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of autoimmune diseases; specific agents include, but are not limited to, immunomodulatory agents such as glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin anthracyclines, mitomycin C, bleomycin, etc.), and the like. and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab (Remicade®), etanercept (Enbrel®), or adalimumab (Humira®)), mycophenolic acid, fingolimod, and myriocin.

[0311] In one embodiment, a compound of the present invention is co-administered with another therapeutic agent for the treatment and / or prevention of an infectious disease; specific agents include, but are not limited to, antibiotics. In a specific embodiment, a compound of the present invention is co-administered with another therapeutic agent for the treatment and / or prevention of an infectious disease in any organ of the human body; specific agents include, but are not limited to, aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, antimycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol, and tinidazole.

[0312] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of vasculitis; specific agents include, but are not limited to, steroids (e.g., prednisone, prednisolone), cyclophosphamide, and, in the case of skin infections, consequently, antibiotics (e.g., cephalexin, etc.).

[0313] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of esophagitis; specific agents include, but are not limited to, antacids (e.g., formulations containing aluminum hydroxide, magnesium hydroxide, and / or simethicone), H2-antagonists (e.g., cimetidine, ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole), and glucocorticoids (e.g., prednisone, budesonide, etc.).

[0314] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of IPF; specific agents include, but are not limited to, pirfenidone and bosentan.

[0315] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of asthma and / or rhinitis and / or COPD; specific agents include, but are not limited to, beta-2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting beta-2 agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), and combinations of inhaled steroids and long-acting bronchodilators. (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), phosphodiesterase-4 inhibitors (e.g., roflumilast), biological modulators of IgE responses (e.g., omalizumab), antihistamines (e.g., ceterizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymetazoline, xylomethazoline, naphazoline, and tramazoline).

[0316] Additionally, the compounds of the invention can be administered in combination with emergency treatments for asthma and / or COPD, including oxygen or heliox administration, nebulized salbutamol or terbutaline, optionally with an anticholinergic (e.g., ipratropium), systemic steroids (oral or intravenous (e.g., prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone)), intravenous salbutamol, nonspecific β-agonists, injected or inhaled (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g., glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, amifylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0317] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory bowel disease (IBD). Specific agents include, but are not limited to, glucocorticoids (e.g., prednisone, budesonide), synthetic disease-modifying immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine), and biologic disease-modifying immunomodulators (e.g., infliximab, adalimumab, rituximab, and abatacept).

[0318] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of pain, for example, a non-narcotic analgesic and a narcotic analgesic; specific agents include, but are not limited to, paracetamol, acetylsalicylic acid, NSAIDs, codeine, dihydrocodeine, tramadol, pentazocine, pethidine, tilidine, buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, piritramide, tapentadol, or combinations thereof.

[0319] Treatment courses for leukemia include chemotherapy, biological therapy, targeted therapy, radiation therapy, bone marrow transplantation, and / or combinations thereof.

[0320] Examples of additional therapeutic agents for acute lymphoblastic leukemia (ALL) include methotrexate, nelarabine, asparaginase Erwinia chrysanthemum, blinatumomab, daunorubicin, clofarabine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib vincristine, mercaptopurine, pegaspargase, and / or prednisone.

[0321] Examples of additional therapeutic agents for acute myeloid leukemia (AML) include arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and / or vincristine.

[0322] Examples of additional therapeutic agents for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, mechlorethamine, prednisone, and / or rituximab.

[0323] Examples of additional therapeutic agents for chronic myeloid leukemia (CML) include bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, mechlorethamine, nilotinib, and / or omacetaxine.

[0324] Examples of additional therapeutic agents for hairy cell leukemia include cladribine, pentostatin, and / or interferon alpha-2b.

[0325] As those skilled in the art will understand, simultaneous administration includes any means of delivering two or more therapeutic agents to patients as part of the same treatment regimen.Two or more agents can be administered simultaneously in a single formulation, but this is not necessary.Agents can also be administered in different formulations at different times.

[0326] In one embodiment, a compound of the invention is co-administered with one or more additional therapeutic agents for the treatment and / or prevention of a fibrotic disorder. In certain embodiments, a compound of the invention is co-administered with one or two additional therapeutic agents for the treatment and / or prevention of a fibrotic disorder. In certain embodiments, a compound of the invention is co-administered with one additional therapeutic agent for the treatment and / or prevention of a fibrotic disorder.

[0327] In one embodiment, additional therapeutic agents for the treatment and / or prevention of fibrotic disorders include, but are not limited to, 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone), nintedanib (Ofev® or Vargatef®); STX-100 (ClinicalTrials.gov identifier NCT01371305), FG-3019 (ClinicalTrials.gov identifier NCT01890265), lebrikizumab (CASn#953400-68-5); tralokinumab (CASn#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), tipelukast (MN-001; ClinicalTrials.gov identifier NCT02503657), ND-L02-s020l (ClinicalTrials.gov identifier NCT02503657). ClinicalTrials.gov identifier NCT03538301), KD025 (ClinicalTrials.gov identifier NCT02688647), TD139 (ClinicalTrials.gov identifier NCT02257177), VAY736 (ClinicalTrials.gov identifier NCT03287414), PRM-151 (ClinicalTrials.gov identifier NCT02550873), and PBI-4050 (ClinicalTrials.gov identifier NCT02538536). In certain embodiments, the additional therapeutic agent for the treatment and / or prevention of fibrotic diseases is an autotaxin (or ectonucleotide pyrophosphatase / phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are those described in WO2014 / 139882, such as GLPG1690.

[0328] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of NASH, including, but not limited to, a weight loss therapeutic agent (e.g., sibutramine or orlistat), an insulin sensitizer (e.g., metformin, thiazolidinedione, rosiglitazone, or pioglitazone), a lipid-lowering agent (e.g., gemfibrozil), an antioxidant (e.g., vitamin E, N-acetylcysteine, betaine, or pentoxifylline), an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, a monounsaturated fatty acid, or a polyunsaturated fatty acid. FXR agonists (e.g., obeticholic acid), LOXL2 antagonists (e.g., simtuzumab), ASK1 antagonists (e.g., selonsertib), PPAR agonists (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinediones, ibuprofen, GW-9662, aleglitazar, muraglitazar, or tesaglitazar), acetyl-CoA-carboxylase (ACC) antagonists (e.g., NDI-010976, PF-05221304), CCR2 / CCR5 (e.g., cenicriviroc), VAP1 antagonists.

[0329] Examples of agents with which the combinations of the present invention can be combined include, but are not limited to, treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for HIV, such as ritonavir; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; treatments for multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®, treatments for schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian drugs; cardiovascular disease treatments, such as beta blockers, A CE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; liver disease treatments, such as corticosteroids, cholestyramine, interferons, and antivirals; blood disease treatments, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., metabolic degradation inhibitors) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and immunodeficiency disease treatments, such as gamma globulin.

[0330] In certain embodiments, the combination therapy of the invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic.

[0331] These additional agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention in one composition. When administered as part of a multiple dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0332] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a combination of the present invention may be administered simultaneously with another therapeutic agent, sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0333] The amount of additional therapeutic agent present in the compositions of the invention is no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to about 100% of the amount that would normally be present in a composition comprising that therapeutic agent as the only therapeutically active agent.

