HK40115037A - Oxer1 antagonists and uses thereof - Google Patents

Description

OXER1 antagonists and their uses

Cross-references to related applications

This application claims the benefit of U.S. Provisional Application No. 63/291,555, filed December 20, 2021, the entire contents of which are hereby incorporated by reference.

Technical Field

This invention relates to compounds and methods suitable for antagonizing the G protein-coupled receptor OXER1. The invention also provides pharmaceutically acceptable compositions comprising the compounds of this invention and methods for treating various conditions using said compositions.

Background of the Invention

Arachidonic acid is a key biological intermediate that can be converted into a large number of bioactive eicosanoic acids. Arachidonic acid is metabolized via the 5-lipoxygenase (5-LO) pathway to form leukotrienes such as LTB ₄ , LTC ₄ , and LTD ₄ , as well as 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE). 5-HETE is then oxidized to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) by 5-hydroxyeicosate dehydrogenase (a microsomal enzyme found in leukocytes, platelets, endothelial cells, and epithelial cells).

5-O-ETE is a potent chemotherapeutic agent for eosinophils and neutrophils, inducing a variety of rapid responses in these cells. Examples of responses in these cells, in addition to cell migration and tissue invasion, include actin polymerization, calcium mobilization, integrin expression, L-selectin desquamation, degranulation, and superoxide production. Eosinophils are likely the primary target of 5-O-ETE, and it is the most potent chemotherapeutic agent for these cells in lipid mediators. It has been shown to induce eosinophil migration across the endothelium and to induce eosinophil and neutrophil infiltration into the skin. 5-O-ETE also promotes the survival of eosinophils and possibly other types of inflammatory cells by, for example, inducing the release of GM-CSF from monocytes. 5-O-ETE is also a chemotherapeutic agent for monocytes and has been shown to stimulate the proliferation of prostate tumor cells. Eosinophil migration to body sites such as the skin, lungs, and intestines is mediated by eosinophil chemical inducers (such as 5-oxo-ETE) and plays a key role in type 2 inflammatory-driven diseases, including skin, respiratory, and gastrointestinal disorders such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, and acne. Eosinophil migration has also been shown to play a role in certain cancers, such as prostate cancer.

OXER1 is a G protein-coupled receptor (GPCR) with high selectivity for 5-oxo-ETE. It is also known as G protein-coupled receptor 170 (GPR170), hGPCR48, HGPCR48, and R527. The interaction between 5-oxo-ETE and OXER1 is an important mediator of eosinophil migration. Selective OXER1 antagonists can be used as therapeutics or preventative agents for the aforementioned diseases.

Invention Overview

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective antagonists of OXER1. In some embodiments, the present invention provides compounds having the formula presented herein.

The compounds of this invention and their pharmaceutically acceptable compositions may be used to treat a variety of diseases, conditions, or disorders associated with OXER1. Such diseases, conditions, or disorders include those described herein.

The compounds provided by this invention can also be used to study the role of OXER1 in biological and pathological phenomena; to study the migration of eosinophils to body sites such as skin, lungs and intestines; and to conduct comparative evaluations of new OXER1 inhibitors or other eosinophil migration regulators in vivo and in vitro.

Detailed Implementation

1. General description of certain embodiments of the present invention:

In some respects, the present invention provides compounds of formula I:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^L2 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined below and described in the embodiments herein.

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

In some embodiments, the present invention provides a method for treating OXER1-mediated diseases, conditions, or disorders, the method comprising administering a compound of formula I or an N-oxide or a pharmaceutically acceptable salt thereof to a patient in need.

2. Compounds and definitions;

The compounds of this invention include those generally described herein and further illustrated by the categories, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999; and “March’s Advanced Organic Chemistry,” 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain (which is fully saturated or contains one or more unsaturated units) or a monocyclic or bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units) with a single connection point to the rest of the molecule, but which is not aromatic (also referred to herein as "carbocyclic,""cycloaliphatic," or "cycloalkyl"). Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") refers to a fully saturated or containing one or more unsaturated units, but not aromatic, monocyclic _C3 - _C6 hydrocarbon with a single connection point to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic system having at least one bridging bond, i.e., a carbocyclic or heterocyclic system. As defined by IUPAC, a "bridging bond" is a non-branched or valence bond connecting two bridgeheads of multiple atoms or a single atom, wherein a "bridgehead" is any skeletal atom of a ring system bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as set forth with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

The term "lower alkyl" refers to a _C1-4 straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to a _C1-4 straight-chain or branched alkyl group that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternized form of basic nitrogen; or substituted nitrogen of heterocycles, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl) or NR ⁺ (as in N-substituted pyrrolealkyl)).

As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

As used herein, the term “divalent _C1-8 (or _C1-6 ) saturated or unsaturated straight or branched hydrocarbon chain” refers to a straight or branched divalent alkylene, alkenyl, or ynylene chain as defined herein.

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 are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene containing at least one double bond and one or more hydrogen atoms replaced by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group.

The term "halogen" refers to F, Cl, Br, or I.

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

The term "aryl," used alone or as part of a larger portion of "aralkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system that may carry one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthylimide, phenanthridine, or tetrahydronaphthyl.

The terms “heteroaryl” and “heteroaryl-” (e.g., “heteroarylalkyl” or “heteroarylalkoxy”) used alone or as part of a larger part refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur; and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, indazinyl, purinyl, naphthidyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein, unless otherwise specified, the group or connecting point is on the heteroaryl ring or on one of the rings to which the heteroaryl ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaryl," any of which includes optionally substituted rings. The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When used with respect to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or ⁺ NR (e.g., in N-substituted pyrrolealkyl).

Heterocycles can be attached to their side groups at any heteroatom or carbon atom to produce a stable structure, and any ring atom can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxyl, dioxazolidinyl, dioxazolidinyl, diazaspirolyl, diazaspirolyl, oxazolidinyl, thioazolidinyl, morpholinyl, 2-oxa-6-azaspirol[3.3]heptane, and quininecycloyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indolyl, chromanyl, phenanthridineyl, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moiety are independently and optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but not to include aryl or heteroaryl moieties.

Partially aromatic bicyclic refers to a bicyclic ring in which one ring is aromatic and the other ring is not aromatic.

As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by a suitable substituent. Unless otherwise indicated, the "optionally substituted" group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably combinations that form stable or chemically viable compounds. The term "stable" as used herein means a compound that remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and in some embodiments recovered, purified, and used for the purposes disclosed herein.

The suitable monovalent substituents on the substituted carbon atoms of the "optionally substituted" groups are independently halogens; -( _CH2 ) _0-4Ro ; -(CH2)0-4ORo; -O( _CH2 ) ^0-4Ro ; -O-( _CH2 ) _0-4C ( ^{O) ORo} ; -(CH2)0-4CH(IRo)2; -(CH2) _0-4SRo ; -( _CH2 )0-4Ph, which can be substituted by Ro; -( _CH2 ) _0-4I ( ^CH2 ) _0-1Ph, which can be substituted by ^Ro ; -CH=CHPh-, which can be substituted ^by Ro; -( _CH2 ) _0-4O (CH2) _{0-1 - pyridyl} , which can be substituted by ^Ro ; -NO2; -CN; _-N3 ; -( _CH2 ) _0-4O ( _CH2 ) _0-1- pyridyl, which can be substituted by ^Ro ; -NO2; -CN; -N3; -(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted by ^Ro ; -NO2; -CN; -N3; - _(CH2 ) _0-4O (CH2)0-4O( _CH2 ) _0-1 -pyridyl, which can be substituted by ^Ro ; _-NO2 ; -CN; _-N3 ; -(CH2)0-4O(CH2)0-4O(CH2)0-1O(CH2 ₎ 0-4 ... ) _0-4 N(R ^o ) ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ;-N(R ^o )C(S)R ^o ;-(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )C(S)NR ^o ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ;-N(R ^o )N(R ^o )C(O)R ^o ;-N(R ^o )N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )N(R ^o )C(O)OR ^o ;-N(R ^o )C(NR ^o )N(R ^o )2;-(CH ₂ ) _0-4 C(O)R ^o ;-C(S)R ^o ;-(CH ₂ ) _0-4 C ₍ O)OR ^o ;-(CH ₂ ) _0-4 C(O)SR ^o ;-(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ;-(CH ₂ ) _0-4 OC(O)R ^o ;-OC(O)(CH ₂ ) _0-4 SR ^o ;-SC(S)SR ^o ;-(CH ₂ ) _0-4 SC(O)R ^o ;-(CH ₂ ) _0-4 C(O)NR ^o ₂ ;-C(S)NR ^o ₂ ;-C(S)SR ^o ;-SC(S)SR ^o ,-(CH ₂ ) _0-4 OC(O)NR ^o ₂ ;-C(O)N(OR ^o )R ^o ;-C(O)C(O)R ^o ;-C(O)CH ₂ C(O)R ^o ;-C(NOR ^o )R ^o ;-(CH ₂ ) _0-4 SSR ^o ;-(CH ₂ ) _0-4 S(O) ₂ R ^o ;-(CH ₂ ) _0-4 S(O) ₂ OR ^o ;-(CH ₂ ) _0-4 OS(O) ₂ R ^o ;-S(O) ₂ NR ^o ₂ ;-(CH ₂ ) _o-4 S(O)R ^o ;-N(R ^o )S(O) ₂ NR ^o ₂ ;-N(R ^o )S(O) ₂ R ^o ;-N(OR ^o )R ^o ;-C(NH)NR ^o ₂ ;-P(O) ₂ R ^o ;-P(O)R ^o ₂ ;-OP(O)R ^o ₂ ;-OP(O)(OR ^o ) ₂ ;-SiR ^o ₃ ;-(C _1-4 straight-chain or straight-chain alkylene)ON( ^Ro ) ₂ ; or -( _C1-4 straight-chain or straight-chain alkylene)C(O)ON( ^Ro ) ₂ , wherein each ^Ro may be substituted as defined below and is independently hydrogen, _C1-6 aliphatic, _-CH2Ph , -O( _CH2 ) _0-1Ph , _-CH2- (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, regardless of the above definitions, two independently occurring ^Ros together with one or more intermediary atoms form a 3-12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on ^Ro (or a ring formed by two independently occurring ^Ro atoms and their intervening atoms) are independently halogens, -( _CH₂ ) _O₻₂R ^· , -(halo group R ^· ), -( _CH₂ ) _O₻₂OH , -(CH₂) _O₻₂OR ^· , -( _CH₂ ) _O₻₂CH (OR ^· ) _₂ ; -O( _halo group R ^· ), -CN, _-N₃ , -( _CH₂ ) _O₻₂C (O)R ^· , -( _CH₂ ) _O₻₂C (O)OH, -( _{CH₂ ) O₻₂C} (O)OR ^· , -( _CH₂ ) _O₻₂SR ^· , -( _CH₂ ) _O₻₂SH , -( _CH₂ ) _{O₻₂NH₂ ,} -( _CH₂ ) _O₻₂NHR ^1. -( _CH₂ ) _₀- 2NR₁ ^2. _{-NO₂ 3. -OSiR₁} ^3. _{-C(O)SR₁ 4.} ^- _{( C₁} - ₄ straight-chain or branched alkylene)C(O) ^OR₁ or ^-SSR₁ , wherein each ^R₁ is unsubstituted or, if preceded by a "halogen group", substituted by only one or more halogens, and independently selected from C₁ _-4 aliphatic groups, _-CH₂Ph , -O( _CH₂ ) _₀- 1Ph ^, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for the saturated carbon atom of ^R₂ include =O and =S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) _2R ^* , =NR ^* , triNOR ^* , -O(C(R ^* ₂ )) _2-3O- or -S(C( _R ^* ₂ )) _2-3S- , wherein _each R ^* is independently selected from hydrogen, a _C1-6 aliphatic group that may be substituted as defined below, or an unsubstituted 5-6 saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents for adjacent substituted carbons of the "optionally substituted" group include: -O(CR ^* ₂ ) _2-3O- , wherein R ^* is independently selected each time it appears from hydrogen, _C1-6 aliphatic groups that may be substituted as defined below, or unsubstituted 5-6 saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogens, -R ^· , -(halogen R ^· ), -OH, -OR ^· , -O(halogen R ^· ), -CN, -C(O)OH, -C(O)OR ^· , _-NH2 , -NHR ^· , -NR ^· ₂ or _-NO2 , wherein each ^R1 is unsubstituted or substituted with only one or more halogens if preceded by "halogen", and is independently _C1-4 aliphatic groups, _-CH2Ph , -O( _CH2 ) _0-1Ph or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the substituted nitrogen of the "optionally substituted" group include, or wherein each is independently hydrogen, a _C1-6 aliphatic group that may be substituted as defined below, an unsubstituted -OPh, or an unsubstituted 5-6 saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently occurring groups together with one or more intervening atoms to form a 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group are independently halogens, -R ^· , -(halogen R ^· ), -OH, -OR ^· , -O(halogen R ^· ), -CN, -C(O)OH, -C(O)OR ^· , _-NH2 , -NHR ^· , -NR ^· ₂ or _-NO2 , wherein each R ^· is unsubstituted or substituted by only one or more halogens if preceded by "halogen", and is independently _C1-4 aliphatic groups, _-CH2Ph , -O( _CH2 ) _0-1Ph or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

As used herein, the term "pharmaceutically acceptable salt" means those salts that, to the extent of reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described 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 formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N ⁺ ( _C1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate).

Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformations)) of said structures; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers for each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention, including those in which hydrogen is replaced by deuterium or tritium or carbon is replaced by carbon enriched in ^13C- or ^14C- , are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, probes in bioassays, or therapeutic agents according to the present invention.

In some embodiments, ^R1 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R2 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R3 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R4 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R5 of the provided compound contains one or more deuterium atoms. In some embodiments, ^L1 of the provided compound contains one or more deuterium atoms. In some embodiments, ^L2 of the provided compound contains one or more deuterium atoms. In some embodiments, ^L3 of the provided compound contains one or more deuterium atoms. In some embodiments, ring A of the provided compound contains one or more deuterium atoms. In some embodiments, ring B of the provided compound contains one or more deuterium atoms. In some embodiments, ring C of the provided compound contains one or more deuterium atoms. In some embodiments, R of the provided compound may be substituted with one or more deuterium atoms. In some embodiments, ^Rz of the provided compound may be substituted with one or more deuterium atoms.

The drawn structures represent relative configurations unless marked as absolute configurations. This invention covers individual enantiomers and racemic mixtures. It also covers diastereomeric mixtures.

As used herein, an "OXER1 antagonist" or "OXER1 inhibitor" is a molecule that reduces, inhibits, or otherwise mitigates one or more of the biological activities of OXER1 (e.g., Gαi signaling, increased immune cell migration, and secretion of pro-inflammatory cytokines). Antagonism by an OXER1 antagonist does not necessarily indicate complete elimination of OXER1 activity. In fact, activity can be reduced by statistically significant amounts, including, for example, a reduction in OXER1 activity of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% compared to a suitable control. In some embodiments, the OXER1 antagonist reduces, inhibits, or otherwise diminishes the activity of OXER1. The compounds disclosed in this invention bind directly to OXER1 and inhibit its activity.