[0334] In one embodiment, the present invention provides a composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agents may be administered together with the compound of Formula I, or may be administered before or after the administration of the compound of Formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of Formula I may be administered up to 5, 10, 15, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of Formula I may be administered up to 5, 10, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0335] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biopharmaceuticals, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), (R)), azathioprine (Imuron®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" drugs such as anakinra (Kineret®) and rilonacept (Arcalyst®), anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®),"Anti-IL-6" agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as For example, cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives, for example, milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, Senokot®, anticholinergics or antispasmodics, for example, dicyclomine (Bentyl®), Singulair®, beta-2 agonists, for example, albuterol (Ventolin® HFA, Proventil® H), FA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide, etc. (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines, such as theophylline (Theo-Dur®,Theolair®, Slo-bid®, Uniphyl®, Theo)-24® and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors®, zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), , didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors, delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine ) (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors, amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), and others. Entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®),combination with lenalidomide (Revlimid®), or any combination thereof.

[0336] In another embodiment, the present invention provides combinations of a compound of Formula I with aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leuke®), and the like. ran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®), and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as rilonacept (Arcalyst®), antibodies, e.g., rituximab (Rituxan®), "anti-T cell" agents, e.g., abatacept (Orencia®), and "anti-IL-6" agents, e.g., tocilizumab (Actemra®).

[0337] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and nonsteroidal anti-inflammatory drugs (NSAIDS) such as celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies such as tanezumab.

[0338] In some embodiments, the present invention provides methods for treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0339] In some embodiments, the present invention provides methods of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0340] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of Formula I and Singulair®, a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), an inhaled corticosteroid such as prednisone, prednisolone, beclomethasone dipropionate, or the like. and administering one or more additional therapeutic agents selected from fluconazole (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®).

[0341] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and a β2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an antihistamine (Antichritis Infectious Diseases ... and administering one or more additional therapeutic agents selected from cholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0342] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0343] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0344] In another embodiment, the present invention provides a method for treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL ((Ramirez et al. "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012) published online July 17, and incorporated herein by reference in its entirety).

[0345] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0346] In another embodiment, the present invention provides a method for treating multiple myeloma, comprising administering to a patient in need thereof the compound of Formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0347] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering a compound of Formula I and a BTK inhibitor to a patient in need thereof, wherein the disease is selected from: inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, ord's thyroiditis. thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis , scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV) type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx), type 1 hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis , chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Scholein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis,Phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colon cancer, pancreatic cancer, bone and joint diseases, including, but not limited to, rheumatoid arthritis, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), basal ganglia, rheumatoid arthritis ... Chet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, thromboembolic diseases (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), inflammatory pelvic diseases, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, hypertension Irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE),Rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0348] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disease, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disease, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disease, a destructive bone disease, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0349] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from: benign or malignant tumors, carcinomas or solid tumors of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, abdomen, stomach tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer, colorectal carcinoma, head Cervical tumors, epidermal hyperproliferation, psoriasis, benign prostatic hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphomas (e.g., non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin's disease or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, diseases such as Cowden syndrome, Lhermitte-Dudos disease, and Banayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, intrinsic (non-allergic) asthma and extrinsic (allergic) asthma ) Asthma of any type or cause, including both mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), for example, dyspnea associated with chronic bronchitis or emphysema, exacerbation of airway hyperresponsiveness due to other medications, especially other inhaled medications, bronchitis of any type or cause, including but not limited to acute, arachidonic, Zinc bronchitis, catarrhal bronchitis, croupus bronchitis, chronic bronchitis or phthinoid bronchitis, pneumoconiosis (inflammatory lung diseases, generally occupational, often resulting in chronic or acute airway obstruction, caused by repeated inhalation of dust), e.g., aluminum lung disease, anthracosis, asbestosis, stone disease, trichiasis, siderosis, silicosis, tobacco disease and cotton fibrolosis, Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestation (e.g., tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (e.g., Churg-Strauss syndrome),Eosinophil-related diseases affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose such as allergic rhinitis, inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, true erythroid aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, ulcerative colitis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, neurodegenerative diseases caused by trauma, glutamate neurotoxicity and hypoxia.

[0350] In some embodiments, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disease. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0351] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2-binding compound is a compound of Formula I. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated by reference in its entirety. Suitable JH1 domain-binding compounds include those described in WO2015131080(A1), each of which is incorporated by reference in its entirety.

[0352] The compounds and compositions of the present invention can be administered in any amount and using any route of administration effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorders. The exact amount required may vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "dosage unit form" refers to a physically discrete unit of agent appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will vary depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the patient's age, weight, general condition, sex, and diet; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination with or concomitantly with the particular compound used; and similar factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0353] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as powders, ointments, or drops), bucally, or as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally, one or more times daily, at dosage levels of about 0.01 mg / kg of subject body weight / day to about 50 mg / kg of subject body weight / day, preferably about 1 mg / kg of subject body weight / day to about 25 mg / kg of subject body weight / day, to achieve the desired therapeutic effect.

[0354] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0355] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0356] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0357] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a compound depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0358] For example, compositions for rectal or vaginal administration are preferably suppositories which can be prepared, for example, by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0359] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0360] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0361] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is customary, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, or may be of a composition that releases the active ingredient(s) only in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0362] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0363] According to one embodiment, the present invention relates to a method for inhibiting OXER1 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising a compound.

[0364] According to another embodiment, the present invention relates to a method for inhibiting the activity of OXER1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising a compound.

[0365] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0366] Inhibition of OXER1 (or its variants) activity in biological samples is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0367] Another embodiment of the invention relates to a method of inhibiting OXER1 activity in a patient, comprising administering to the patient a compound of the invention, or a composition comprising a compound.

[0368] According to another embodiment, the present invention relates to a method for inhibiting the activity of OXER1 or a mutant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method for reversibly or irreversibly inhibiting the activity of one or more of OXER1 or a mutant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a disorder mediated by OXER1 or a mutant thereof in a patient in need thereof, the method comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0369] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0370] The compounds of the invention may also be used advantageously in combination with other therapeutic compounds, hi some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target / decrease protein or lipid kinase activity; and further antiangiogenic compounds; compounds that target, decrease or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG. (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer and leucovorin). The term "aromatase inhibitor", as used herein, relates to a compound which inhibits the production of estrogens, e.g. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The term includes, but is not limited to, atamestane, exemestane, and formestane, particularly non-steroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten™. Combinations of the invention that include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor-positive tumors, such as breast tumors.

[0371] The term "anti-estrogen" as used herein refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex™. Raloxifene hydrochloride is sold under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations of the present invention that include chemotherapeutic agents that are anti-estrogen are particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0372] The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological effects of androgen hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0373] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form that it is marketed under the trademark Camptosar™. Topotecan is sold under the trade name Hycamptin™.