"Specific antagonist" means an agent that reduces, inhibits, or otherwise diminishes the activity of a defined target to a greater extent than an unrelated target. For example, an OXER1 specific antagonist reduces the biological activity of at least one OXER1 by a statistically greater amount than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the _IC50 of the antagonist against the target _is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the antagonist against the non-target. The compounds disclosed in this invention may or may not be specific OXER1 antagonists. Specific OXER1 antagonists reduce the biological activity of OXER1 by a statistically greater amount than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the OXER1 antagonist specifically inhibits the activity of OXER1. In some of these embodiments, the _IC50 of the OXER1 antagonist against OXER1 is approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or lower than the IC50 of the _OXER1 antagonist against closely related GPCRs (e.g., free fatty acid receptors (FFARs), such as GPR40 (FFAa1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other types of GPCRs (e.g., type A GPCRs).

The compounds of the present invention can be tethered to a detectable moiety. It should be understood that such compounds can be used as developing agents. Those skilled in the art will recognize that the detectable moiety can be linked to the provided compound via suitable substituents. As used herein, the term "suitable substituent" refers to a moiety capable of covalently linking to the detectable moiety. Such moieties are well known to those skilled in the art and include the group containing, for example, carboxylic acid ester moieties, amino moieties, thiol moieties, or hydroxyl moieties, etc. It should be understood that such moieties can be linked directly or via tethering groups (e.g., divalent saturated or unsaturated hydrocarbon chains). In some embodiments, such moieties can be linked via click chemistry. In some embodiments, such moieties can be linked via a 1,3-cycloaddition of an azide compound with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described in 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 portions may be connected via strained alkynes. Methods for achieving rapid Cu-free click chemistry using strained alkynes are known in the art and include those described in: Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

As used herein, the terms “detectable portion” and “label” are used interchangeably and refer to any portion that can be detected (e.g., primary and secondary labels). Primary labels, such as radioisotopes (e.g., tritium, ^32P , ^33P , ^35S , or ^14C ), mass tags, and fluorescent labels, are signals that can be detected without further modification to generate reporter genes. Detectable portions also include luminescent and phosphorescent groups.

As used herein, the term "secondary label" refers to a portion that requires the presence of a second intermediate to generate a detectable signal (e.g., biotin and various protein antigens). In the case of biotin, the secondary intermediate may include an antibiotic streptavidin-enzyme conjugate. In the case of antigen labeling, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group via non-radiative fluorescence resonance energy transfer (FRET), and the second group generates a detection signal.

As used herein, the terms “fluorescent label,” “fluorescent dye,” and “fluorophore” refer to the portion that absorbs light energy at a defined excitation wavelength and emits light energy at different wavelengths. Examples of fluorescent labels include, but are not limited to: 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, and BODI. PY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), carboxy-rhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Anthocyanin Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl Acetate, Dapoxyl, DialkylaminoCoumarin, 4′,5′-Dichloro-2,7-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Rhodamine B, Marie Marina Blue, Methoxycoumarin, Naphthalene Fluorescein, 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.

As used herein, the term "quality tag" refers to any portion that can be specifically detected by mass spectrometry (MS) techniques by virtue of its mass. Examples of quality tags include electrophoretic release tags, such as N-[3-[4′-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglycero]isopiperidinecarboxylic acid, 4′-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and derivatives thereof. The synthesis and utility of these quality tags are described in U.S. Patents 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 quality tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers having varying lengths and base compositions. A wide variety of organic molecules (neutral and charged (biomolecules or synthetic compounds)) with appropriate mass ranges (100-2000 Daltons) can also be used as quality labels.

The compounds of this invention can be tethered to the E3 ligase-binding moiety. It should be understood that such compounds can be used as degrading 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 the E3 ligase-binding moiety can be linked to the provided compounds via suitable substituents as defined above. Such degrading agents have been found to be useful for targeted degradation of G protein-coupled receptors (Li et al., Acta Pharm. Sin. B. 2020, 10(9), 1669-1679.).

As used herein, the term “E3 ligase-binding moiety” is used interchangeably with the term “E3 ligase binder” and refers to any moiety capable of binding to and/or recruiting E3 ligases (e.g., cIAP1, MDM2, cereblon, VHL, APC/C) for targeted degradation.

The compounds of this invention can be tethered to lysosomal targeting moieties. It should be understood that such compounds can be used as degrading agents (see, for example, Banik et al., 2020. Nature 584, 291-297.). Those skilled in the art will recognize that lysosomal targeting moieties can be linked to the provided compounds via suitable substituents as defined above. Such degrading agents have been found to be useful for the targeted degradation of secretory and membrane proteins (Banik et al., 2020).

As used herein, the term “lysosome-targeting portion” may be used interchangeably with the term “lysosome-binding portion” and refers to any portion capable of binding to and/or recruiting cell surface lysosome-targeting receptors (e.g., cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

As used herein, the terms “measurable affinity” and “measurable inhibition” refer to a measurable change in OXER1 activity between a sample containing the compounds of the present invention or combinations thereof and an OXER1 GPCR and an equivalent sample containing an OXER1 GPCR in the absence of said compounds or combinations thereof.

As used herein, the terms “a” and “an” mean “one or more” and include plurals, unless the context is inappropriate.

Throughout this specification, when a composition is described as having, including, or comprising specific components, or when a process and method is described as having, including, or comprising specific steps, it is also contemplated that there are inventive compositions substantially composed of or consisting of the listed components, and that there are inventive processes and methods substantially composed of or consisting of the listed processing steps.

Generally, unless otherwise specified, the specified percentages of the composition are by weight.

3. Description of exemplary implementation schemes:

As described above, in some embodiments, the present invention provides a compound of formula I:

Or its N-oxide or pharmaceutically acceptable salt, 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 a phenyl ring.

^L1 is one of the following:

(a) A _C1-5 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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 bond;

Each R is independently hydrogen, or a group optionally substituted from the following: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

The two R groups on the same nitrogen atom optionally form a 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring with nitrogen and 0-3 independently selected heteroatoms other than nitrogen, oxygen and sulfur.

Each -Cy- is independently a divalent ring that is optionally substituted, selected from 4-7 membered saturated or partially unsaturated heterocyclic alkenyl groups having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl alkenyl groups; 3-7 membered saturated or partially unsaturated carbocyclic alkenyl groups; or 5-6 membered heteroaryl alkenyl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

^L2 is one of the following:

(a) A _C1-7 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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 bond;

^R1 is selected from (i) -C(O)OR, -C(O)N(R)S(O) _2R , -C(O)N(R)OR, -C(O)NR2, -CN, -OH and hydrogen; (ii) a 5-6 membered partially unsaturated oxoheterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n ^R5 ; and (iii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n R5;

^R2 is one of the following:

(a) Phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by p R ⁶ ; or

(b) C _1-7 aliphatic groups, -C≡CR, -C(O)OR, or -C(O)R; each of which is replaced by p R ⁶ groups; or

(c) Hydrogen;

^R3 is one of the following:

(a) _C1-6 aliphatic groups optionally substituted with one or more -OH or -N(R) ₂ groups;

(b)-CD ₃ ;

(c) Hydrogen; or

(d) Does not exist;

Each ^R4 is independently hydrogen, deuterium, ^Rz , -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)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

The two ^R4 groups may optionally form =O together; or

The two ^R4 groups, together with their intermediary atoms, can optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

Each ^R5 and ^R6 is independently hydrogen, deuterium, ^Rz , 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)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 ^R5 groups can optionally be combined to form =O;

The two ^R6 groups can optionally be combined to form =O;

The two ^R5 groups, together with their intermediary atoms, optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur; or

The two ^R6 groups, together with their intermediary atoms, can optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

Each R ^z is independently selected from optionally substituted groups, said groups being selected from _C1-6 aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

m can be 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3 or 4;

The condition is that if ^L1 - ^{R1 is a hexyl group} and the ring A and its ^R3 and ^R4 substituents are hexyl groups, then ^L2 - ^R2 is not a n-hexyl group, and

The condition is that if ^L1 - ^R1 is a hexyl group and the ring A and its ^R3 and ^R4 substituents are hexyl groups, then ^L2 - ^R2 is not a hexyl group.

As generally defined above, 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 a phenyl ring.

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 a phenyl group.

In some implementations, ring A replaced by ^R4 , ^R3 , -C(O) ^-L1 - ^R1 , and ^-L2 - ^R2 is...

In some implementations, ring A is selected from those shown in Table 1 below.

As generally defined above, ^L1 is one of the following: (a) a _C1-5 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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) a covalent bond.

In some embodiments, ^L1 is a _C1-5 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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- .

In some embodiments, ^L1 is a _C1-5 divalent straight-chain or branched saturated hydrocarbon chain. In some embodiments, ^L1 is...

In some embodiments, ^L1 is a _C1-5 divalent straight-chain or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is substituted with -Cy-, wherein Cy is a divalent ring selected from 4-7 membered saturated heterocyclic alkenyl groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^L1 is

In some implementations, ^L1 is a covalent bond.

In some implementations, ^L1 is ^...

In some implementations, ^L1 is selected from those shown in Table 1 below.

As generally defined above, each R is independently hydrogen, or a group optionally substituted from the following: _C1-6 aliphatic groups; phenyl; 8-10 membered bicyclic aryl rings; 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from _C1-6 aliphatic groups. In some embodiments, R is phenyl. In some embodiments, R is an 8-10 membered bicyclic aryl ring or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 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.

As defined above, two R groups on the same nitrogen atom optionally together with nitrogen form a 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having 0-3 independently selected heteroatoms other than nitrogen, oxygen and sulfur.

In some embodiments, the two R groups on the same nitrogen atom optionally form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring with nitrogen and 0-3 independently selected heteroatoms other than nitrogen, oxygen, and sulfur.

In some implementations, R is selected from those shown in Table 1 below.

As generally defined above, each -Cy- is independently a divalent ring that is optionally substituted, selected from 4-7 member saturated or partially unsaturated heterocyclic alkenyl groups having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl alkenyl groups; 3-7 member saturated or partially unsaturated carbocyclic alkenyl groups; or 5-6 member heteroaryl alkenyl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, -Cy- is a divalent ring optionally substituted from the following: a 4- to 7-membered saturated or partially unsaturated heterocyclic alkenyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementations, -Cy- is phenyl.

In some embodiments, -Cy- is a 3-7 member saturated or partially unsaturated carbocyclic alkenyl group, or a 5-6 member heteroaryl alkenyl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementations, -Cy- is selected from those shown in Table 1 below.

As generally defined above, ^L2 is one of the following: (a) a _C1-7 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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) a covalent bond.

In some embodiments, ^L2 is a _C1-7 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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- .

In some embodiments, ^L2 is a _C1-7 divalent straight-chain or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is substituted with -O-. In some embodiments, ^L2 is -( _CH2 ) _3-4 -O-( _CH2 ) _1-2- . In some embodiments, ^L2 is -( _CH2 ) _3-4 -O-(C(H)( _CH3 ))-. In some embodiments, ^L2 is a _C1-7 divalent straight-chain or branched unsaturated hydrocarbon chain. In some embodiments, ^L2 is a _C1 divalent straight-chain unsaturated hydrocarbon chain.

In some implementations, ^L2 is a covalent bond.

In some implementations, ^L2 is

In some implementations, ^L2 is selected from those shown in Table 1 below.

As generally defined above, ^R1 is selected from (i) -C(O)OR, -C(O)N(R)S(O) _2R , -C(O)N(R)OR, -C(O) _NR2 , -CN, -OH and hydrogen; (ii) a 5- to 6-membered partially unsaturated oxoheterocyclic group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n ^R5 ; and (iii) a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n ^R5 .

In some embodiments, ^R1 is selected from (i)-C(O)OR, -C(O)N(R)S(O) _2R , -C(O)N(R)OR, -C(O) _NR2 , -CN, -OH, and hydrogen. In some embodiments, ^R1 is a 5-6 membered partially unsaturated oxoheterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted by n ^R5 . In some embodiments, ^R1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted by n ^R5 .

In some embodiments, ^R1 is selected from (i)-C(O)OR, -C(O)N(R)S(O) _2R 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; which is substituted by n ^R5 .

In some embodiments, ^R1 is -C(O)OR. In some embodiments, ^R1 is -C(O)N(R)S(O) _2R . In some embodiments, ^R1 is -C(O)N(R)OR. In some embodiments, ^R1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted by n ^R5s .

In some embodiments, ^R1 is -C(O) _NR2 . In some embodiments, ^R1 is ^{-CN .} In some embodiments, ^R1 is -OH. In some embodiments, ^R1 is hydrogen.

In some implementations, ^R1 is selected from those shown in Table 1 below.

As defined above, ^R² is one of the following:

(a) Phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by p R ⁶ ; or

(b) C _1-7 aliphatic groups, -C≡CR, -C(O)OR, or -C(O)R; each of which is replaced by p R ⁶ groups; or

(c) Hydrogen.

In some embodiments, ^R2 is a phenyl group substituted with p ^R6 atoms. In some embodiments, ^R2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with p ^R6 atoms. In some embodiments, ^R2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; substituted with p ^R6 atoms. In some embodiments, ^R2 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with p ^R6 atoms. In some embodiments, ^R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with p ^R6 atoms. In some embodiments, ^R2 is a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with p ^R6 atoms. In some embodiments, ^R2 is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; it is substituted with p ^R6 groups. In some embodiments, ^R2 is a _C1-7 aliphatic group, which is substituted with p ^R6 groups. In some embodiments, ^R2 is -C≡CR. In some embodiments, ^R2 is -C(O)OR. In some embodiments, ^R2 is -C(O)R. In some embodiments, ^R2 is hydrogen.

In some implementations, ^R2 is ^...

In some embodiments, ^R2 is -C≡CR. In some embodiments, ^R2 is -C≡C- (a 3-7 member saturated monocyclic carbon ring substituted with one or two halogen groups). In some embodiments, ^R2 is -C≡C- (a cyclobutyl group substituted with one or two halogen groups).

In some implementations, ^R2 is selected from those shown in Table 1 below.

As defined above, ^R3 is one of the following: (a) a _C1-6 aliphatic group optionally substituted with one or more -OH or -N(R) ₂ groups; (b) _-CD3 ; (c) hydrogen; or (d) absent.

In some embodiments, ^R3 is a _C1-6 aliphatic group optionally substituted with one or more -OH or -N(R) ₂ . In some embodiments, ^R3 is _-CH3 . In some embodiments, ^R3 is _-CD3 . In some embodiments, ^R3 is hydrogen. In some embodiments, ^R3 is present. In some embodiments, ^R3 is absent.

In some implementations, ^R3 is selected from those shown in Table 1 below.

As generally defined above, each ^R₄ is independently hydrogen, deuterium, ^R₂ , -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)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 .

In some implementations, ^R4 is hydrogen, deuterium, ^Rz , -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)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 .

In some embodiments, ^R4 is hydrogen. In some embodiments, R4 is -Cl. In some embodiments, ^R4 is ^-CF3 . In some embodiments, ^R4 is _-OCH3 . In some embodiments, ^R4 is _-OCF3 . In some embodiments, ^R4 is _-CN . In some embodiments, ^R4 is...

As defined above, two ^R4 groups can optionally be combined to form =O.

In some implementations, the two ^R4 groups optionally form =O together.

As defined above, two ^R4 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R4 groups, together with their intermediary atoms, optionally form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur.

In some implementations, ^R4 is selected from those shown in Table 1 below.

As defined above, each ^R5 and ^R6 is independently hydrogen, deuterium, ^Rz , 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)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 .

In some implementations, ^R5 is hydrogen, deuterium, ^Rz , 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) ₂ NR ₂ , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(0)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 .