[0374] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and podophyllotoxin, etoposide, and teniposide. Etoposide is sold under the trade name Etopophos™. Teniposide is sold under the trade name VM26-Bristol. Doxorubicin is sold under the trade name Acriblastin™ or Adriamycin™. Epirubicin is sold under the trade name Farmorubicin™. Idarubicin is sold under the trade name Zavedos™. Mitoxantrone is sold under the trade name Novantron.

[0375] The term "microtubule active agent" refers to microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubule polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; cochicine, epothilones, and their derivatives. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastin RP™. Vincristine sulfate is sold under the trade name Farmistin™.

[0376] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™. Ifosfamide is sold under the trade name Holoxan™.

[0377] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including but not limited to suberoylanilide hydroxamic acid (SAHA).

[0378] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[0379] The term "platin compounds" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0380] The term "compounds that target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity, or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as: a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), e.g., compounds that target, reduce, or inhibit the activity of PDGFR; compounds which target, reduce or inhibit the activity of the insulin-like growth factor receptor I (IGF-IR), for example compounds which target, reduce or inhibit the activity of the IGF-IR, in particular compounds which inhibit the kinase activity of the IGF-I receptor, or compounds which inhibit the cellular activity of the IGF-I receptor. Antibodies targeting the ectodomain or growth factors thereof; d) compounds that target, decrease or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, decrease or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that target, decrease or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of the C-kit receptor, which is part of the PDGFR family. i) compounds that target, reduce or inhibit the activity of receptor tyrosine kinases, for example compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g. BCR-Abl kinase) and mutants, for example compounds that target reducing or inhibiting the activity of members of the c-Abl family and their gene fusion products;N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 or dasatinib (BMS-354825) from ParkeDavis; j) Compounds that target, decrease, or inhibit the activity of: protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PD members of the cyclin-dependent kinase family (CDK), such as members of the K1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC families, and / or staurosporine derivatives, e.g., midostaurin; further exemplary compounds include UCN-01, safingol, BAY43-9006, bryostatin 1, perifosine; ilmofosine; RO318220 and RO320432; GO6976; lsis3521 LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds which target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, for example tyrphostins, such as compounds which target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, for example imatinib mesylate (Gleevec™) or tyrphostins. For example, tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin);l) Compounds which target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and variants thereof, for example compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family, in particular members of the EGF receptor tyrosine kinase family, for example EGF receptor, ErbB2, ErbB3, and ErbB4, or which inhibit EGF or EGF-related ligands, CP358774, ZD 1839, ZM105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease, or inhibit the activity of the c-Met receptor, e.g., For example, compounds that target, decrease, or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or that bind to HGF; n) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), such as, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, monoclonal antibody (MACE1), and / or monoclonal antibody (MACE2). melotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K), such as, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupalisib, pictorelisib, PF-4691502, BYL-719, ductrib, XL-147, XL-765, and idelalisib;q) Compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothing Mechanism (SMO) pathways, such as, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib);

[0381] As used herein, the term "PI3K inhibitor" includes compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupallisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0382] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), such as AVL-292 and ibrutinib.

[0383] The term "SYK inhibitors" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, for example, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0384] The term "Bcl-2 inhibitors" as used herein includes compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), such as, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitor Acenta, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0385] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0386] Further examples of SYK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2003063794, WO2005007623 and WO2006078846, which are incorporated herein by reference in their entireties.

[0387] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are hereby incorporated by reference in their entirety.

[0388] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are hereby incorporated by reference in their entirety.

[0389] Examples of further anti-angiogenic compounds include compounds having a different mechanism of action regarding their activity, for example Thalomid (trademark) and TNP-470, which are unrelated to protein or lipid kinase inhibition.

[0390] Examples of proteasome inhibitors useful for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0391] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0392] Examples of compounds that induce the cell differentiation process include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0393] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0394] The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0395] As used herein, the term "heparanase inhibitor" refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0396] As used herein, the term "inhibitor of Ras oncogenic isoforms," ​​such as H-Ras, K-Ras, or N-Ras, refers to a compound that targets, reduces, or inhibits the oncogenic activity of Ras. For example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0397] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases, or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0398] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN341.

[0399] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

[0400] As used herein, the term "compounds used in the treatment of hematological malignancies" includes, but is not limited to, compounds that target, decrease, or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranylcytosine (ara-c), and bisulfan; ALK inhibitors (compounds that target, decrease, or inhibit anaplastic lymphoma kinase), and Bcl-2 inhibitors.

[0401] Compounds that target, decrease, or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0402] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, and compounds that target, reduce, or inhibit the degradation of HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 include, among others, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds, radicicol, and HDAC inhibitors.

[0403] The term "anti-proliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0404] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly in combination with therapies used to treat AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful in the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutation, comprising administering a compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), a staurosporine derivative (e.g., midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0405] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogues of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US Pat. No. 6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Approaches that damage tumor cells refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, which is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0406] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, such as, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are, in particular, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0407] Also included are, inter alia, VEGF compounds, proteins or monoclonal antibodies, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g., VEGF aptamers such as rhuMAb and RHUFab, Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozyme (RPI4610) and bevacizumab (Avastin™).

[0408] As used herein, photodynamic therapy refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0409] As used herein, angiogenic antisteroids refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0410] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0411] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds, antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0412] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those described above, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention can be mixed with the other drug substances in a fixed pharmaceutical composition, or can be administered separately, before, simultaneously with, or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention described above with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0413] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 agonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247; LTD4 antagonists, such as montelukast, zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Allofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β2 adrenergic receptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and, in particular, formoterol, and pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salts and CHF4226 (Chiesi), and glycopyrrolate.

[0414] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0415] Other useful combinations of compounds of the invention with anti-inflammatory agents are antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0416] The structures of active compounds identified by code number, generic name or trade name can be obtained from the actual edition of the standard compendium "The Merck Index" or from databases such as international patents (eg IMS World Publications).

[0417] Representative tumor immunotherapy agents In some embodiments, the one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that is effective in enhancing, stimulating, and / or upregulating an immune response in a subject. In some embodiments, administering an immuno-oncology agent together with a compound of the present invention has a synergistic effect in treating cancer.

[0418] The immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biological molecule or small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0419] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including costimulatory) signal on T cells, both of which amplify antigen-specific T cell responses.

[0420] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate members of the TNF receptor family. These include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2- L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDA R, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0421] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0422] In some embodiments, the combination of a compound of the present invention and an immuno-oncology agent can stimulate a T cell response. In some embodiments, the immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0423] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0424] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, such as, but not limited to, a CSF-1R antagonist, e.g., a CSF-1R antagonist antibody, e.g., RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0425] In some embodiments, the immuno-oncology agent is selected from one or more of: an agonist agent that ligates positive costimulatory receptors; a blocking agent that attenuates signaling through inhibitory receptors; an antagonist; and one or more agents that increase the frequency of anti-tumor T cells systemically; an agent that overcomes different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction)); an agent that depletes or inhibits Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion); an agent that inhibits metabolic enzymes such as IDO; or reversing / preventing T cell energy or exhaustion); and an agent that causes innate immune activation and / or inflammation at the tumor site.