As defined above, two ^R5 groups can optionally be combined to form =O.

In some implementations, the two ^R5 groups optionally form =O together.

As defined above, two ^R5 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R5 groups, together with their intermediary atoms, optionally form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

In some implementations, ^R5 is selected from those shown in Table 1 below.

In some implementations, ^R6 is hydrogen, deuterium, ^Rz , 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) 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 .

As defined above, two ^R6 groups can optionally be combined to form =O.

In some implementations, the two ^R6 groups optionally form =O together.

As defined above, two ^R6 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

In some implementations, ^R4 and ^R6 each independently represent hydrogen, halogen, or _C1-6 aliphatic groups each time they appear.

In some embodiments, the two ^R6 groups, together with their intermediary atoms, optionally form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur.

In some implementations, ^R6 is selected from those shown in Table 1 below.

As generally defined above, each Rz is independently selected from optionally substituted groups selected from C 1-6  aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, Rz is independently selected from optionally substituted groups selected from C 1-6  aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementations, Rz is selected from those shown in Table 1 below.

As defined above, m can be 0, 1, 2, 3, or 4.

In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4.

In some implementations, m is selected from those shown in Table 1 below.

As defined above, n is 0, 1, 2, 3, or 4.

In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

In some implementations, n is selected from those shown in Table 1 below.

As defined above, p can be 0, 1, 2, 3, or 4.

In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

In some implementations, p is selected from those shown in Table 1 below.

In some embodiments, if ^L1 - ^R1 is and ring A and its ^R3 and ^R4 substituents are, then ^L2 - ^R2 is not a _C3-6 alkyl group, and

The condition is that if ^L1 - ^R1 is a C3-6 alkyl group and the ring A and its ^R3 and ^R4 substituents are _C3-6 alkyl groups, then ^L2 - ^R2 is not a C3-6 alkyl group.

In some embodiments, if ^L1 - ^R1 is and ring A and its ^R3 and ^R4 substituents are, then ^L2 - ^R2 is not a _C3-8 alkyl group, and

The condition is that if ^L1 - ^R1 is a C3-8 alkyl group and the ring A and its ^R3 and ^R4 substituents are _C3-8 alkyl groups, then ^L2 - ^R2 is not a C3-8 alkyl group.

In some embodiments, the present invention provides compounds of formula I, wherein ring A is indole, azaindole, benzothiophene, or benzofuranyl, to provide compounds of formula I-a-1, I-a-2, I-a-3, or I-a-4:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^L1 , ^L2 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ^L1 is 2-methylpropylidene, to provide a compound of formula Ib-1, Ib-2, or Ib-3:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L2 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein ^L1 is pyrrolidinyl, piperidinyl, or aziridine, to provide compounds of formula Ib-4, Ib-5, or Ib-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L2 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein ^L2 is a _C4-6 alkylene group optionally substituted with a -OH or -F group, to provide compounds of formula Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Ic-8, Ic-9, or Ic-10:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ^L2 is a compound of formula Ic-11, Ic-12, Ic-13 or Ic-14:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein ^L1 is hexyl, and wherein a methylene unit of the chain is independently substituted with -O-, to provide compounds of formula Ic-15, Ic-16, Ic-17, Ic-18, or Ic-19:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein ^L1 is a compound of formula Ic-20, Ic-21, or Ic-22:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^R1 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ^R1 is a carboxyl group, a tetrazolium group, or to provide a compound of formula Id-1, Id-2, or Id-3:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^L2 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein ^R2 is phenyl, pyridyl, pyrimidinyl, or pyrazinyl; each of which is substituted with p ^R6 to provide compounds of formula Ie-1, Ie-2, Ie-3, or Ie-4:

   

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^L2 , ^R1 , ^R3 , ^R4 , ^R6 , m and p is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ^R2 is methyl, ethyl, isopropyl, tert-butyl, _-CF3 , or is provided as a compound of formula Ie-5, Ie-6, Ie-7, Ie-8, Ie-9, or Ie-10:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of rings A, ^L1 , ^L2 , ^R1 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5, or I-f-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^R4 , ^R6 and p is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-g-1, I-g-2, I-g-3, I-g-4, I-g-5, or I-g-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^R4 , ^R6 and p is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-h-1, I-h-2, I-h-3, I-h-4, I-h-5, or I-h-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^R4 , ^R6 and p is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-i-1, I-i-2, I-i-3, I-i-4, I-i-5, or I-i-6:

               

Or its N-oxide or pharmaceutically acceptable salt, wherein each of R, ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-j-1, I-j-2, I-j-3, I-j-4, I-j-5, or I-j-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^R3 , ^R4 , ^R6 , m and p, individually and in combination, is as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-j-7, I-j-8, I-j-9, I-j-10, I-j-11 or I-j-12:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^R3 , ^R4 , ^R6 , m and p, individually and in combination, is as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-k-1, I-k-2, I-k-3, I-k-4, I-k-5, or I-k-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^R3 , ^R4 , ^R6 , m and p, individually and in combination, is as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-q-1, I-q-2, I-q-3, I-q-4, I-q-5, or I-q-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^L2 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have any one of formula I-q-7, I-q-8, I-q-9, or I-q-10:

             

Or a pharmaceutically acceptable salt thereof, wherein each of ^L2 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-q-11:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L2 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-r-1, I-r-2, I-r-3, I-r-4, I-r-5, or I-r-6:

Or its N-oxide or pharmaceutically acceptable salt, wherein each of ^L2 , ^R2 , ^R3 , ^R4 and m is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have any one of formulas I-r-7, I-r-8, and I-r-9:

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above and as described in the embodiments herein.

In some embodiments, the present invention provides compounds of formula I, wherein the compounds have formula I-r-10:

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above and as described in the embodiments herein.

Another aspect of the present invention provides a compound of formula I-1:

Or its N-oxide or pharmaceutically acceptable salt, 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 a phenyl ring.

^L1 is one of the following:

(a) A _C1-5 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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 bond;

Each R is independently hydrogen, or a group optionally substituted from the following: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

The two R groups on the same nitrogen atom optionally form a 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring with nitrogen and 0-3 independently selected heteroatoms other than nitrogen, oxygen and sulfur.

Each -Cy- is independently a divalent ring that is optionally substituted, selected from 4-7 membered saturated or partially unsaturated heterocyclic alkenyl groups having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl alkenyl groups; 3-7 membered saturated or partially unsaturated carbocyclic alkenyl groups; or 5-6 membered heteroaryl alkenyl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

^L2 is one of the following:

(a) A _C1-7 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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 bond;

^R1 is selected from (i) -C(O)OR, -C(O)N(R)S(O) _2R 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; which is substituted by n ^R5 ;

^R2 is one of the following:

(a) Phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by p R ⁶ ; or

(b) C _1-7 aliphatic groups, -C≡CR, -C(O)OR, or -C(O)R; each of which is replaced by p R ⁶ groups; or

(c) Hydrogen;

^R3 is one of the following:

(a) _C1-6 aliphatic groups optionally substituted with one or more -OH or -N(R) ₂ groups;

(b)-CD ₃ ;

(c) Hydrogen; or

(d) Does not exist;

Each ^R4 is independently hydrogen, deuterium, ^Rz , -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)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(I)(R)NR ₂ , -P(O)(R)OR or -P(I)R ₂ ; or

The two ^R4 groups may optionally be combined to form =I; or

The two ^R4 groups, together with their intermediary atoms, can optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

Each ^R5 and ^R6 is independently hydrogen, deuterium, ^Rz , 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)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

The two ^R5 groups can optionally be combined to form =O;

The two ^R6 groups can optionally be combined to form =O;

The two ^R5 groups, together with their intermediary atoms, optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur; or

The two ^R6 groups, together with their intermediary atoms, can optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

Each R ^z is independently selected from optionally substituted groups, said groups being selected from _C1-6 aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

m can be 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3 or 4;

The condition is that if ^L1 - ^{R1 is a hexyl group} and the ring A and its ^R3 and ^R4 substituents are hexyl groups, then ^L2 - ^R2 is not a n-hexyl group, and

The condition is that if ^L1 - ^R1 is a hexyl group and the ring A and its ^R3 and ^R4 substituents are hexyl groups, then ^L2 - ^R2 is not a hexyl group.

In some implementations, the definitions of one or more of the variables ^R1 , ^R2 , ^R3 , ^R4 , ^L1 , ^L2 , ring A, or m are one of the implementations described in the above-mentioned combination formula I.

In some embodiments, the compound has the advantage of low binding affinity to plasma proteins in the subject. Low plasma protein binding affinity allows for higher concentrations of the free compound in the subject, resulting in superior therapeutic effects. The binding of the compound to plasma proteins can be analyzed according to methods described in the literature for assessing the binding of the compound to plasma proteins.

Exemplary compounds of the present invention are described in Table 1 below.

Table 1. Exemplary Compounds

In some embodiments, the present invention provides the compounds set forth in Table 1 above, or their N-oxides or pharmaceutically acceptable salts. In some embodiments, the present invention provides the compounds set forth in Table 1 above, or their pharmaceutically acceptable salts. In some embodiments, the present invention provides the compounds set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds set forth in Table 1 above, or their N-oxides or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the present invention provides compounds selected from compounds I-13 to I-304 as described in Table 1 above. In some embodiments, the present invention provides compounds selected from compounds I-305 to I-467 as described in Table 1 above. In some embodiments, the present invention provides compounds selected from compounds I-13 to I-304 as described in Table 1 above, or their N-oxides or pharmaceutically acceptable salts. In some embodiments, the present invention provides compounds selected from compounds I-305 to I-467 as described in Table 1 above, or their N-oxides or pharmaceutically acceptable salts. In some embodiments, the present invention provides compounds selected from compounds I-13 to I-304 as described in Table 1 above, or their pharmaceutically acceptable salts. In some embodiments, the present invention provides compounds selected from compounds I-305 to I-467 as described in Table 1 above, or their pharmaceutically acceptable salts.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound selected from compounds I-13 to I-304 set forth in Table 1 above, or their N-oxides or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound selected from compounds I-305 to I-467 set forth in Table 1 above, or their N-oxides or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the present invention provides a compound of formula I as defined above, or its N-oxide or pharmaceutically acceptable salt, or a pharmaceutical composition comprising a compound of formula I as defined above, or its N-oxide or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, adjuvant or mediator, which is used as a pharmaceutical agent.

In the chemical structures in Table 1 above and the examples below, the stereoisomer centers are described according to the enhanced stereo representation format (MDL/Biovia, e.g., using the notations “or1”, “or2”, “abs”, “and1”).

Additional exemplary compounds include those set forth in the table below. In some embodiments, the compound may be one of the compounds in the table below, or its N-oxide or pharmaceutically acceptable salt.

In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds set forth in the table above, or their N-oxides or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the present invention provides compounds in the table above, or their N-oxides or pharmaceutically acceptable salts, or pharmaceutical compositions comprising compounds in the table above, or their N-oxides or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, adjuvants or mediators, which are used as pharmaceutical agents.

In some embodiments, the present invention also provides compounds of Formula I or pharmaceutical compositions described herein for use in methods of inhibiting OXER1 as described herein, methods of modulating the immune response of a subject in need as described herein, and/or methods of treating OXER1-dependent conditions as described herein.

In some embodiments, the present invention also provides compounds of formula I or pharmaceutical compositions described herein for use in methods of inhibiting OXER1 as described herein.

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

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

In some embodiments, the present invention also provides the use of the Formula I compound or the pharmaceutical composition described herein for the manufacture of agents for inhibiting OXER1, agents for modulating the immune response of a subject in need, and/or agents for treating OXER1 dependence.

In some embodiments, the present invention also provides the use of the compound of formula I described herein or the pharmaceutical composition described herein for the manufacture of an agent for inhibiting OXER1.

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

In some embodiments, the present invention also provides the use of the Formula I compound or the pharmaceutical composition described herein for the manufacture of an agent for treating OXER1 dependence.

In some embodiments, the present invention also provides the use of the Formula I compound or pharmaceutical composition described herein in methods for inhibiting OXER1 as described herein, methods for modulating the immune response of a subject in need as described herein, and/or methods for treating OXER1-dependent conditions as described herein.

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

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

In some embodiments, the present invention also provides the use of the Formula I compound or pharmaceutical composition described herein in a method of treating OXER1 dependence as described herein.

General methods for providing the compounds of the present invention

The compounds of the present invention can generally be prepared or isolated by methods known to those skilled in the art for the synthesis and/or semi-synthesis of similar compounds and by methods described in detail in the examples herein.

5. Use, preparation and application

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 mediator. The amount of the compound in the composition of the present invention is such that it can effectively inhibit OXER1 or its mutants in a measurable manner in a biological sample or patient. In some embodiments, the amount of the compound in the composition of the present invention is such that it can effectively inhibit OXER1 or its mutants in a measurable manner in a biological sample or patient. In some embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant, or catalyst" refers to a non-toxic carrier, adjuvant, or catalyst that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or catalysts that can be used in the compositions of this invention include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water; 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 carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polypropylene oxide block polymers; polyethylene glycol; and lanolin.

"Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the compound of the present invention that can directly or indirectly provide, when administered to a recipient, the compound of the present invention or its inhibitory metabolites or residues.

As used herein, the term "its inhibitory metabolite or residue" refers to its metabolite or residue, which is also an inhibitor of OXER1 or its mutants.

The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of the present invention. Metabolites include compounds produced by methods comprising exposing the compounds of the present invention to mammals for a duration sufficient to produce their metabolites. If the compounds of the present invention are bases, the desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside amino acids (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc. If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, such as treating 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. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (e.g., piperidine, morpholine, and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The compounds of this invention may be in the form of "prodrugs," which comprise compounds having a portion that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo via esterases or other mechanisms that activate the drug. 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 may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free acid form or with a suitable esterifying agent, respectively. The hydroxyl group may be converted to an ester via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionates), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), amide lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., methyl, halogenated, or methoxy-substituted) aryl and aryl-lower alkyl esters, amides, lower alkylamides, di-lower alkylamides, and hydroxyamides. Prodrugs that are converted into their active form in vivo via other mechanisms are also included. In all respects, the compounds of the present invention are prodrugs of any formula herein.

The compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implantable receptacle. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of this invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media.

For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. For example, fatty acids of oleic acid and their glycerol derivatives can be used to prepare injectable formulations, such as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylene form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and 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.

The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of the present invention can be used for administration in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutically acceptable compositions of the present invention can also be applied topically, especially when the therapeutic target includes areas or organs easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations for each of these areas or organs are readily prepared.

For local application to the lower intestine, it can be achieved in the form of rectal suppositories (see above) or in the form of suitable enemas. Topical transdermal patches may also be used.

For topical application, the pharmaceutically acceptable compositions provided may be formulated as suitable ointment forms containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated as suitable lotions or creams containing an 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 alcohol, cetyl octadecanol, 2-octyl dodecanol, benzyl alcohol, and water.

For ocular use, the pharmaceutically acceptable composition provided may be formulated as a micron-sized suspension, with or without a preservative (e.g., benzylalkonium chloride), in isotonic pH-adjusted sterile saline solution, or preferably as a solution in isotonic pH-adjusted sterile saline solution. Alternatively, for ocular use, the pharmaceutically acceptable composition may be formulated as an ointment, such as paraffin oil.

The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in pharmaceutical formulation and can be prepared into solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and/or other conventional solvents or dispersants.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may 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.