[0426] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0427] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). In some embodiments, the immuno-oncology agent can be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein called AMP-224, which is composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0428] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0429] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG-3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0430] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0431] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0432] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0433] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0434] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0435] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0436] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0437] In some embodiments, the tumor immunomodulator is MGA271 (directed against B7H3) (WO11 / 109400).

[0438] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0439] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can relieve the suppression of activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in an increasing number of tumor histologies, including some tumor types not previously considered susceptible to immunotherapy. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who have experienced disease progression during or after previous antiangiogenic therapy.

[0440] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics that may be used in the present invention include pomalidomide (Pomalyst®, Celgene), lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEOPharma).

[0441] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a gene-modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions of melanoma.In some embodiments, the immuno-oncology agent is selected from oncolytic virotherapy, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex), a thymidine kinase (TK)-deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312). Biotherapeutics; colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627). pelareorep (Reolysin®, Oncolytics), a variant of the respiratory enteric orphan virus (reovirus) that does not replicate in cells without RAS activation, has been shown to be effective in many cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627). Biotech); ovarian cancer (NCT02028117); Enadenotsiliev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein in metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucoronidase or β-gal / human sodium iodide symporter (hNIS), respectively, studied in 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0442] In some embodiments, the immuno-oncology agent is JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase that can convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics that target hard-to-treat RAS mutations; TILT-123 (TILT Biotherapeutics), an engineered adenovirus called Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choroiditis virus (LCMV), which expresses antigen-specific CD8 + and (which can be further engineered to express an antigen designed to elicit a T cell response).

[0443] In some embodiments, the tumor immunotherapy agent is a T cell engineered to express a chimeric antigen receptor, or CAR. Such T cells engineered to express a chimeric antigen receptor are called CAR-T cells.

[0444] CARs have been constructed that consist of a binding domain, which may be derived from a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, fused to a functional end-domain of the T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, which can generate an activation signal in T lymphocytes. Upon antigen binding, such CARs couple to the endogenous signaling pathways of the effector cell, generating an activation signal similar to that initiated by the TCR complex.

[0445] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Pat. No. 8,906,682 (June et al.; incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to contain an extracellular domain with an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T-cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in T cells, the CAR can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, there are over 200 clinical trials underway employing CAR-T cells in a wide range of indications [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0446] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17-expressing innate immune cell subpopulations, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0447] In some embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for B-cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0448] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0449] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0450] In some embodiments, the immune stimulatory therapeutic is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being clinically tested as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immune stimulatory agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 (IL15:sIL-15RA) complexed with the soluble IL-15 binding protein IL-15 receptor alpha chain, which is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0451] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, 603-622, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule that targets an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0452] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, 319-329, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is a pathway-targeting agent, such as those described in Peter L. Toogood.

[0453] In some embodiments, the tumor immunoagent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BITE®) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8):e0183390, the entire contents of which are incorporated herein by reference. In some embodiments, the tumor immunoagent is a bispecific T cell engager (BITE®) antibody construct. In some embodiments, the bispecific T cell engager (BITE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells and releases cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, resulting in the induction of bystander cell lysis. In some embodiments, the bystander cells are within a solid tumor. In some embodiments, the bystander cells to be lysed are in proximity to the BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the tumor immunoagent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor immunoagent is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the tumor immunogen is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAA).

[0454] Exemplary Immune Checkpoint Inhibitors In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor described herein.

[0455] The term "checkpoint inhibitor" as used herein refers to an agent useful for preventing cancer cells from evading a patient's immune system. One of the main mechanisms of anti-tumor immune destruction is known as "T cell exhaustion," which occurs when chronic exposure to antigens causes the upregulation of inhibitory receptors. These inhibitory receptors function as immune checkpoints to prevent uncontrolled immune responses.

[0456] PD-1 and its co-inhibitory receptors, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain 3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223), and others, are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular signals to determine whether or not to proceed with cell cycle progression and other intracellular signaling processes.

[0457] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1, which binds to the programmed cell death 1 receptor (PD-1) and prevents the receptor from binding to the inhibitory ligand PDL-1, thereby abolishing the tumor's ability to suppress the host's anti-tumor immune response.

[0458] In some embodiments, the checkpoint inhibitor is a biotherapeutic or small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In a further aspect, the vaccine is a dendritic cell (DC) vaccine.

[0459] Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors, or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted for blockade or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (a member of the CD2 family of molecules, including all NK, gamma delta, and memory CD8 +(expressed on αβ)T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Examples of immune checkpoint inhibitors include, but are not limited to, tremelimumab (a CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (a PD-1 blocking antibody), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and ipilimumab (an anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0460] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb), pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-MyersSquibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0461] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[0462] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody that has been studied in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); or pidilizumab, also known as CT-011, an antibody that binds to PD-1 in clinical trials for diffuse large B-cell lymphoma and multiple myeloma. (CureTech); avelumab (Bavencio®, Pfizer / MerckKGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody in clinical trials in non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 in clinical trials in non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that is being studied in clinical trials for multiple indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer, non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, liver metastases, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0463] In some embodiments, the checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin-containing protein 3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being studied in solid tumors (NCT02817633). LY3321367 (El iLilly) is an anti-TIM-3 antibody being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being studied in advanced malignancies (NCT02608268).

[0464] In some embodiments, the checkpoint inhibitor is an inhibitor of TIGIT, a T cell immunoreceptor with Ig and ITIM domains or an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0465] In some embodiments, the checkpoint inhibitor is a lymphocyte-activation gene 3 (LAG-3) inhibitor. LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being studied in malignant tumors (NCT03005782). IMP321 (Immutep S.A.), an LAG-3-Ig fusion protein, is being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0466] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti-OX40 antibody in metastatic renal carcinoma (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); and MCI, an agonistic anti-OX40 antibody in advanced solid tumors (NCT02318394 and NCT02705482). EDI0562 (Medimmune / AstraZeneca); MEDI6469, an agonistic anti-OX40 antibody (Medimmune / AstraZeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-MyersSquibb), an agonistic anti-OX40 antibody in advanced cancers (NCT02737475).

[0467] Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-MyersSquibb), an agonistic anti-CD137 antibody in melanoma and skin cancer (NCT02652455), glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).

[0468] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that have been studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics), an agonistic anti-CD27 antibody in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0469] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody in solid tumors and lymphomas (NCT02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR ligand molecule with a human IgG1 Fc domain in advanced solid tumors (NCT02583165).

[0470] Checkpoint inhibitors that can be used in the present invention include inducible T-cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody in lymphoma (NCT02520791), GSK3359609 (Merck), an agonistic anti-ICOS antibody in Phase 1 (NCT02723955), and JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody in Phase 1 (NCT02904226).

[0471] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-MyersSquibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the three domains of the long cytoplasmic tail (KIR3DL2) in lymphoma (NCT02593045).

[0472] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors undergoing clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of SIRPa that binds to CD47 and inhibits CD47 / SIRPa-mediated signaling (NCT03013218); TTI-621 (SIRPa-Fc, Trillium), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which acts by binding human CD47 and preventing it from sending a "do not eat" signal to macrophages (NCT02890368 and NCT02663518). Therapeutics); CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0473] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being investigated in clinical trials include MEDI9447 (Medimmune) (NCT02503774), an anti-CD73 antibody in solid tumors, and BMS-986179 (Bristol-Myers Squibb) (NCT02754141), an anti-CD73 antibody in solid tumors.

[0474] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). STING agonists being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide in lymphoma (NCT03010176), and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).

[0475] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being investigated in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors. (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available CSF1R inhibitor in advanced solid tumors (NCT02829723).

[0476] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors, including monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody being studied in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0477] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0478] The compounds of the present invention can also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit low sensitivity to radiation therapy.

[0479] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of a fixed combination, or the compounds of the present invention and one or more other therapeutic compounds can be administered staggered or independently, or a fixed combination can be administered in combination with one or more other therapeutic compounds.The compounds of the present invention can be administered in addition to or in addition to chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment.As mentioned above, long-term treatment is also possible, as well as adjuvant therapy in conjunction with other treatment strategies.Other possible treatments include therapy to maintain the patient's condition after tumor regression, or chemopreventive therapy for, for example, at-risk patients.

[0480] These additional agents can be administered separately from the compound-containing composition of the present invention as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of the present invention in one composition. When administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0481] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously with another therapeutic agent, sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0482] The amount of a compound of the invention and additional therapeutic agent (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of the invention will be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of a compound of the invention can be administered.

[0483] In those compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dosage of 0.01 to 1,000 μg / kg body weight / day.

[0484] The amount of additional therapeutic agent present in the compositions of the invention is no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to about 100% of the amount that would normally be present in a composition comprising that therapeutic agent as the only therapeutically active agent.

[0485] The compounds of the present invention or pharmaceutical compositions thereof can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of thrombus formation or platelet activation. These undesirable effects can be prevented or reduced by pre-coating the device with a pharmaceutically acceptable composition containing an OXER1 inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention. [Example]

[0486] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While the general methods illustrate the synthesis of specific compounds of the invention, it will be understood that the following general methods, and other methods known to those of skill in the art, are applicable to all compounds, subclasses, and species of each of these compounds, as described herein. Additional compounds of the invention were prepared by methods substantially similar to those described in the Examples herein and known to those of skill in the art.

[0487] General information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported in δ values ​​(ppm) using the deuterated solvent as an internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained on an Agilent 1200 Series 6110 or 6120 mass spectrometer using electrospray ionization, unless otherwise noted. *Typical LCMS conditions were: Waters XBridge C18 column (50 mm × 4.6 mm); flow rate: 2.0 mL / min, column temperature: 40 °C. HPLC analysis was performed using one of the following methods: Method 1: Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 1.6 min, then held in this state for 1.4 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 min, and held in this state for 0.7 min. Method 2: Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 2.0mL / min; mobile phase: 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then held in this state for 1.4 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and held in this state for 0.7 minutes. Method 3: Agilent HPLC 1200; Column: L-column2 ODS (150mm*4.6mm*5.0μm); Column temperature: 40℃; Flow rate: 1.0mL / min; Mobile phase: 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [CH3CN + 0.1% TFA] in 10 minutes, then changed to this state for 5 minutes, and finally changed to 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] in 0.1 minutes, and held in this state for 5 minutes. Method 4: Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0mL / min; Mobile phase: 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then held in this state for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and held in this state for 5 minutes.

[0488] General Procedure A (Wittig reaction to obtain alkene intermediate): To a suspension of phosphorus ylide (1.0 equiv.) in THF was added t-BuOK (3.0 equiv.) at 0 °C. The mixture was stirred for 30 min, and then aldehyde (1.0 equiv.) in THF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Saturated NH4Cl solution was added at 0 °C, and the mixture was acidified to pH 3 with HCl (1.0 M) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography to give the alkene intermediate.

[0489] General Procedure B (hydrogenation of an alkene to a saturated alkane): To a stirred solution of an alkene (1.0 equiv.) in EtOAc was added 10% Pd / C (0.1 equiv. w / w) under an atmosphere of H2 (1.0 atm). The reaction mixture was stirred at room temperature for 8 hours until the reaction was complete (by LCMS) and then filtered. The residue was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure to give the saturated alkane intermediate.

[0490] General Procedure C (Reduction of Carboxylic Acid to Primary Alcohol): To a stirred solution of carboxylic acid (1.0 equiv.) in THF at -20 °C, LiAlH (1.0 equiv.) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 5 h until the reaction was complete (by LCMS). The reaction was quenched by the sequential dropwise addition of water (2.0 equiv.), NaOH (15% aqueous solution, 2.0 equiv.), and water (6.0 equiv.) at 0 °C. The mixture was filtered, and the filtrate was dried over anhydrous NaSO and evaporated under reduced pressure to give the crude alcohol, which was used directly in the next step.

[0491] General procedure D (esterification of alcohol derivatives to mesylate esters with MsO): To a solution of alcohol derivative (1.0 equiv.) and TEA (2.0 equiv.) in THF was added MsO (1.5 equiv.) at 0 °C. The mixture was allowed to warm to room temperature and stirred for an additional 2 h, then quenched with water and extracted with DCM. The combined organic phases were washed with water and brine, dried over anhydrous NaSO, and concentrated to give the crude mesylate ester, which was used directly in the next step.

[0492] General Procedure E (bromo derivative formation from mesylate ester): To a solution of mesylate ester (1.0 equiv.) in acetone was added LiBr (2.0 equiv.) at room temperature. The mixture was stirred at reflux overnight. Water was added, and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the bromo derivative, which was used directly in the next step.

[0493] General procedure F (phosphorus ylide formation from bromo derivative): To a stirred solution of the bromo derivative (1.0 equiv.) in acetonitrile was added PPh3 (2.0 equiv.). The reaction mixture was refluxed at 80 °C overnight. The solvent was evaporated under reduced pressure, and the crude material was purified by silica gel chromatography (10% MeOH / DCM) to give the phosphorus ylide derivative.

[0494] General Procedure G (Acylation Step): To a stirred solution of the indole / azaindole derivative (1.0 equiv.) in dichloromethane was added MeAlCl (1.0 M in hexanes, 2.0 equiv.) at 0 °C. After 45 min, acyl chloride (2.0 equiv.) in CHCl (1 mL) was added dropwise at room temperature, and the reaction mixture was stirred for an additional 2 h. The reaction was quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over NaSO. The solvent was evaporated under reduced pressure, and the crude material was purified by silica gel chromatography (30% EtOAc / Hex) to give the acylated product.

[0495] General Procedure H (Hydrolysis of Ester to Carboxylic Acid): To a mixture of the ester derivative (1.0 equiv.) in THF / HO (5 / 1, v / v) was added lithium hydroxide (5.0 equiv.). The reaction mixture was stirred at room temperature for 16 h until the reaction was complete (by LCMS). Saturated NH4Cl solution was added at 0 °C, and the mixture was acidified with HCl (1.0 M) to pH 6.0, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude was purified by preparative HPLC to give the desired product.