The amount of the compounds of the present invention that can be combined with carrier materials to produce compositions in a single dosage form will vary depending on the host being treated and the specific mode of administration. Preferably, the provided compositions are formulated as inhibitors that can be administered to patients receiving these compositions at doses between 0.01 and 100 mg/kg body weight/day.

It should 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 used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the attending physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

Use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally suitable for inhibiting the signal transduction activity of one or more GPCRs. In some embodiments, the GPCR inhibited by the compounds and methods of the present invention is OXER1.

The compounds disclosed in this invention can be used to inhibit the activity of OXER1, a G protein-coupled receptor (GPCR) with high selectivity for 5-oxo-ETE.

Arachidonic acid metabolites, such as 5-oxo-ETE and other eicosanoids, are potent chemotherapeutic agents for eosinophils and neutrophils. The effects of these eicosanoids are mediated by approximately 20 G protein-coupled receptors, producing a variety of detrimental and beneficial effects on airway smooth muscle and inflammatory cells closely associated with asthma pathophysiology (Powell, Clinical Science (2021), 135, 1945–1980). Eicosanoids stimulate a variety of responses in these cells, such as 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 a variety of inflammatory cells as well as tumor cells. Eicosanoids act via OXE receptors (such as OXER1), inducing eosinophil and neutrophil migration. Eosinophils are major effector cells in the immune system, and are part of the innate immune system. When activated, they release a mixture of cytotoxic proteins and cytokines from their eosinophilic granules. Eosinophils play a crucial role in type 2 inflammation-driven diseases and may help regulate the types of immune responses produced. Cytokines such as IL-4, IL-13, and IL-25 are present in eosinophilic granules. They guide Th2 polarization responses, which are associated with asthma and other allergic and inflammatory diseases. Activated eosinophils also release lipid mediators that may cause airway smooth muscle contraction and lead to airway hyperresponsiveness. Abnormally activated eosinophils are known to exist in patients with severe asthma and other eosinophil-related diseases (Klion, A.D., Ackerman, S.J. and Bochner, B.S. Contributions of Eosinophils to Human Health and Disease. Annu. Rev. Pathol. Mech. Dis. 15, 179-209 (2020). Ramirez, G.A. et al. Eosinophils from Physiology to Disease: A Comprehensive Review. Biomed Res Int 2018, e9095275 (2018)).

The 5-oxo-ETE/OXER1 axis plays a crucial role in cell migration and survival, as well as in the pathogenesis 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 provide inhibition of eosinophil and neutrophil migration. Therefore, treatment or prevention of disease states that can be alleviated by inhibiting eosinophil or neutrophil migration is also covered.

5-O-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 treatment for eosinophilic diseases (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 as defined herein for the treatment of eosinophilic diseases.

Metabolomics studies have identified 5-oxo-ETE as a key metabolite, and its receptor OXER1 is significantly increased in the plasma of patients with acute myocardial infarction (AMI). 5-oxo-ETE and OXER1 appear to play important roles in inducing myocardial ischemic injury through branched-chain amino acid transaminase 1 (BCAT1), and overexpression of BCAT1/BCAT2 (branched-chain amino acid transaminase 2) in the heart is believed to improve myocardial ischemic injury. Therefore, targeting OXER1 and BCAT1/BCAT2 is a promising strategy 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 as defined herein that offer promising therapeutic options for the clinical management of AMI.

5-O-ETE/OXER1-mediated eosinophil infiltration into the lungs of asthmatic patients has been shown to be a cause of advanced inflammatory asthma. OXER1 antagonists, by alleviating asthma symptoms by preventing eosinophil migration to the lungs during asthma attacks, may be a promising treatment for advanced inflammatory asthma (Gore et al., J. Med. Chem., (2013), 56, 3725-3732). In one embodiment, the present invention provides compounds, combinations, compositions, and methods as defined herein that offer promising treatment for advanced inflammatory asthma.

Selective OXER1 antagonists have been shown to inhibit allergen-induced eosinophil infiltration into the skin of experimentally house dust mite-sensitive rhesus monkeys and to suppress lung inflammation induced by aerosolized allergens (Powell W.S., 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 (such as glucocorticoids or cysLT1 antagonists) that act through different mechanisms, potentially producing synergistic effects between these medications. In one embodiment, the present invention provides compounds, combinations, compositions, and methods as defined herein that can provide promising treatments for asthma and other eosinophilic diseases, alone or in combination with current asthma medications.

High expression of OXER1 has been shown to be a major cause of poor prognosis in triple-negative and ER-positive breast cancer (Masi et al., Oncogenesis, (2020), 9, 105). In one embodiment, the present invention provides compounds, combinations, compositions, and methods as defined herein that can represent promising and rational remedies for personalized treatment of triple-negative and ER-positive breast cancer through OXER1 inhibition.

5-O-ETE has been shown to induce an effective migration response, and LTB ₄ induces basophil degranulation (Iikura et al., J Allergy Clin Imminol, (2005), 116, 578-585), suggesting that 5-O-ETE may offer an opportunity for therapeutic targeting of allergic inflammation. In one embodiment, the present invention provides compounds, combinations, compositions, and methods as defined herein that can provide a promising treatment for allergic inflammation through OXER1 inhibition.

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

5-O-ETE has been shown to stimulate the proliferation of prostate tumor cells, and the OXE receptor is expressed on prostate tumor cells. Arachidonic acid metabolites, including HETE and oxo-ETE, have been shown to increase the growth and promote the survival of various cancers, including lung cancer, pancreatic cancer, and prostate cancer. Furthermore, 5-hydroxyeicosatetraene compounds are major arachidonic acid metabolites in prostate cancer cells (see, for example, WO 2007/025254 and US 2005/0106603 for the role of G protein-coupled eicosanoic acid receptors in cancer). These findings suggest a potential role for 5-oxo-ETE receptor antagonists of the compounds defined herein in the treatment or prevention of certain cancers and in inducing apoptosis in these cancer cells. Therefore, in one embodiment, compounds, combinations, compositions, and methods defined herein are provided for the treatment or prevention of cancers, including lung cancer, pancreatic cancer, and/or prostate cancer. In one aspect, this document provides a method for the treatment or prevention of lung cancer, pancreatic cancer, and/or prostate cancer. On the other hand, a method is provided that can be used to induce apoptosis in cancer cells (e.g., lung cancer, pancreatic cancer, and/or prostate cancer cells).

Therefore, the compounds, combinations, and compositions provided herein can be used to treat or prevent diseases or disorders involving 5-oxo-ETE. Thus, compounds, combinations, compositions, and methods as defined herein are provided that can provide treatment or prevention for eosinophilia and inflammatory disorders.

Many diseases or conditions are essentially inflammatory. For example, inflammatory diseases affecting populations include asthma, severe eosinophilic asthma, chronic obstructive pulmonary disease (COPD), eosinophilic syndrome (HES), nasal polyps, allergic rhinitis, atopic dermatitis, chronic spontaneous 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 be caused by a variety of factors, 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 protective response, which can be caused by physical trauma, infection, chronic diseases (such as those mentioned above), and/or chemical and/or physiological responses to external stimuli (e.g., as part of an allergic reaction). Any such reaction that can be used to destroy, dilute, or isolate harmful substances and damaged tissue can manifest as, for example, fever, swelling, pain, redness, vasodilation and/or increased blood flow, leukocyte invasion of the affected area, loss of function, and/or any other symptoms known to be associated with inflammatory disorders. Therefore, the term "inflammation" should also be understood to include any inflammatory disease, condition, or disorder itself, any disorder with associated inflammatory components, and/or any condition presenting with symptoms of inflammation, provided it is related to a respiratory disease or disorder, including acute, chronic, ulcerative, specific, allergic, and necrotizing inflammation, as well as other forms of inflammation known to those skilled in the art. Therefore, for the purposes of this invention, the term also includes inflammatory pain, general pain, and/or fever.

In one aspect, compounds, combinations, compositions, and methods as defined herein are provided for the treatment or prevention of respiratory diseases or disorders, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic rhinitis, rhinitis, and any other respiratory disease or disorder having an inflammatory component, characterized by inflammation, or characterized by eosinophilia.

In one embodiment, compounds, combinations, compositions, and methods as defined herein are provided for the treatment or prevention of asthma, the methods comprising administering the disclosed compounds or compositions to a subject.

Asthma is a common chronic airway disease characterized by complex symptoms, including airflow obstruction, bronchoconstriction, and underlying inflammation. Treatment options for asthma vary depending on the severity of the condition.

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.

In one embodiment, compounds, combinations, compositions, and methods as defined herein are provided that can provide treatment or prevention for chronic obstructive pulmonary disease (COPD). COPD refers to a group of lung diseases in which airways narrow, typically caused by an abnormal inflammatory response in the lungs. Non-limiting examples of COPD include bronchitis and emphysema. Idiopathic pulmonary fibrosis (IPF) is another lung disease also associated with eicosanoids.

In one embodiment, compounds, combinations, compositions, and methods as defined herein are provided that can provide treatment or prevention for allergic rhinitis. Allergic rhinitis is an inflammation of the nasal cavity, often accompanied by watery nasal discharge and itching of the nose and eyes. An allergy occurs when the immune system overreacts to airborne particles and produces an allergic reaction.

According to another aspect, compounds, combinations, compositions, and methods as defined herein are provided that can provide treatment or prevention for diseases or conditions involving eicosanoids, such as 5-oxo-ETE and 5-HETE.

According to another aspect, compounds, combinations, compositions, and methods as defined herein are provided that can be used to inhibit the effects of eicosanoic acids, such as 5-oxo-ETE, 5-HETE, and 5-oxo-15-HETE.

According to another aspect, compounds, combinations, compositions, and methods as defined herein are provided that can be used to antagonize 5-oxo-ETE receptors, such as OXE receptors.

It should be understood that, in addition to blocking biological responses to 5-oxo-ETE, 5-oxo-15-HETE, and 5-HETE, the compounds and compositions of the present invention can also block biological responses to other related eicosanoid acids that can also act as ligands for OXE receptors. Therefore, as used herein, "eicosanoid acid" refers to substances derived from fatty acids having 20 carbon atoms (e.g., eicosanoidic acid), and in one aspect, to a fatty acid unsaturated at position 8. Non-limiting examples of eicosanoic acid-like acids covered in the methods proposed herein include 5-oxo-ETE, 5-HETE, 5-HPETE, arachidonic acid, 5-oxo-ETrE (5-oxo-6E,8Z,11Z-eicosatotrienoic acid), 5-HETrE (5-hydroxy-6E,8Z,11Z-eicosatotrienoic acid), eicosato-5Z,8Z,11Z-trienoic acid, 5-oxo-EDE (5-oxo-6E,8Z-eicosatodienoic acid), and eicosato-5Z,8Z-dienoic acid. Additionally, certain 18-carbon polyunsaturated fatty acids are also included, such as 5-oxo-ODE (5-oxo-6E,8Z-octadecadienoic acid), 5-HODE (5-hydroxy-6E,8Z-octadecadienoic acid), and oleic acid (5Z,8Z-octadecadienoic acid).

In one aspect, compounds, combinations, compositions, and methods as defined herein are provided for the treatment or prevention of viral infections (e.g., influenza, the common cold).

In one aspect, compounds, combinations, compositions, and methods as defined herein are provided for the treatment or prevention of atopic dermatitis, psoriasis, and/or acne.

5-LO products are considered a factor in the development of tissue inflammation. The synthesis of leukotrienes and 5-oxo-ETE is controlled by 5-lipoxygenase.

The pharmacological effects of 5-LO products have been studied in psoriasis. It has been shown that inhibiting 5-LO products may be helpful in treating psoriasis. Tissue inflammation is a component of the acne process. Therefore, inhibitors of 5-lipoxygenase products may be useful compounds for treating acne vulgaris.

Atopic dermatitis is a chronic, relapsing skin condition. Its pathophysiology is thought to involve the release of inflammatory mediators. 5-LO products are believed to play a role in inflammation and atopic disorders. Therefore, modulators of 5-LO products may be helpful in the treatment of atopic dermatitis.

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

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

The compounds disclosed in this invention bind directly to OXER1 and inhibit its signaling activity. In some embodiments, the compounds disclosed in this invention reduce, inhibit, or otherwise attenuate OXER1-mediated inflammatory responses.

The compounds disclosed in this invention may or may not be specific OXER1 antagonists. Specific OXER1 antagonists reduce the biological activity of OXER1 by a statistically greater amount than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the compounds disclosed in this invention specifically inhibit the signaling activity of OXER1. In some of these embodiments, the _IC50 of the OXER1 antagonist against OXER1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or lower than the IC50 of the _OXER1 antagonist against another GPCR activated by free fatty acids (FFA) or other GPCR types (e.g., class A GPCRs).

The compounds disclosed in this invention can be used in methods for inhibiting OXER1. Such methods involve contacting OXER1 with an effective amount of the compounds disclosed in this invention. "Contact" means bringing the compound into sufficient proximity with isolated OXER1 GPCRs or cells expressing OXER1 (e.g., T cells or B cells) such that the compound can bind to OXER1 and inhibit its activity. Contacting the compound with OXER1 can be achieved in vitro or in vivo by administering the compound to a subject.

Any method known in the art for measuring the signaling activity of OXER1 can be used to determine whether OXER1 has been inhibited, including in vitro determination or measurement of downstream biological effects of OXER1 signaling activity.

The compounds disclosed in this invention can be used to treat OXER1-dependent conditions. As used herein, "OXER1-dependent condition" is a pathological condition in which OXER1 activity is required to cause or maintain the pathological condition. In some embodiments, OXER1-dependent condition is an inflammatory condition.

The compounds disclosed in this invention can also be used to modulate the immune response of subjects in need. Such methods include administering an effective amount of the compounds of this invention.

As used in this article, “regulation of immune response” refers to the regulation of any immunogenic response to an antigen.

In another aspect of the invention, the invention provides novel compounds of the invention for use in therapeutic applications.

In an additional aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic schemes and routes disclosed herein.

Therefore, the main objective of this invention is to provide compounds of this invention that can alter the activity of OXER1 and thus prevent or treat any disease that may be causally related to it.

Other objectives and advantages will become apparent to those skilled in the art from the following detailed implementation.

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

This disclosure provides a method for modulating (e.g., inhibiting) OXER1 activity, the method comprising administering to a patient a compound provided herein or a pharmaceutically acceptable salt thereof.

In one aspect, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

In the methods described herein, the compounds of the present invention or pharmaceutical compositions thereof are administered to a subject suffering from cancer.

In some embodiments, the subject matter disclosed herein relates to a method for treating OXER1 dependence, the method comprising administering to a subject in need an effective amount of the compound or pharmaceutical composition of the invention described herein. In some aspects of this embodiment, OXER1 dependence is cancer.

In some embodiments, the subject matter disclosed herein relates to a method for treating chronic viral infections. In some embodiments, the subject matter disclosed herein relates to using OXER1 inhibitors as adjunctive therapy to enhance the efficacy of vaccination.

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

In some respects, the present invention provides a method for treating cell proliferation disorders, including cancer.

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

In some implementations, cell proliferation disorder is referred to as cancer.

Examples of cancers that can be treated with the compounds disclosed herein include, but are not limited to, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, and combinations of said cancers.

In some embodiments, the cancers that can be treated with the compounds of this disclosure include, but are not limited to, blood cancers (e.g., lymphomas, leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of said cancers).

In some implementations, the cancer is leukemia. In another implementation, the cancer is selected from the group consisting of acute myeloid leukemia and chronic myeloid leukemia.