[0496] General Procedure I (Ether Formation): To a stirred solution of alcohol (1.0 equiv.) in DMF was added NaH (60% in mineral oil, 1.0 equiv.). The reaction mixture was stirred at 0° C. under N for 0.5 h, and then the bromo derivative (1.0 equiv.) was added slowly. The reaction mixture was stirred at room temperature for 2 h until the reaction was complete. The suspension was diluted with NaCl (aq.) and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, concentrated in vacuo, and purified by column chromatography to give the ether derivative.

[0497] General Procedure J (oxidation of alcohol to aldehyde): To a solution of alcohol (1.0 equiv.) in DCM was added DMP (1.2 equiv.) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Saturated NaHCO (aq.) was added to the mixture and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography to give the aldehyde product.

[0498] General Procedure K (Addition of Grignard Reagent to Aldehyde): To a solution of aldehyde (1.0 equiv.) in THF was added Grignard reagent (1.2 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography to give the corresponding secondary alcohol product.

[0499] General Procedure L (Alkylation of Terminal Alkynes): To a suspension of terminal alkyne (1.0 equiv.) in THF was added n-BuLi (1.2 equiv.) at −78° C. The mixture was stirred for 1 min, and the bromo derivative (1.0 equiv.) in HMPA was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for an additional 16 h. Saturated NH4Cl solution was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude was purified by silica gel chromatography to give the desired alkylated product.

[0500] General Procedure M (Sonogashira Coupling): To a stirred solution of aryl halide (1.0 equiv.) in THF was added terminal alkyne (1.1 equiv.), Pd(PPh3)2Cl2 (0.1 equiv.), CuI (0.1 equiv.), and TEA (3.0 equiv.). The reaction mixture was stirred at 60 °C under nitrogen for 16 h. The mixture was filtered through a pad of Celite, and then water and EA were added. The organic phase was collected, evaporated under reduced pressure, and purified by silica gel chromatography to give the coupling product.

[0501] General Procedure N (cyclization to give indole / azaindole derivatives): To a stirred solution of alkyne (1.0 equiv.) in DMF was added t-BuOK (1.4 equiv.). The reaction mixture was stirred under nitrogen at 80° C. for 0.5 h. The mixture was filtered through a pad of diatomaceous earth and purified by preparative HPLC to give the indole / azaindole derivatives.

[0502] Example 1: Synthesis of Compound I-24 Synthesis scheme of compound I-24 [ka] [ka] 1.1 Synthesis of intermediate 1-2 [ka]

[0503] To a suspension of (3-carboxypropyl)triphenylphosphonium bromide (207.6 g, 483.7 mmol) in THF (1600 mL) was added t-BuOK (135.7 g, 1.21 mol) at 0 °C. The mixture was stirred for 30 min, and 1-1 (68 g, 483.7 mmol) in THF (200 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Saturated NH4Cl solution was added at 0 °C, the mixture was acidified to pH 3 with HCl (1.0 M), extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (20% EtOAc / hexane) to give 1-2 (71.0 g, 70%) as a colorless oil. LC-MS m / z: 211.2 [M+H] + .

[0504] 1.2 Synthesis of intermediates 1-3 [ka] To a stirred solution of 1-2 (71.0 g, 338.1 mmol) in EtOAc (500 mL) was added 10% Pd / C (8.0 g) under an H atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 8 h until the reaction was complete (by LCMS) and then filtered. The residue was washed with EtOAc, and the combined filtrate was concentrated under reduced pressure to give 1-3 (71 g, 99%) as a colorless oil. LC-MS m / z: 213.1 [M+H] + .

[0505] 1.3 Synthesis of intermediates 1-4 [ka] To a stirred solution of 1-3 (71 g, 334.9 mmol) in THF (500 mL) was added LiAlH (12.7 g, 334.9 mmol) slowly at -20 °C. The reaction mixture was allowed to warm to room temperature and stirred for 5 h until the reaction was complete (by LCMS). The reaction was quenched by the dropwise addition of water (13 mL), NaOH (15% aqueous solution, 13 mL), and water (39 mL) successively at 0 °C. The mixture was filtered, and the filtrate was dried over anhydrous NaSO and evaporated under reduced pressure to give crude product 1-4 (60.6 g, 91%) as a brown oil, which was used directly in the next step. LC-MS m / z: 199.9 [M+H] + .

[0506] 1.4 Synthesis of intermediates 1-5 [ka] To a solution of 1-4 (60.6 g, 305 mmol) and TEA (61.6 g, 610 mmol) in THF (800 mL) was added methanesulfonic anhydride (63.6 g, 366 mmol) at 0 °C under an Ar atmosphere. The mixture was then warmed to room temperature and stirred for an additional 2 h. Saturated NaHCO (aqueous, 80 mL) was added to the mixture, which was then extracted with DCM (300 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 1-5 (84.0 g, 91%) as a yellow oil. LC-MS m / z: 277.2 [M+H] + .

[0507] 1.5 Synthesis of intermediates 1-6 [ka] To a solution of 1-5 (84.0 g, 303.5 mmol) in acetone (800 mL) was added LiBr (52.7 g, 606.9 mmol) at room temperature. The mixture was stirred at reflux overnight. Water (300 mL) was added, and the mixture was extracted with DCM (400 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-6 (75.4 g, yield: 95%) as a yellow oil. LC-MS m / z: 263.1 [M+H] + .

[0508] 1.6 Synthesis of intermediates 1-7 [ka] To a stirred solution of 1-6 (75.4 g, 288.2 mmol) in acetonitrile (600 mL) was added PPh3 (151.0 g, 576.4 mmol). The reaction mixture was refluxed at 80 °C overnight. The solvent was evaporated under reduced pressure, and the crude material was purified by silica gel chromatography (10% MeOH / DCM) to give 1-7 (115.0 g, 76%) as a white solid. LC-MS m / z: 423.1 [M+H] + .

[0509] 1.7 Synthesis of intermediates 1-9 [ka] To a stirred solution of 1-8 (50.0 g, 312.5 mmol) in DMF (600 mL) was added HATU (148.4 g, 390.6 mmol) and DIEA (155 mL, 937.5 mmol) in an ice bath. After stirring at room temperature for 1 h, pyridin-2-ylmethanol (40.88 g, 375.0 mmol) was added, and the reaction mixture was stirred overnight. Upon completion of the reaction (by LCMS), the reaction mixture was quenched with water (1.0 L), extracted with EtOAc (600 mL × 3), washed with water and brine, and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (10–33% EtOAc / PE) and preparative HPLC. The enantiomers 1-9 and 1-10 were separated by chiral HPLC under supercritical fluid conditions (column: CHIRALPAK AY-3 (4.6 mm × 100 mm), solvent: 15% EtOH in liquid CO at 35 °C and 2000 psi, flow rate: 2 mL / min, detector: 215 nm) to give 1-9 (t R 1.542 min, 18 g, yield: 23%) was obtained as a yellow oil. R :1.895 minutes.

[0510] 1.8 Synthesis of Intermediate 1-11 [ka] To a stirred solution of 1-9 (18.0 g, 71.6 mmol) in MeOH (200 mL) was added 15% Pd / C (2.7 g) under an H atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 2 h until the reaction was complete (by LCMS) and then filtered. The residue was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0.1% formic acid in 24% EtOAc / PE) to give 1-11 (8.5 g, yield: 74%) as a pale yellow oil. LC-MS m / z: 161.2 [M+H] + .

[0511] 1.9 Synthesis of Intermediates 1-12 [ka] A solution of 1-11 (200 mg, 1.25 mmol) in SOCl (1.5 mL) was stirred at 70 °C for 1 h. The residue was concentrated under reduced pressure to give a crude product, which was co-distilled with DCM (2 × 10 mL) to give the product 1-12 (190 mg, yield: 85%) as a yellow oil, which was used directly in the next step.

[0512] 1.10 Synthesis of Intermediate 1-14 [ka] To a solution of 1-13 (5.0 g, 25.4 mmol) and K2CO3 (10.5 g, 76.3 mmol) in DMF (30 mL) was added methyl iodide (7.2 g, 50.9 mmol) under an Ar atmosphere. The mixture was stirred at room temperature overnight until the reaction was complete (by LCMS). The reaction mixture was slowly poured into cold water, and the precipitate was collected and dried to give 1-14 (5.0 g, 88%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.17 (s, 1H), 4.15 (s, 3H), 3.95 (s, 3H).

[0513] 1.11 Synthesis of intermediate 1-15 [ka] To a stirred solution of 1-14 (5.0 g, 22.3 mmol) in THF (50 mL) was added LiAlH (848 mg, 22.3 mmol) slowly at -20 °C. The reaction mixture was allowed to warm to room temperature and stirred for 5 h until the reaction was complete (by LCMS). The reaction was quenched by the dropwise addition of water (0.9 mL), NaOH (15% aqueous solution, 2.7 mL), and water (0.9 mL) successively at 0 °C. The mixture was filtered, and the filtrate was dried over anhydrous NaSO and evaporated under reduced pressure to give crude product 1-15 (3.1 g, 71%) as a gray solid, which was used directly in the next step.

[0514] 1.12 Synthesis of intermediate 1-16 [ka] To a mixture of 1-15 (3.1 g, 15.8 mmol) in DCM (25 mL) was added MnO (31.0 g, 356 mmol). The reaction mixture was stirred at room temperature for 4 h until the reaction was complete (by LCMS) and then filtered. The residue was washed with EtOAc, and the combined filtrate was concentrated under reduced pressure to give 1-16 (2.5 g, 80%) as a gray solid.

[0515] 1.13 Synthesis of intermediate 1-17 [ka] To a suspension of 1-16 (2.5 g, 12.6 mmol) in THF (100 mL) was added LiHMDS (1.0 M in THF, 31.6 mL, 31.6 mmol) at −78° C. The mixture was stirred at 30° C. for 30 min, and then 1-7 (9.7 g, 50.3 mmol) in THF (100 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. Saturated NH4Cl solution was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (5% EtOAc / hexane) to give 1-17 (2.9 g, 64%) as a pale yellow solid.

[0516] 1.14 Synthesis of intermediate 1-18 [ka] To a stirred solution of 1-17 (2.9 g, 8.1 mmol) in EtOAc (30 mL) was added 10% Pd / C (580 mg) under an H atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 1 h until the reaction was complete (by LCMS) and then filtered. The residue was washed with EtOAc, and the combined filtrate was concentrated under reduced pressure to give 1-18 (2.3 g, 79%) as a pale yellow solid.

[0517] 1.15 Synthesis of intermediate 1-19 [ka] To a stirred solution of 1-18 (360 mg, 1.0 mmol) in dichloromethane (15 mL) was added MeAlCl (1.0 M in hexanes, 1.0 mL, 1.0 mmol) at 0 °C. After 45 min, 1-12 (1.4 g, 6.4 mmol) in CHCl (1 mL) was added dropwise at room temperature, and the reaction mixture was stirred for an additional 2 h. The reaction was quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over NaSO. The solvent was evaporated under reduced pressure, and the crude material was purified by silica gel chromatography (30% EtOAc / Hex) to give 1-19 (320 mg, 64%) as a yellow oil.

[0518] 1.16 Synthesis of Compound I-24 [ka] To a mixture of 1-19 (320 mg, 0.64 mmol) in THF / HO (10 mL / 2 mL) was added lithium hydroxide (120 mg, 3.2 mmol), and the reaction mixture was stirred at room temperature for 16 h until the reaction was complete (by LCMS). Saturated NH4Cl solution was added at 0 °C, and the mixture was acidified with HCl (1.0 M) to pH 6.0, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford I-24 (130 mg, 42%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.18 (br, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.31-7.26 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 3.80 (s, 3H), 3.18 (t, J = 7.6 Hz, 2H), 3.04 (dd, J = 16.4, 5.6 Hz, 1H), 2.86 (dd, J = 16.8, 7.6 Hz, 1H), 2.58 (t, J = 7.6 Hz, 2H), 2.41 (d, J = 5.6 Hz, 1H), 2.37 (d, J = 5.6 Hz, 1H), 2.17 (dd, J = 15.6, 8.0 Hz, 1H), 1.60-1.56 (m, 4H), 1.46-1.41 (m, 2H), 1.38-1.34 (m, 2H), 0.96 (d, J = 6.8 Hz, 3H). LC-MS m / z: 489.0 [M+H] + .

[0519] Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein, and data for these compounds are shown in Tables 2 and 2a below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 3]

[0520] Example 2: Synthesis of Compound I-60 Synthesis scheme of compound I-60 [ka] 2.1 Synthesis of intermediate 2-2 [ka] To a stirred solution of propane-1,3-diol (25.9 g, 340.7 mmol) in DMF (150 mL) was added NaH (1.4 g, 34.1 mmol, 60% in mineral oil). The reaction mixture was stirred at 0 °C under N atmosphere for 0.5 h, then 2-1 (7.0 g, 34.1 mmol) was added slowly and the reaction mixture was stirred at room temperature for 2 h until the reaction was complete. The suspension was diluted with NaCl (aqueous solution 500 mL) and extracted with EtOAc (500 mL × 2). The organic layer was washed with brine (500 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 2-2 (6.8 g, crude) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.27-7.25 (m, 2H), 7.21-7.19 (m, 1H), 4.48 (d, J = 6.8 Hz, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.38 (s, 1H), 1.88-1.85 (m, 2H).