In some embodiments, the cancer is selected from leukemia and blood cancers. In certain embodiments, the cancer is present in adult patients; in other embodiments, the cancer is present in pediatric patients. In certain embodiments, the cancer is AIDS-related.

In a specific implementation, the cancer is selected from leukemia and blood cancers. In a specific implementation, the cancer is selected from the group consisting of: myelodysplastic neoplasms, myelodysplastic syndrome, myelodysplastic/myelodysplastic neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myelodysplastic neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blastocyst-stage chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasmacytoma including plasmacytoma and multiple myeloma. The leukemia mentioned herein may be acute or chronic.

In some embodiments, diseases and indications for which the compounds disclosed herein can be used for treatment include, but are not limited to, hematologic cancers.

Exemplary hematologic 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 lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, and myeloproliferative disorders (such as primary myelofibrosis). Polycythemia vera (PMF), polycythemia vera (PV), essential thrombocythemia (ET), spinal dysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, pilocellular lymphoma, chronic myeloma, and Burkitt's lymphoma.

As used herein, the term 'inflammatory disease' refers to a group of diseases including: inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, lung diseases (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung disease (e.g., idiopathic pulmonary fibrosis (IPF))), psoriasis, gout, allergic airway diseases (e.g., asthma, rhinitis), and endotoxin-driven disease states (e.g., complications following bypass surgery or chronic endotoxin states causing, for example, chronic heart failure). Specifically, the term refers to rheumatoid arthritis, allergic airway diseases (e.g., asthma), and inflammatory bowel disease. In another specific aspect, the term refers to uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments designed to activate an immune response.

As used herein, the term 'pain' refers to a disease or condition characterized by a feeling of discomfort, usually caused by a severe or damaging stimulus, and includes, but is not limited to, nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration), and neuropathic or dysfunctional pain (caused by damage or dysfunction of the nervous system) and/or pain associated with or caused by the disorders mentioned herein. Pain can be acute or chronic.

As used herein, the term 'leukemia' refers to a disease of the growth of blood and blood-forming organs. Such diseases can cause dysfunction of the bone marrow and immune system, making the host highly susceptible to infection and bleeding. Specifically, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

In some embodiments, the compounds of the present invention can be used to prevent or reduce the risk of any of the diseases mentioned herein; for example, to prevent or reduce the risk of an individual who may be susceptible to a disease, ailment or condition but has not yet experienced or exhibited the pathology or symptomology of the disease.

The compounds disclosed in this invention may be administered in any suitable manner known in the art. In some embodiments, the compounds of this invention, or their pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives, may be administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorally, intraorally, by inhalation, intrathecally, intratumorally, or intranasally.

In some embodiments, the OXER1 antagonist is administered continuously. In other embodiments, the OXER1 antagonist is administered intermittently. Furthermore, treating a subject with an effective amount of the OXER1 antagonist may include monotherapy or a series of treatments.

It should be understood that the appropriate dosage of an active compound depends on a number of factors within the knowledge of a physician or veterinarian with general skills. The dosage of an active compound will vary, for example, depending on the subject's age, weight, general health condition, sex and diet, time of administration, route of administration, excretion rate, and any combination of drugs.

It should also be understood that the effective dose of the compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, or derivative used for treatment may increase or decrease over a specific treatment course. Dosage variations may be caused by and become apparent from diagnostic assays.

In some embodiments, the OXER1 antagonist is administered to the subject at a dose between about 0.001 μg/kg and about 1000 mg/kg, including 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.

In the methods described herein, the method may further include administering a chemotherapeutic agent to a subject. In some aspects of this embodiment, the chemotherapeutic agent and a compound or composition are administered to the subject simultaneously. In some aspects of this embodiment, the chemotherapeutic agent is administered to the subject prior to the administration of the compound or composition. In some aspects of this embodiment, the chemotherapeutic agent is administered to the subject after the administration of the compound or composition.

As used herein, the term "treatment/treat/treating" refers to reversing or alleviating a disease or condition or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered when symptoms are absent. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

The term "administration/administering" refers to the route by which a compound is introduced into a subject to exert its intended function. Examples of possible routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

The term "effective amount" refers to the amount that effectively achieves the desired outcome at the required dose and time period. The effective amount of a compound can be varied based on factors such as the subject's disease state, age, weight, and the compound's ability to elicit the desired response in the subject. Dosing regimens can be adjusted to provide the optimal therapeutic response.

As used in this article, the phrases “systemic administration,” “systemic application,” “peripheral application,” and “peripheral application” refer to the administration of a compound, drug, or other substance to the patient’s system, where it undergoes metabolism and other similar processes.

The phrase "therapeutic effective amount" means the amount of the compound of the present invention that achieves the following effects: (i) treating or preventing a specific disease, ailment, or condition; (ii) alleviating, improving, or eliminating one or more symptoms of a specific disease, ailment, or condition; or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, ailment, or condition described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent slow down and preferably terminate) the invasion of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down and preferably terminate) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more of the symptoms associated with cancer to some extent. The drug may have cell growth inhibitory and/or cytotoxic effects to the extent that it can prevent the growth of existing cancer cells and/or kill existing cancer cells. For cancer therapies, efficacy may be measured, for example, by assessing time to progression (TTP) and/or determining response rate (RR).

The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the subject is a human.

Combination therapy

Depending on the specific ailment or disease to be treated, additional therapeutic agents typically administered to treat said ailment may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically administered to treat a specific ailment or disease are referred to as “the ailment or disease to be treated”.

In some embodiments, the provided combination or composition thereof is administered in combination with another therapeutic agent.

The compounds of the present invention can be used as therapeutic agents for treating diseases in mammals that are causally related to or attributable to abnormal OXER1 activity and/or abnormal OXER1 expression and/or abnormal OXER1 distribution.

Therefore, the compounds and pharmaceutical compositions of the present invention are suitable as therapeutic agents for the prevention and/or treatment of inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia and/or diseases involving impaired immune cell function in mammals, including humans.

Therefore, in one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use as pharmaceutical agents.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of pharmaceutical preparations.

In another aspect, the present invention provides a method for treating mammals suffering from or at risk of developing the diseases disclosed herein. In one particular aspect, the present invention provides a method for treating mammals, including humans, suffering from or at risk of developing inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia, and/or diseases involving impaired immune cell function, said method comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention described herein.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of inflammatory disorders. In one specific embodiment, the inflammatory disorder 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 disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments aimed at activating an immune response.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of inflammatory disorders. In one specific embodiment, the inflammatory disorder 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 disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments aimed at activating an immune response.

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

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from inflammatory diseases, the methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions described herein. In one specific embodiment, the inflammatory disease 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 disease is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments aimed at activating an immune response.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of pain. In one specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of pain. In one specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing pain in mammals susceptible to or suffering from pain, the methods comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions. In one specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention, which are suitable for manufacturing agents for the prevention and/or treatment of neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, or autoimmune encephalomyelitis, said methods comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions thereof.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of infectious diseases. In one specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacteriaceae.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of infectious diseases. In one specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacteriaceae.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from infectious diseases, said methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions described herein. In one specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacteriaceae.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of autoimmune diseases and/or diseases involving impaired immune cell function. In one specific embodiment, the autoimmune diseases and/or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of autoimmune diseases and/or diseases involving impaired immune cell function. In one specific embodiment, the autoimmune diseases and/or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from autoimmune diseases and/or diseases involving impaired immune cell function, said methods comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions. In one specific embodiment, 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.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of endocrine and/or metabolic disorders. In one specific embodiment, the endocrine and/or metabolic disorders are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of endocrine and/or metabolic disorders. In one specific embodiment, the endocrine and/or metabolic disorders are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from endocrine and/or metabolic disorders, said methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention described herein. In one specific embodiment, the endocrine and/or metabolic disorders are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

As another aspect of the invention, a compound of the invention is provided, which is used particularly as a medicament in the treatment or prevention of the aforementioned diseases and ailments. The use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned diseases and ailments is also provided herein.

One specific embodiment of the method of the present invention includes administering an effective amount of the compound of the present invention to a subject suffering from an inflammatory disease for a period of time sufficient to reduce the inflammation level of the subject and preferably terminate the process causing the inflammation. Another specific embodiment of the method includes administering an effective amount of the compound of the present invention to a subject susceptible to or developing an inflammatory disease for a period of time sufficient to reduce or prevent inflammation in the patient and preferably terminate the process causing the inflammation.

Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, lasting from about 1 to about 120 h, and especially 24 to 96 h. Preloaded pellets of about 0.1 mg/kg to about 10 ng/kg or more may also be administered to achieve adequate steady-state levels. For human patients weighing 40 to 80 kg, the maximum total dose is expected not to exceed about 2 g/day.

Transdermal delivery is often chosen to provide blood levels similar to or lower than those achieved with injectable delivery.

When used to prevent the onset of a disease, the compounds of the present invention should generally be administered to patients at risk of having the disease at the dosage levels described above, as advised by and under the supervision of a physician. Patients at risk of having a particular disease generally include those with a family history of the disease, or those identified by genetic testing or screening as particularly susceptible to the disease.

The compounds of the present invention can be administered as a single active agent or in combination with other therapeutic agents, including other compounds that exhibit the same or similar therapeutic activity and have been proven safe and effective for such combination administration. In one specific embodiment, co-administration of two (or more) agents allows for a significant reduction in the dosage of each agent to be used, thereby mitigating observed side effects.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory disorders; the specific agent includes, but is not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, for example), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g., rheumatoid arthritis); the specific agent includes, but is not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (e.g., but not limited to methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiouralate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin) and biological DMARDs (e.g., but not limited to infliximab, etanercept, adalimumab, rituximab, golimumab, pegylated cetuzumab, tosilimumab, interleukin-1 blockers, and abatacept).

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of autoimmune diseases; the specific agent includes, but is not limited to: glucocorticoids, cell growth inhibitors (e.g., purine analogs), alkylating agents (e.g., nitrogen mustard (cyclophosphamide), nitrosourea, platinum compounds, etc.), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., actinomycin anthracycline, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, and), cyclosporine, tacrolimus, rapamycin (sirolimus), interferon (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate mofetil, fingolimod, and myriocin.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of infectious diseases; the specific agent includes, but is not limited to, antibiotics. In one specific embodiment, the compound of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of infection of any organ in the human body; the specific agent includes, but is not limited to: aminoglycosides, anesamcinolone, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monoamides, nitrofurans, penicillins, polypeptides, quinolinones, sulfonamides, tetracyclines, anti-mycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol, and tinidazole.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of vasculitis, the specific agent including but not limited to steroids (e.g., prednisone, prednisolone), cyclophosphamide, and a final antibiotic (e.g., cephalexin) in cases of skin infection.

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

In one embodiment, the compounds of the present 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.

In one embodiment, the compounds of the present 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: β2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), adrenaline (inhaled or tablet form), anticholinergic agents (e.g., ipratropium bromide), long-acting β2-agonists of glucocorticoids (oral or inhaled) (e.g., salmeterol, formoterol, bamboolol, and sustained-release oral salbutamol), and combinations of inhaled steroids with long-acting bronchodilators (e.g., fluticasone/salmeterol, budesonide). Nidone/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., roflurane), biological modulators of IgE response (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, and fexofenadine), and vasoconstrictors (e.g., oxymethazoline, xylomethazoline, nafazoline, and tramazoline).

Additionally, the compounds of the present invention can be administered in combination with emergency therapies for asthma and/or COPD, including oxygen or helium-oxygen mixtures, nebulized salbutamol or terbutaline (optionally in combination with an anticholinergic agent such as ipratropium), systemic steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone, or corticosteroids), intravenous salbutamol, nonspecific beta-agonists, and injectable or inhaled formulations (such as epinephrine, isoetharine, etc.). Adrenaline, meprocarline, anticholinergic agents (IV or nebulized, such as glycopyrrolate, atropine, ipratropium), methylxanthine (theophylline, aminophylline, bamiphylline), inhaled anesthetics with bronchodilatory effects (such as isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD); the specific agents include, but are not limited to: glucocorticoids (e.g., prednisone, budesonide); synthetic disease modifiers and immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine) and biological disease modifiers and immunomodulators (infliximab, adalimumab, rituximab, and abatacept).

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of pain, such as non-anesthetic and anesthetic analgesics; specific agents include, but are not limited to: acetaminophen, acetylsalicylic acid, NSAID, codeine, dihydrocodeine, tramadol, tebuconazole, meperidine, tetridin, buprenorfine, fentanyl, hydromorfon, methadone, morphine, oxycodone, piperonitrile, tapentadol, or combinations thereof.

The treatment process for leukemia includes chemotherapy, biological therapy, targeted therapy, radiotherapy, bone marrow transplantation, and/or combinations thereof.

Examples of other therapeutic agents used for acute lymphoblastic leukemia (ALL) include methotrexate, nerabine, asparaginase, Erwinia chrysanthemi, blinatumomab, daunorubicin, clofarapine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib, vincristine, mercaptopurine, pegaspargase, and/or prednisone.

Examples of other therapeutic agents used for acute myeloid leukemia (AML) include arsenic trioxide, donomycin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and/or vincristine.

Examples of other therapeutic agents used for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ovarumumab, bendamustine, cyclophosphamide, fludarabine, atoruzumab, ibrutinib, idelalisib, nitrogen mustard, prednisone, and/or rituximab.

Examples of other therapeutic agents used for chronic myeloid leukemia (CML) include besutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, nitrogen mustard, nilotinib, and/or omaltazine.

Examples of other therapeutic agents used for hairy cell leukemia include cladiribine, pentostatin, and/or interferon alpha-2b.

As will be apparent to those skilled in the art, co-administration includes any method of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. It is not necessary that the two or more agents be administered simultaneously in a single formulation. The agents may be in different formulations and administered at different times.

In one embodiment, the compound of the present invention is co-administered with one or more other therapeutic agents for the treatment and/or prevention of fibrotic diseases. In a particular embodiment, the compound of the present invention is co-administered with one or two other therapeutic agents for the treatment and/or prevention of fibrotic diseases. In a more particular embodiment, the compound of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of fibrotic diseases.

In one implementation, other therapeutic agents for treating and/or preventing fibrotic diseases include, but are not limited to, 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone); nintedanib (or); STX-100 (ClinicalTrials.gov identifier NCT01371305), FG-3019 (ClinicalTrials.gov identifier NCT01890265), raprecizumab (CASn#953400-68-5); tarozinumab (CASn#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), and tyrosine (MN-001; ClinicalTrials.gov identifier NCT03142191). The following are listed: s.gov identifier NCT02503657, ND-L02-s020l (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 one particular implementation, another therapeutic agent for treating and/or preventing fibrotic diseases is an autocrine motor factor (or exonucleic acid pyrophosphatase/phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are described in WO 2014/139882, such as GLPG1690.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of NASH. Specific agents include, but are not limited to, weight-loss therapeutic agents (e.g., sibutramine or orlistat), insulin sensitizers (e.g., metformin, thiazolidinedione, rosiglitazone, or pioglitazone), lipid-lowering agents (e.g., gemfibrozil), antioxidants (e.g., vitamin E, N-acetylcysteine, betaine, or pentoxifylline), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, monounsaturated fatty acids, or polyunsaturated fatty acids. FXR agonists (e.g., obeticholic acid), LOXL2 antagonists (e.g., cintuzumab), ASK1 antagonists (e.g., seloselte), PPAR agonists (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinedione, ibuprofen, GW-9662, agliflozin, moggliflozin, or ticaggliflozin), acetyl-CoA-carboxylase (ACC) antagonists (e.g., NDI-010976, PF-05221304), CCR2/CCR5 (e.g., denivilol), and VAP1 antagonists.

Examples of pharmaceutical agents that can also be combined with the present invention include, but are not limited to: those for the treatment of Alzheimer's disease, such as ritonavir, and those for the treatment of HIV; and those for the treatment of Parkinson's disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, and trihexyphenidyl. Trihexephendyl and amantadine; medications used to treat multiple sclerosis (MS), such as beta-interferon (e.g., and mitoxantrone); medications used to treat asthma, such as albuterol; and medications used to treat schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids. Steroids, TNF blockers, IL-1RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's agents; agents used to treat cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, and calcium. Ion channel blockers and statins; agents used to treat liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents used to treat blood disorders, such as corticosteroids, antileukemic agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir); and agents used to treat immunodeficiency disorders, such as gamma globulin.

In some embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

These additional agents may be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present invention to form a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals between each other (typically within five hours).

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

The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be applied in the form of a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed in the present invention will be in the range of about 50% to 100% of the amount normally present in a composition containing said pharmaceutical agent as the sole active agent.

In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent 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 some embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 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 before the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 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.

In another embodiment, the present invention provides a method for treating an inflammatory disease, condition, or disorder by administering a compound of formula I and one or more additional therapeutic agents to a patient in need. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin, and celecoxib, colchicine corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat, sulfasalazine, antimalarial drugs such as hydroxychloroquine and chloroquine, methotrexate gold salts such as glucosinolate gold, thiomalate gold, and auronoxine, D-penicillamine (or), azathioprine, cyclophosphamide, chlorambucil, and cyclosporine. Levofloxacin and "anti-TNF" agents such as etanercept, inliximab, golimumab, pegylated cetuzumab and adalimumab; "anti-IL-1" agents such as anaproletin and linacip, cananamumab; anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab; "anti-T cell" agents such as abatacept; "anti-IL-6" agents such as tocilizumab, diclofenac, cortisone, hyaluronic acid (or), monoclonal antibodies such as tanizumab, anticoagulants such as heparin (or) and warfarin; antidiarrheal drugs such as diphenhydramine and loperamide; bile acid conjugates such as cholestyramine, allosetron, rubiprostone; mild laxatives such as magnesium oxide. Emulsions, polyethylene glycol, and anticholinergics or antispasmodics such as bicyclic amines, β-2 agonists such as salbutamol (HFA, L-salbutamol), mesoproterenol, pibuterol acetate, terbutaline sulfate, salmeterol and formoterol, anticholinergics such as ipratropium bromide and tiotropium, inhaled corticosteroids such as beclomethasone dipropionate (and), triamcinolone acetonide, mometasone, budesonide and flunisolone, sodium cromoglycate, methylxanthines such as theophylline and aminophylline, IgE antibodies such as omalizumab, nucleoside reverse transcriptase inhibitors such as zidovudine, abacavir, abacavir/lamivudine, abacavir/lamivudine Fudovudine/zidovudine, didanofin, emtricitabine, lamivudine, lamivudine/zidovudine, stavudine and zalcitabine, non-nucleoside reverse transcriptase inhibitors such as deraviridine, efavirenz, lavin, and travirine, nucleotide reverse transcriptase inhibitors such as tenofovir, protease inhibitors such as ampravir, atazanavir, darunavir, fazanavir, indinavir, lopinavir and ritonavir, nefenavir, ritonavir, saquinavir (or) and telanavir, entry inhibitors such as enfvirdi and maraviro, integrase inhibitors such as raltegravir, doxorubicin, vincristine, bortezomib and dexamethasone with lenalidomide or any combination thereof.

In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin, and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; sulfasalazine antimalarial drugs such as hydroxychloroquine and chloroquine; methotrexate gold salts such as glucosinolate gold, thiomalate gold, and auronoxine; D-penicillamine (or), azathioprine, cyclophosphamide, chlorambucil, cyclosporine, leflunomide, and "anti-TNF" agents such as etanercept, inliximab, golimumab, pegylated sertuzumab, and adalimumab; "anti-IL-1" agents such as anaerobiculin and linaccept; antibodies such as rituximab; "anti-T cell" agents such as abatacept; and "anti-IL-6" agents such as tocilizumab.

In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin and celecoxib, diclofenac, cortisone, hyaluronic acid (or) and monoclonal antibodies such as tanizumab.

In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin, and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarial drugs such as hydroxychloroquine and chloroquine, cyclophosphamide, methotrexate, azathioprine, and anticoagulants such as heparin (or) and warfarin.

In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: mesalamine, sulfasalazine, antidiarrheals such as diphenoxylate and loperamide, cholic acid conjugates such as cholestyramine, allosetronil, lubiprostone, laxatives such as magnesium oxide emulsion, polyethylene glycol, and anticholinergics or antispasmodics such as bicyclic amine, anti-TNF agents, steroids, and antibiotics such as metronidazole (Flagyl) or ciprofloxacin.

In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists such as salbutamol (HFA, HFA), levosalbutamol, mesodeoxycholine, pibuterol acetate, terbutaline sulfate, salmeterol hydroxynaphthenic acid, and formoterol; anticholinergics such as ipratropium bromide and tiotropium; inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (and), triamcinolone acetonide, mometasone acetate, budesonide, and flunisolone; sodium cromoglycate; methylxanthines such as theophylline and aminophylline; and IgE antibodies such as omalizumab.

In some embodiments, the present invention provides a method for treating COPD, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists such as salbutamol (HFA, HFA), levosalbutamol, mesoproterenol, pibuterol acetate, terbutaline sulfate, salmeterol and formoterol; anticholinergics such as ipratropium bromide and tiotropium; methylxanthines such as theophylline and aminophylline; inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate, triamcinolone acetonide, mometasone acetate, budesonide, and flunisolone.

In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof to a patient in need.

In another embodiment, the present invention provides a method for treating solid tumors, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from the group consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof to a patient in need.

In another embodiment, the present invention provides a method for treating a hematological malignancy, the method comprising administering a compound of formula I and a hedgehog (Hh) signaling pathway inhibitor to a patient in need. 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 1ymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, hedgehog signaling inhibitors, and combinations thereof to a patient in need.

In another embodiment, the present invention provides a method for treating multiple myeloma, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: bortezomib and dexamethasone hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide.

In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering a compound of formula I and a BTK inhibitor to a patient in need, 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, Graves' disease, autoimmune diseases, etc. Thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lymeneuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, strabismus-clonic myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody 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, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic nervous system dysfunction, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, scleroderma, vulvar pain, hyperplastic diseases, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion, systemic allergic reactions, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes). Type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, 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, fibrositis, gastritis, gastroenteritis, allergic purpura (Henoch-Schonlein purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritoneum Inflammation, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma/Wald's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasmacytoma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma). Marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia, or lymphoma-like granuloma, breast cancer, prostate cancer), or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mast cell hyperplasia), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, serologically negative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, Hughley's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic diseases (e.g.) Such conditions include myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass grafting, restenosis after aortocoronary artery bypass grafting, stroke, transient ischemic attack, peripheral artery occlusion, pulmonary embolism, deep vein thrombosis, inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Hugh Lane's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), and autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome). (Symptoms), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpassuia syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative arthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering a compound of formula I and a PI3K inhibitor to a patient in need, wherein the disease is selected from cancer, neurodegenerative diseases, angiogenic diseases, viral diseases, autoimmune diseases, inflammatory diseases, hormone-related diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune disorders involving T-cell activation, cardiovascular diseases, and CNS diseases.

In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering a compound of formula I and a PI3K inhibitor to a patient in need, wherein the disease is selected from benign or malignant tumors; cancers or solid tumors of the brain, kidneys (e.g., renal cell carcinoma (RCC)), liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcomas; glioblastoma; neuroblastoma; multiple bone tumors. Myeloma or gastrointestinal cancer, especially colon cancer or colorectal adenoma or head and neck tumors; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; tumor formation; epithelial-characteristic tumor formation; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease)); breast cancer; follicular carcinoma; undifferentiated carcinoma; papillary carcinoma; seminoma; melanoma or leukemia, including diseases such as Cowden syndrome, Lermit-Dudor... Lhermitte-Dudos disease and Bannayan-Zonana syndrome; or diseases involving abnormal activation of the PI3K/PKB pathway; asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection; acute lung injury (ALI); adult/acute respiratory distress syndrome (ARDS). Chronic obstructive pulmonary, airway, or lung disease (COPD, COAD, or COLD), including chronic bronchitis or related dyspnea, emphysema, and exacerbations of airway hyperresponsiveness caused by other drug therapies, particularly other inhaled drug therapies; bronchitis of any type or origin, including but not limited to acute, peanut inhalation, catarrhal, croupus, chronic, or tuberculous bronchitis; pneumoconiosis of any type or origin (inflammatory, usually occupational lung disease, whether chronic or acute, often accompanied by...) (Included by airway obstruction and caused by repeated inhalation of dust), including, for example, aluminum deposition, carbon deposition, asbestos deposition, stone deposition, eyelash loss, iron deposition, silica deposition, tobacco deposition, and cotton wool deposition; Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polynodular arteritis (including Churg-Strauss syndrome), eosinophilic... Granulomatous diseases and eosinophilic disorders affecting the airways caused by drug reactions; psoriasis; contact dermatitis; atopic dermatitis; alopecia areata; erythema multiforme; herpetic dermatitis; scleroderma; leukoplakia; hypersensitivity vasculitis; urticaria; bullous pemphigoid; lupus erythematosus; pemphigus; acquired epidermolysis bullosa; conjunctivitis; dry eye; and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases with autoimmune reactions or autoimmune components or etiologies, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia). Allergic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura; cutaneous lupus erythematosus; systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; Wegener's granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Stevens-Johnson syndrome; idiopathic stomatitis; autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease); endocrine ophthalmopathy; Graves' disease; sarcoidosis; alveolitis; chronic... Allergic pneumonia; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry eye and vernal keratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy); restenosis; cardiac hypertrophy; atherosclerosis; myocardial infarction; ischemic stroke and congestive heart failure; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; and cerebral ischemia; as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

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

In some embodiments, the disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplant-related disease. 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 herein by reference in its entirety. Suitable JH1-domain-binding compounds include those described in WO2015131080A1, the entire of which is incorporated herein by reference.

The compounds and compositions according to the method of the present invention can be administered in any effective dose and via any effective route of administration for treating or reducing the severity of autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases. The precise amount required will vary depending on the individual subject, including species, age and general condition, severity of infection, specific agent, mode of administration, etc. The compounds of the present invention are preferably formulated in unit dosage forms for ease of administration and dose uniformity. As used herein, “unit dosage form” refers to a physically discrete unit of the agent suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disease to be treated and its severity; the activity of the specific compound used; the specific composition used; the patient’s age, weight, general health condition, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), or buccally (e.g., orally or via nasal spray), depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention can be administered orally or parenterally at the following dosage levels to achieve the desired therapeutic effect: about 0.01 mg to about 50 mg per kg of subject body weight per day, preferably about 1 mg to about 25 mg, once or more daily.

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 emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

Injectable formulations can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators and solvents include water, Ringer's solution (U.S.P.), and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

Injectable formulations can be sterilized, for example, by filtration via a bacterial trapping filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

To prolong the effects of the compounds of this invention, it is generally necessary to slow the absorption of compounds injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Therefore, the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable reservoir forms are manufactured by forming microcapsule matrices of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

Compositions for rectal or vaginal application are preferably suppositories prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

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 starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solvent inhibitors, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They may optionally contain emulsifiers and may also have compositions that release or optionally delay the release of the active ingredient only or preferentially in a portion of the intestine. Examples of usable encapsulation compositions include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

The active compound may also be present in microencapsulation form with one or more excipients as noted above. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). As is customary, such dosage forms may also contain additional substances besides inert diluents, such as tablet-making lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain an emulsifier and may also have a composition that releases or optionally releases the active ingredient only or preferentially in a portion of the intestine. Examples of encapsulation compositions that may be used include polymers and waxes.

Dosage forms for topical or transdermal application of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also covered within the scope of this invention. Additionally, this invention covers 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 prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

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

According to another embodiment, the present invention relates to a method for inhibiting the activity of OXER1 or its mutants in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

Inhibition of OXER1 (or its mutants) activity in biological samples is suitable for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassay.

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

According to another embodiment, the present invention relates to a method for inhibiting the activity of OXER1 or its mutants in a patient, the method comprising the step of administering a compound of the present invention or a composition comprising the compound to the patient. According to some embodiments, the present invention relates to a method for reversibly or irreversibly inhibiting one or more of OXER1 or its mutants in a patient, the method comprising the step of administering a compound of the present invention or a composition comprising the compound to the patient. In other embodiments, the present invention provides a method for treating OXER1- or mutant-mediated conditions in patients in need, the method comprising the step of administering a compound of the present invention or a pharmaceutically acceptable composition thereof to the patient. Such conditions are described in detail herein.

Depending on the specific ailment or disease to be treated, additional therapeutic agents typically used to treat said ailment may also be present in the compositions of the present invention. As used herein, additional therapeutic agents typically used to treat a specific ailment or disease are referred to as “the ailment or disease to be treated”.

The compounds of the present invention can also be used in combination with other therapeutic compounds for an advantageous position. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; 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; anti-proliferative antimetabolites; platinum compounds; compounds that target/reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparinase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematologic malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors, such as those from Conforma. Therapeutics' 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; temozolomide kinin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and formyltetrahydrofolate. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as the conversion of substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane; and particularly non-steroids, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the brand name Aromasin ^™ . Formestane is marketed under the brand name Lentaron ^{™. Fadrozole is marketed under the brand name Afema™ .} Anastrozole is marketed under the brand name Arimidex ^™ . Letrozole is marketed under the brand names Femara ^™ or Femar ^™ . Aminoglutethimide is marketed under the brand name Orimeten ^™ . Combinations of the present invention containing chemotherapeutic agents as aromatase inhibitors are particularly suitable for treating hormone receptor-positive tumors, such as breast tumors.

As used herein, the term "anti-estrogenic" 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, ranoxifene, and ranoxifene hydrochloride. Tamoxifen is marketed under the brand name Nolvadex ^™ . Ranoxifene hydrochloride is marketed under the brand name Evista ^™ . Fulvestrant can be administered under the brand name Faslodex ^™ . Combinations of the present invention comprising chemotherapeutic agents as anti-estrogens are particularly suitable for treating estrogen receptor-positive tumors, such as breast tumors.

As used herein, the term "anti-androgen" refers to any substance capable of inhibiting the biological effects of androgens, and includes, but is not limited to, bicalutamide (Casodex ^™ ). The term "gonadotropin-releasing hormone agonist" as used herein includes, but is not limited to, abalex, goserelin, and goserelin acetate. Goserelin can be administered under the brand name Zoladex ^™ .

As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecian and the macrocamptothecian conjugate PNU-166148. Irinotecan may be administered, for example, in its marketed form, such as under the trademark Camptosar ^™ . Topotecan is marketed under the trade name Hycamptin ^™ .