[0521] 2.2 Synthesis of intermediate 2-3 [ka] To a stirred solution of 2-2 (6.5 g, 32.5 mmol) in DCM (100 mL) was added CBr4 (16.2 g, 48.7 mmol) and PPh3 (8.5 g, 48.7 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h until the reaction was complete. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel chromatography (PE / EA = 3 / 1) to give 2-3 (5.6 g, yield: 66%) as a colorless oi...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or an N-oxide, or a pharmaceutically acceptable salt thereof, Ring A is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; L １ is one of the following: (a) C １ - ５ a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of said chain are independently optionally —O—, —C(O)—, —C(S)—, —Cy—, —C(R) ２ -, -CH(R)-, -CH(OR)-, -C(F) ２ -, -N(R)-, -S-, -S(O)-, or -S(O) ２ -substituted); or (b) covalently bonded; Each R is independently hydrogen or C １ - ６ an optionally substituted group selected from aliphatic; phenyl; an 8- to 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally join together to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is independently an optionally substituted divalent ring selected from a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl, or a 5- to 6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L ２ is one of the following: (a) C １ - ７ a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of said chain are independently optionally selected from -O-, -C(O)-, -C(S)-, -Cy-, -C(R) ２ -, -CH(R)-, -CH(OR)-, -CH(F)-, -C(F) ２ -, -N(R)-, -S-, -S(O)-, or -S(O) ２ -substituted); or (b) covalently bonded; R １ is (i) -C(O)OR, -C(O)N(R)S(O) ２ R, -C(O)N(R)OR, -C(O)NR ２ , —CN, —OH, and hydrogen; (ii) 5-6 membered partially unsaturated oxo-heterocyclyl (n R ５ and (iii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (where n R ５ ) are selected from the following: R ２ is one of the following: (a) phenyl; a 5-6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7-membered saturated or partially unsaturated monocyclic carbocycle; a 4-8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10-membered saturated or partially unsaturated spirocycle having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10-membered aromatic or partially aromatic bicyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (each of which is selected from p R ６ replaced by an instance of (b) C １ - ７ aliphatic, —C≡CR, —C(O)OR, or —C(O)R (each of which has p R ６ replaced by an instance of (c) hydrogen; R ３ is one of the following: (a) one or more —OH or —N(R) ２ C optionally substituted with １ - ６ aliphatic group; (b)-CD ３ ; (c) hydrogen; or (d) absence; R ４ Each instance of ｚ , -C≡CR, halogen, -CN, -NO ２ , -OR, -OCF ３ , -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -CF ２ R, -CF ３ , -CR ２ (CN), -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -C(S)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)NR ２ , -N(R)S(O) ２ NR ２ , -N(R)S(O) ２ R, -N=S(O)R ２ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ２ , -SiR ３ , -P(O)(R)NR ２ , -P(O)(R)OR or -P(O)R ２ or Two R's ４ the groups optionally taken together form =0; or Two R's ４ groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ５ and R ６ Each instance of ｚ , halogen, -CN, -NO ２ , -OR, -OCF ３ , -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -CF ２ R, -CF ３ , -CR ２ (CN), -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -C(S)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)NR ２ , -N(R)S(O) ２ NR ２ , -N(R)S(O) ２ R, -N=S(O)R ２ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ２ , -SiR ３ , -P(O)(R)NR ２ , -P(O)(R)OR or -P(O)R ２ or Two R's ５ the groups optionally taken together form =0; Two R's ６ the groups optionally taken together form =0; Two R's ５ groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R's ６ groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ｚ Each instance of C １ - ６ Independently selected from optionally substituted groups selected from aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; However, L １ -R １ but 【Chemistry 2】 and R ３ and R ４ Ring A containing a substituent of 【Transformation 3】 If L ２ -R ２ is n-hexyl, 【Chemistry 4】 rather than; L １ -R １ but 【Transformation 5】 and R ３ and R ４ Ring A containing a substituent of 【Transformation 6】 If L ２ -R ２ is not n-hexyl).

2. (R ４ ) ｍ , R ３ , -C(O)-L １ -R １ , and -L ２ -R ２ Ring A substituted with 【Chemistry 7-1】 【Chemistry 7-2】 2. The compound or N-oxide of claim 1, wherein:

3. The compound has the formula I-a-2: 【Transformation 8】 or N-oxide, or a pharmaceutically acceptable salt thereof, of the compound of claim 1 .

4. L １ But C １ - ５ 2. The compound or N-oxide of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a divalent linear or branched saturated hydrocarbon chain of the formula:

5. L １ but, 【Chemistry 9】 5. The compound or N-oxide of claim 4, wherein:

6. L １ but, 【Chemistry 10】 2. The compound or N-oxide of claim 1, wherein:

7. L １ and R １ but, 【Chemistry 11】 7. The compound or N-oxide of claim 6, wherein:

8. L ２ But C １ - ７ 2. The compound of claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein:

9. L ２ But -(CH ２ ) ３－４ -O-(CH ２ ) １－２ 2. The compound of claim 1, wherein the N-oxide is -, or a pharmaceutically acceptable salt thereof.

10. L ２ but, 【Chemistry 12-1】 【Chemistry 12-2】 2. The compound or N-oxide of claim 1, wherein:

11. L ２ and R ２ but, 【Chemistry 13】 11. The compound or N-oxide of claim 10, wherein:

12. R １ but, 【Chemistry 14】 2. The compound or N-oxide of claim 1, wherein:

13. R ２ but, 【Chemistry 15】 2. The compound or N-oxide of claim 1, wherein:

14. R ２ but, 【Chemistry 16】 14. The compound or N-oxide of claim 13, wherein:

15. R ３ But -CH ３ 2. The compound or N-oxide of claim 1, wherein:

16. R ４ 2. The compound or N-oxide of claim 1, or a pharmaceutically acceptable salt thereof, wherein is -Cl, or -CN.

17. 2. The compound or N-oxide of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

18. The compound has any one of formula I-j-7, I-j-8, I-j-9, I-j-10, I-j-11, or I-j-12: 【Chemistry 17】 2. The compound or N-oxide of claim 1, wherein:

19. The compound has any one of formulas I-k-1, I-k-2, I-k-3, I-k-4, I-k-5, or I-k-6: [Chemistry 18] 2. The compound or N-oxide of claim 1, wherein:

20. The compound has any one of formula I-g-4, I-g-5, or I-g-6: 【Chemistry 19】 2. The compound or N-oxide of claim 1, wherein:

21. The compound has any one of formula I-h-1, I-h-2, I-h-3, I-h-4, I-h-5, or I-h-6: 【Chemistry 20】 2. The compound or N-oxide of claim 1, wherein:

22. The compound has any one of formula I-h-4, I-h-5, or I-h-6: 【Chemistry 21】 22. The compound or N-oxide of claim 21, wherein:

23. R ４ and R ６ are each independently for each occurrence hydrogen, halogen, or C １ - ６ 21. The compound or N-oxide of claim 20, or a pharmaceutically acceptable salt thereof, which is aliphatic.

24. 2. The compound or N-oxide, or a pharmaceutically acceptable salt thereof, of claim 1, wherein the compound is selected from the compounds shown in Table 1.

25. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or an N-oxide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

26. 25. A medicament for treating an OXER1-mediated disorder, disease, or condition in a patient, comprising a compound according to any one of claims 1 to 24, or an N-oxide, or a pharmaceutically acceptable salt thereof.

27. 27. The pharmaceutical composition of claim 26, wherein the disease, disorder, or condition is asthma, severe eosinophilic asthma, late-onset inflammatory asthma, chronic obstructive pulmonary disease (COPD), hypereosinophilic syndrome (HES), nasal polyps, allergic inflammation, allergic rhinitis, atopic dermatitis, chronic idiopathic urticaria, psoriasis, acne, idiopathic pulmonary fibrosis, eosinophilic gastritis, eosinophilic esophagitis (EoE), eosinophilic gastroenteritis, arthritis, atherosclerosis, or acute myocardial infarction.

28. 27. The method of claim 26, wherein the disease, disorder, or condition is asthma.

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