As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx ^™ ), doxorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones mitoxantrone and losoxantrone; and podophyllotoxins etoposide and teniposide. Etoposide is marketed under the brand name Etopophos ^™ . Teniposide is marketed under the brand name VM 26-Bristol. Doxorubicin is marketed under the brand names Acriblastin ^™ or Adriamycin ^™ . Epirubicin is marketed under the brand name Farmorubicin ^™ . Idarubicin is marketed under the brand name Zavedos ^™ . Mitorubicin is marketed under the brand name Novantron.

The term "microtubule activator" refers to microtubule stabilizing, microtubule destabilizing, and microtubule polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vincaine or vinca sulfate, vincristine or vinca sulfate and vinorelbine; discormolide; colchicine and epothilone and their derivatives. Paclitaxel is marketed under the trade name Taxol ^™ . Docetaxel is marketed under the trade name Taxotere ^™ . Vinca sulfate is marketed under the trade name Vinblastin RP ^™ . Vinca sulfate is marketed under the trade name Farmistin ^™ .

As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin ^™ . Ifosfamide is marketed under the trade name Holoxan ^™ .

The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes, but is not limited to, succinyl aniline oxime acid (SAHA).

The term "anti-metabolic 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 folic acid antagonists (such as pemetrexed). Capecitabine is marketed under the brand name Xeloda ^™ . Gemcitabine is marketed under the brand name Gemzar ^™ .

As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, and oxaliplatin. Carboplatin may be administered, for example, in its marketed form, such as under the trademark Carboplat ^™ . Oxaliplatin may be administered, for example, in its marketed form, such as under the trademark Eloxatin ^™ .

As used herein, the term "compounds that target/reduce the activity of protein or lipid kinases, or protein or lipid phosphatases; or other anti-angiogenic compounds" 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), such as compounds that target, reduce, or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR). c) Compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce, or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or apirelin B4 inhibitors; e) Compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) Compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; g) Compounds that target, reduce, or inhibit the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) Compounds that target, reduce, or inhibit the activity of C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit c-Kit receptors, such as imatinib; i) Compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, such as compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib or nilotinib (AMN107) from Parke Davis. PD180970, AG957, NSC680410, PD173955; or dasatinib (BMS-354825); j) compounds that target, reduce, or inhibit the activity of serine/threonine kinases, members of the protein kinase C (PKC) and Raf family, MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK, and TEC family and/or members of the cyclin-dependent kinase family (CDK), including astrocytocin derivatives such as midostaurin; other examples include UCN-01, safingol, and BAY. 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) Compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as imatinib mesylate (G1eevec ^™ ) or tyrosine phosphorylation inhibitors (Tyrphostin), such as tyrosine phosphorylation inhibitors A23/RG-50810; AG 99; tyrosine phosphorylation inhibitor AG213; tyrosine phosphorylation inhibitor AG 1748; Tyrosine phosphorylation inhibitor AG 490; Tyrosine phosphorylation inhibitor B44; Tyrosine phosphorylation inhibitor B44(+) enantiomer; Tyrosine phosphorylation inhibitor AG 555; AG 494; Tyrosine phosphorylation inhibitors AG 556, AG 957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adaphostin); l) Compounds that target, reduce or inhibit the activity of the epidermal growth factor family (EGFR ₁ , ErbB2, ErbB3, ErbB4, in homodimer or heterodimer) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially those that inhibit EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4 or EGF or EGF-associated ligand CP. Compounds, proteins, or antibodies bound to 358774, ZD1839, and ZM 105180; 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, reduce, or inhibit the activity of c-Met receptors, such as compounds that target, reduce, or inhibit the activity of c-Met, especially those that inhibit the kinase activity of c-Met receptors. Compounds that target the extracellular domain of c-Met or antibodies that bind to HGF; n) compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG- 101348, tofacitinib and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL -719, dactolisib, XL-147, XL-765 and idelalisib; and q) compounds that target, reduce or inhibit signal transduction of the hedgehog protein (Hh) or smooth receptor (SMO) pathway, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

13 As used herein, the term “PI3K inhibitor” includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in 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 suitable for use in this invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupazoxib, picotecoxib, PF-4691502, BYL-719, dartoxib, XL-147, XL-765, and adelali.

As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including but not limited to AVL-292 and ibrutinib.

As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogues), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), and Genase. The following compounds are listed: nse)(G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogues, 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 peptide mimic.

Other examples of BTK inhibitory compounds and diseases that can be treated by combination of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

Other examples of SYK inhibitory compounds and diseases that can be treated by combination of such compounds with compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

Other examples of PI3K inhibitory compounds and diseases that can be treated by combination of such compounds with compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

Other examples of JAK inhibitory compounds and diseases that can be treated by combination of such compounds with compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

Other anti-angiogenic compounds include those with a different mechanism of activity (e.g., independent of protein or lipid kinase inhibition), such as thalidomide (Thalomid ^™ ) and TNP-470.

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

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

Compounds that induce cell differentiation include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol or δ-tocopherol, or α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex ^™ ), rofecoxib (Vioxx ^™ ), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2′-chloro-6′-fluoroaniline)phenylacetic acid, luminacoxib.

As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos ^™ . Tiludronic acid is marketed under the trade name Skelid ^™ . Pamidronic acid is marketed under the trade name Aredia ^™ . Alendronic acid is marketed under the trade name Fosamax ^™ . Ibandronic acid is marketed under the trade name Bondranat ^™ . Risedronic acid is marketed under the trade name ^{Actonel™ .} Zoledronic acid is marketed under the trade name Zometa ^™ . The term “mTOR inhibitor” refers to compounds that inhibit mammalian rapamycin target (mTOR) and have antiproliferative activity, such as sirolimus everolimus (Certican ^™ ), CCI-779, and ABT578.

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

As used herein, the term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra ^™ ). The term "telomerase inhibitor," as used herein, refers to compounds that target telomerase, reduce, or inhibit its activity. Compounds that target telomerase, reduce, or inhibit its activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase and reduces or inhibits its activity. Compounds that target methionine aminopeptidase and reduce or inhibit its activity include, but are not limited to, bengamide or its derivatives.

As used herein, the term "proteasome inhibitor" refers to a compound that targets the proteasome and reduces or inhibits its activity. Compounds that target, reduce, or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade ^™ ) and MLN341.

As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes, but is not limited to, collagen peptide mimics and non-peptide mimics, tetracycline derivatives, such as the hydrooxaloyl ester peptide mimics inhibitor batimastat and its oral bioavailable analogues marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

As used herein, the term "compound for the treatment of hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arasulfuran cytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, reduce or inhibit polymorphic lymphoma kinases and Bcl-2 inhibitors.

Compounds that target the FMS-like tyrosine kinase receptor (Flt-3R), reduce or inhibit its activity, especially compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, astrocytocin derivatives, SU11248 and MLN518.

As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity, particularly compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldmycin (17AAG) (a geldmycin derivative); other geldmycin-related compounds; radicicol; and HDAC inhibitors.

As used herein, the term "antiproliferative antibody" includes, but is not limited to, trastuzumab (Herceptin ^™ ), trastuzumab-DM1, erbitux, bevacizumab (Avastin ^™ ), rituximab PRO64553 (anti-CD40), and 2C4 antibody. Antibody means intact monoclonal antibody, polyclonal antibody, multispecific antibody formed from at least two intact antibodies, and antibody fragments, provided they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly those for the treatment of AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and/or other drugs suitable for the treatment of AML, such as donomycin, adenomycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412. In some embodiments, the present invention provides a method of treating AML associated with ITD and/or D835Y mutations, the method comprising administering the compounds of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), astrocytocin derivatives (e.g., midotulin or lestatinib), 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, midotulin, lestatinib, sorafenib, and sunitinib.

Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2′-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogues of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Histone deacetylase (HDAC) inhibitors targeting, for example, sodium butyrate and salinomycinoxime acid (SAHA), and compounds that reduce or inhibit their activity, 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 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-acrylamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, especially lactates. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. The term "ionizing radiation" as used above and below means ionizing radiation occurring in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in, but not limited to, radiotherapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

This also includes 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, including but not limited to fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to resist ALL), and/or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

This also includes, in particular, compounds, proteins, or monoclonal antibodies against VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof; 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin ^™ ; Endostatin ^™ ; o-aminobenzoic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab; VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin ^™ ).

As used in this article, photodynamic therapy refers to the use of certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments using compounds such as Visudyne ^™ and porfimer sodium.

As used in this article, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecocave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, estrone, and dexamethasone.

Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

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

The compounds of this invention are also suitable as adjunctive therapeutic compounds for use in combination with other drugs, such as anti-inflammatory drugs, bronchodilators, or antihistamines, particularly for the treatment of obstructive or inflammatory airway diseases, as mentioned above, for example, as therapeutic enhancers of such drugs or as a method of reducing the required dosage or potential side effects of such drugs. The compounds of this invention can be mixed with other active pharmaceutical ingredients in a fixed pharmaceutical composition or can be administered alone before, simultaneously with, or after other active pharmaceutical ingredients. Therefore, this invention includes combinations of the compounds of this invention as described above with anti-inflammatory, bronchodilator, antihistamine, or antitussive pharmaceutical substances, wherein the pharmaceutical compositions of the compounds and the pharmaceutical substances of this invention may be the same or different.

Suitable anti-inflammatory drugs include steroids, especially glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; and LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, and SC-53228. BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 ( Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659/PD 168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM)CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as salbutamol (hydroxymethyltert-butyladrenergic), mesoproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and their pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts, and CHF 4226 (Chiesi) and glycopyrrolate.

Suitable antihistamine active pharmaceutical ingredients include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

Other suitable combinations of the compounds of the present invention with anti-inflammatory drugs are those with 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, especially 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-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

The structures of active compounds identified by code number, class, or trade name can be obtained from the official standard summary "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications).

Exemplary immuno-oncology agents

In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates, and/or upregulates the immune response of a subject. In some embodiments, immuno-oncology agents, when administered together with the compounds of the present invention, have a synergistic effect in the treatment of cancer.

Immuno-oncology agents can be, for example, small molecule drugs, antibodies, or biomolecules or small molecules. 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 a humanized or human antibody.

In some implementations, immuno-oncology agents are (i) agonists that stimulate (including co-stimulate) receptors or (ii) antagonists that inhibit (including co-inhibitory) signals on T cells, both of which induce an amplified antigen-specific T cell response.

Some stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory 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 co-stimulatory or co-inhibitory receptors is the TNF family, which binds to molecules that are members of the homologous TNF receptor family, including 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, and RANKL. , TWEAKR/Fn14, TWEAK, BAFFR, EDAR, 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.

In some implementations, immuno-oncology agents are cytokines that inhibit T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or cytokines that stimulate T cell activation to stimulate an immune response.

In some embodiments, the combination of the compounds of the present invention with immuno-oncology agents can stimulate T cell responses. In some embodiments, the immuno-oncology agents are: (i) antagonists (e.g., immune checkpoint inhibitors) of proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galactoglobulin 9, CEACAM-1, BTLA, CD69, galactoglobulin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) agonists of proteins that stimulate 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.

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

In some implementations, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-IR antagonists, such as CSF-1R antagonistic antibodies, including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249, WO13169264, WO14/036357).

In some embodiments, immuno-oncology agents are selected from agonists that link positive costimulatory receptors; blockers that attenuate signal transduction by inhibiting receptors, antagonists, and one or more agents that systematically increase the frequency of anti-tumor T cells; agents that overcome unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1/PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., dalizumab) or by depletion via in vitro anti-CD25 beads), inhibiting metabolic enzymes such as IDO, or reversing/preventing T cell energy or depletion); and agents that trigger innate immune activation and/or inflammation at the tumor site.

In some implementations, the tumor immunotherapy agent is a CTLA-4 antagonist. In some implementations, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some implementations, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

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 its antigen-binding moiety 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; WO2012/145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein, termed AMP-224, composed of the fusion of the extracellular domain (B7-DC) of PD-L2 and the Fc moiety of IgG1.

In some embodiments, the tumor immunotherapy 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).

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 LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218) or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

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).

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 (WO 11/028683).

In some implementations, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some implementations, 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); kynuronine-degrading enzymes (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

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.

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).

In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is lucarumumab or dacetuzumab.

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.

In some implementations, the immuno-oncology agent is MGA271 (targeting B7H3) (WO11/109400).

In some implementation schemes, immuno-oncology agents include abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimusab, avelumab, bonatetumab, BMS-936559, catumaxomab, durvalumab, icardostat, epratuzumab, indomod, and others. Inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, olatatumab, pembrolizumab, rituximab, ticilimumab, samalizumab, or trimetumab.

In some implementations, immuno-oncology agents are immunostimulants. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses and increase the number of tumor tissue structures, including some tumor types not conventionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al., (2013) Nat. Immunol. 14, 1212-1218; Zou et al., (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who experience disease progression during or after prior anti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutic agents that can be used in this invention include pomalidomide (Celgene); lenalidomide (Celgene); and ingenol mebutate (LEO Pharma).

In some implementations, the tumor immunotherapy agent is a cancer vaccine. In some implementations, the cancer vaccine is selected from sipuleucel-T (Dendreon/Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (BioVex/Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions of melanoma. In some implementations, the immuno-oncology agent is selected from oncolytic virus therapies, such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly JennerexBiotherapeutics), a thymidine kinase-(TK-)-deficient vaccinia virus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); and Oncolytics B. iotech), a respiratory enteric-coated orphan virus variant (reovirus) that does not replicate in cells not activated by RAS, is found in a variety of 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); enalapril (NG-348, PsiOxus, formerly known as ColoAd1), an engineered variant for use in the ovary. Adenoviruses that express full-length CD80 and antibody fragments specific to the T-cell receptor CD3 protein in cancers (NCT02028117), metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland carcinoma (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676); and peritoneal diseases, colorectal cancer, or ovarian cancer (NCT02963831); GL-ON C1 (GLV-1h68/GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal)/β-glucuronidase or β-gal/human sodium iodide transporter (hNIS), respectively, in peritoneal carcinoma (NCT01443260); fallopian tube cancer and ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

In some implementations, the immuno-oncology agents are selected from JX-929 (SillaJen/formerly JennerexBiotherapeutics), a vaccinia virus engineered to express cytosine deaminase lacking TK and vaccinia growth factor, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapeutic agents targeting refractory RAS mutations; and TILT-123 (TILTBiotherapeutics), an engineered adenovirus named Ad5/3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to produce antigen-specific CD8 ⁺ T cell responses.

In some implementations, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor, or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

A CAR has been constructed that consists of a binding domain derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for cell surface antigens, and an intracellular domain serving as the functional terminus of the T cell receptor (TCR), such as a CD3-ζ signaling domain from the TCR capable of generating activation signals in T lymphocytes. Upon antigen binding, this type of CAR links to endogenous signaling pathways in effector cells and generates activation signals similar to those induced by the TCR complex.

For example, in some embodiments, the CAR-T cells are those described in U.S. Patent 8,906,682 (June et al.; hereby incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (e.g., a domain that binds to CD19) and an intracellular signaling domain fused to the ζ chain of the T cell antigen receptor complex (e.g., CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials using CAR-T in various indications are underway. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, the immunostimulant is an activator of retinoic acid receptor-associated orphan receptor g (RORgt). RORgt 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 in the differentiation of IL-17-expressing innate immune cell subsets (e.g., NK cells). In some embodiments, the activator of RORgt is LYC-55716 (Lycera), which is currently being evaluated in a clinical trial for the treatment of solid tumors (NCT02929862).

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

Other immuno-oncology agents that can be used in this invention include varlilumab (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; and lirilumab (IPH2102/BMS-98). 6015 (Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; molizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

In some implementations, the immunostimulant is selected from elotuzumab, mifamurtide, agonists or activators of Toll-like receptors, and activators of RORgt.

In some embodiments, the immunostimulatory agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 has been tested clinically as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulator is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunostimulator is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex (IL15: sIL-15RA) consisting of a synthetic form of endogenous IL-15 and the α-chain of the soluble IL-15-binding protein IL-15 receptor, which has been tested in a phase 1 clinical trial for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some implementations, recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

In some embodiments, the immuno-oncology agent is selected from the immuno-oncology agents described in Jerry L. Adams et al., “Bigopportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. 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 targeting immuno-oncology targets selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the tumor immunotherapy agent is a small molecule agent selected from the small molecule agents listed in Table 2 of Jerry L. Adams et al.

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, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent that targets pathways as described in Peter L. Toogood.

In some embodiments, the immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T-cell engaging rantibody constructs can immediately by standard tumor cell killing,” PLoS ONE 12(8): e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T-cell engaging rantibody construct. In some embodiments, the bispecific T-cell engaging rantibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, the bispecific T-cell engaging rantibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, the bispecific T-cell engaging rantibody construct activates T cells. In some embodiments, the bispecific T-cell engaging rantibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, a bispecific T-cell conjugate antibody construct activates T cells, leading to induced lysis of neighboring cells. In some embodiments, the neighboring cells are in a solid tumor. In some embodiments, the lysed neighboring cells are adjacent to the activated T cells. In some embodiments, the neighboring cells contain tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the neighboring cells contain EGFR-negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, the immuno-oncology agent is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs).

Exemplary immune checkpoint inhibitors

In some implementations, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

As used in this article, the term "checkpoint inhibitor" refers to agents designed to prevent cancer cells from evading a patient's immune system. One of the main mechanisms of antitumor immune destruction is called "T-cell exhaustion," which is caused by prolonged exposure to antigens that induce upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuation factor (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223), and other receptors are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to indicate whether cell cycle progression and other intracellular signaling processes will continue.

In some implementations, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the planned cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby suppressing the tumor's ability to suppress the host's anti-tumor immune response.

In some embodiments, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a whole-human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits checkpoint proteins selected from the following: 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 ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with ligands selected from the following checkpoint proteins: 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 ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, T-cell growth factor, interleukin, antibody, 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 an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits a suppressive 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. Illustrative 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 (belonging to the CD2 molecule family and expressed on all NK, γδ, and memory CD8 ⁺ (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 their antigen-binding fragments, other binding proteins, biological therapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, tramemumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (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.

In some embodiments, the immune checkpoint inhibitor is selected from PD-1 antagonists, PD-L1 antagonists, and CTLA-4 antagonists. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab, ipilimumab, and pembrolizumab. In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Merck); ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

In some implementations, the checkpoint inhibitors are selected from the group consisting of: lanizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirelizumab, IPH2101, pembrolizumab, and trametumab.

In some implementations, the immune checkpoint inhibitors are REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); and pilithumab (CureTech), also known as CT-011, a drug in clinical trials for diffuse large B-cell lymphoma and... Antibodies that bind to PD-1 for multiple myeloma; Averuma (Pfizer/Merck KGaA, also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody used in clinical trials for 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 used in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Trimetazaprine (CP-675, 206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been investigated in clinical trials for multiple indications, including: mesothelioma, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, non-small cell lung cancer, pancreatic duct adenocarcinoma, pancreatic cancer, germ cell carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic liver cancer, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic undifferentiated thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody investigated in a phase 1 clinical trial for advanced solid tumors (NCT02694822).

In some embodiments, the checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors available in this invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody studied in advanced malignant disease (NCT02608268).

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

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

Checkpoint inhibitors that can be used in this invention include OX40 agonists. OX40 agonists investigated in clinical trials include: PF-04518600/PF-8600 (Pfizer), an agonist anti-OX40 antibody in metastatic renal cell carcinoma (NCT03092856) and advanced cancer and necrozoomas (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist anti-OX40 antibody in a phase 1 cancer trial (NCT02528357); and MEDI0562 (Medimmune/AstraZeneca), an antibody in advanced solid tumors (NCT0231839). 4. Active anti-OX40 antibody in NCT02705482; MEDI6469, active anti-OX40 antibody in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705) (Medimmune/AstraZeneca); and BMS-986178 (Bristol-Myers Squibb), active anti-OX40 antibody in advanced cancer (NCT02737475).

Checkpoint inhibitors that can be used in this invention include CD137 (also known as 4-1BB) agonists. CD137 agonists currently being investigated in clinical trials include utomilumab (PF-05082566, Prizer), an agonist anti-CD137 antibody in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and lesions (NCT02554812 and NCT05082566); utomilumab (BMS-663513, Bristol-Myers Squibb), an agonist anti-CD137 antibody in melanoma and skin cancer (NCT02652455) and glioblastoma and glioma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonist anti-CD137 antibody in metastatic or locally advanced malignant disease (NCT03881488).

Checkpoint inhibitors that can be used in this invention include CD27 agonists. CD27 agonists investigated in clinical trials include: valimumab (CDX-1127, Celldex Therapeutics), an agonistic anti-CD27 antibody in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

Checkpoint inhibitors that can be used in this invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists investigated in clinical trials include: TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody in solid tumors and lymphoma (NCT02740270); and INCAGN01876 (Incyte/Agen). us), agonistic anti-GITR antibodies in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), agonistic anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune/AstraZeneca), agonistic hexameric GITR-ligand molecules with human IgG1 Fc domain in advanced solid tumors (NCT02583165).

Checkpoint inhibitors that can be used in this invention include inducible T-cell co-stimulatory agents (ICOS, also known as CD278) agonists. ICOS agonists investigated 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).

Checkpoint inhibitors that can be used in this invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include: lireuromab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), 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 (KIR3DL2) that binds to three domains of the long cytoplasmic tail region in lymphoma (NCT02593045).

Checkpoint inhibitors that can be used in this invention include CD47 inhibitors that address the interaction between CD47 and signal regulatory protein α (SIRPa). CD47/SIRPa inhibitors investigated in clinical trials include: ALX-148 (AlexoTherapeutics), an antagonistic variant of SIRPa that binds to CD47 and prevents CD47/SIRPa-mediated signal transduction in a phase 1 trial (NCT03013218); and TTI-621 (SIRPa-Fc, TrilliumTherapeutics), which, in phase 1 clinical trials (NCT02890368 and NCT02663518), binds to the N-terminal CD47-binding domain of SIRPa and... A soluble recombinant fusion protein produced by the Fc domain of human IgG1, which functions by binding to human CD47 and preventing it from delivering its "do not eat" signal to macrophages; CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal cysts and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

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

Checkpoint inhibitors that can be used in this invention include agonists of interferon gene-stimulating protein (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING investigated in clinical trials include: MK-1454 (Merck), an agonist of synthetic cyclic dinucleotides in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonist of synthetic cyclic dinucleotides in phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that can be used in this invention include CSF1R inhibitors. CSF1R inhibitors investigated in clinical trials include: pexidartinib (PLX3397, Plexxikon), a small molecule CSF1R inhibitor in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710), as well as melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855). Lilly), an anti-CSF-1R antibody in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and Novartis, an orally effective inhibitor of CSF1R in advanced solid tumors (NCT02829723).

Checkpoint inhibitors that can be used in this invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody in head and neck sarcoma (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

In some implementations, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pilizumab.

The compounds of the present invention can also be used in combination with known treatment methods (e.g., administration of hormones or radiation). In some embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

The compounds of this invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a fixed combination or alternating or independent administration of the compounds of this invention and one or more other therapeutic compounds, or a fixed combination combined with one or more other therapeutic compounds. Furthermore, the compounds of this invention may be combined with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for oncology. As described above, similar to adjuvant therapy in other treatment strategies, long-term therapy is also possible. Other possible treatments include maintenance therapy after tumor regression, or even chemopreventive therapy (e.g., for patients at risk).

These additional agents may be administered separately from the composition containing the compound of the present invention 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 to form a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals between each other (typically within five hours).

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

The amounts of the compounds of the invention that can be combined with a carrier substance to produce a single dosage form and additional therapeutic agents (in those compositions containing additional therapeutic agents as described above) will vary depending on the host being treated and the specific administration method. Preferably, the compositions of the invention should be formulated such that the compounds of the invention can be administered at a dose between 0.01 and 100 mg/kg body weight/day.

In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions will be less than that required in a single therapy using only the therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dose between 0.01 and 1,000 mg/kg body weight/day.

The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be applied in the form of a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed in the present invention will be in the range of about 50% to 100% of the amount normally present in a composition containing said pharmaceutical agent as the sole active agent.

The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Intravascular stents have been used, for example, to overcome restenosis (restriction of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the devices with a pharmaceutically acceptable composition containing an OXER1 inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the invention.

Example

As depicted in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that while the general approach describes the synthesis of certain compounds of the present invention, the following general approach and other methods known to those skilled in the art can be applied to all compounds as described herein and to subclasses and types of each of these compounds. Other compounds of the present invention are prepared by methods substantially similar to those described in the examples herein and by methods known to those skilled in the art.

General Information: All evaporations were performed in vacuum using a rotary evaporator. Samples were dried for analysis in vacuum (1–5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, with spots observed under UV light (214 and 254 nm). Column and rapid chromatography purification 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 as δ values (ppm), with deuterated solvents used as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiplet), coupling constant (Hz), and integral value. LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer equipped with electrospray ionization, and unless otherwise specified, the general LCMS conditions were as follows: Waters X Bridge 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 LCMS1200-6110, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 2.0mL/min; mobile phase: changed from 95% [water + 0.05% TFA] and 5% [ _CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [ _CH3CN + 0.05% TFA] within 1.6min, then held under these conditions for 1.4min, and finally changed to 95% [water + 0.05% TFA] and 5% [ _CH3CN + 0.05% TFA] within 0.05min, and held under these conditions for 0.7min.

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: changed from 95% [water + _{10mM NH4HCO3} ] and 5% [ _CH3CN ] to 0% [water + 10mM _NH4HCO3 ] and 100% [ _CH3CN ] in _1.6min , then held under these conditions for 1.4min, and finally changed to 95% [water + _{10mM NH4HCO3} ] and 5% [ _CH3CN ] in 0.1min, and held under these conditions for 0.7min.

Method 3 : Agilent HPLC 1200; Column: L-column 2ODS (150mm*4.6mm*5.0 μm); Column temperature: 40℃; Flow rate: 1.0mL/min; Mobile phase: changed from 95% [water + 0.1% TFA] and 5% [ _CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [ _CH3CN + 0.1% TFA] within 10 min, then held under these conditions for 5 min, and finally changed to 95% [water + 0.1% TFA] and 5% [ _CH3CN + 0.1% TFA] within 0.1 min, and held under these conditions for 5 min.

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: changed from 95% [water + _{10mM NH4HCO3} ] and 5% [ _CH3CN ] to 0% [water + 10mM _NH4HCO3 ] and 100% [ _CH3CN ] within 10min, then held under these conditions for 5min, and finally changed to 95% [water + _{10mM NH4HCO3} ] and 5% [ _CH3CN ] within 0.1min, and held under these conditions for 5min.

General Procedure A (Wittig reaction to obtain the olefin intermediate): t-BuOK (3.0 equivalents) was added to a suspension of phosphorus ylide (1.0 equivalent) in THF at 0 °C. The mixture was stirred for 30 min, and THF containing an aldehyde (1.0 equivalent) was added dropwise. The reaction mixture was heated to room temperature and stirred for 16 h. A saturated NH4Cl solution was added at 0 °C, and the mixture was acidified to pH ~3 with HCl (1.0 M). Extraction was performed with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous _{Na2SO4 ,} and evaporated under reduced pressure. The crude substance was purified by silica gel chromatography to obtain the olefin intermediate.

General Method B (Hydrogenation of Olefins to Saturated Alkanes): 10% Pd/C (0.1 equivalent w/w) is added to a stirred solution of olefin (1.0 atm) in EtOAc under a _H2 atmosphere (1.0 atm). The reaction mixture is stirred at room temperature for 8 h until the reaction is complete (according to LCMS), followed by filtration. The residue is washed with EtOAc, and the combined filtrates are concentrated under reduced pressure to give a saturated alkane intermediate.

General Method C (Reduction of Carboxylic Acid to Primary Alcohol): _LiAlH₄ (1.0 equivalent) is slowly added to a stirred solution of carboxylic acid (1.0 equivalent) in THF at -20°C. The reaction mixture is heated to room temperature and stirred for 5 hours until the reaction is complete (according to LCMS). The reaction is quenched by adding water (2.0 equivalent), NaOH (15% aqueous solution, 2.0 equivalent), and water (6.0 equivalent) dropwise sequentially at 0°C. The mixture is filtered, and the filtrate is dried over _{anhydrous Na₂SO₄} and evaporated under reduced pressure to give the crude alcohol, which is used directly in the next step.

General Procedure D (Esterification of alcohol derivatives to methanesulfonates with _Ms₂O ): _Ms₂O (1.5 equivalents) is added to a solution of alcohol derivative (1.0 equivalents) and TEA (2.0 equivalents) in THF at 0°C. The mixture is heated to room temperature and stirred for another 2 hours, then quenched with water and extracted with DCM. The combined organic phases are washed with water and brine, _dried over anhydrous _Na₂SO₄ and concentrated to obtain crude methanesulfonate, which is used directly in the next step.

General Method E (Formation of Bromine Derivatives from Methanesulfonates): LiBr (2.0 equivalents) is added to a solution of methanesulfonate (1.0 equivalent) in acetone at room temperature. The mixture is stirred overnight under reflux. Water is added and the mixture is extracted with DCM. The combined organic layers are dried over _{anhydrous Na₂SO₄} , filtered, and concentrated to give the bromine derivative, which is used directly in the next step.

General Procedure F (Formation of Phosphorus Ylides from Bromine Derivatives): PPh ₃ (2.0 equivalents) was added to a stirred solution of bromine derivative (1.0 equivalent) in acetonitrile. The reaction mixture was refluxed overnight at 80°C. The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (10% MeOH/DCM) to obtain the phosphorus ylide derivative.

General Procedure G (Acylation Step): _Me₂AlCl (1.0 M in hexane, 2.0 equivalent) was added to a stirred solution of indole/azaindole derivative (1.0 equivalent) in dichloromethane at 0 °C. After 45 _{min, CH₂Cl₂ (} 1 mL) containing acyl chloride (2.0 equivalent) was added dropwise at room temperature, and the reaction mixture was stirred for another 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and _dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel chromatography (30% EtOAc/Hex) to obtain the acylated product.

General Procedure H (hydrolysis from ester to carboxylic acid): Lithium hydroxide (5.0 equivalents) was added to a mixture of ester derivative (1.0 equivalents) and THF/ _H₂O (5/1, v/v). The reaction mixture was stirred at room temperature for 16 h until complete (according to LCMS). A saturated _NH₄Cl solution was added at 0 °C, and the mixture was acidified to pH ~6.0 with HCl (1.0 M), followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over _{anhydrous Na₂SO₄} , and evaporated under reduced pressure. The crude material was purified by preparative HPLC to obtain the desired product.

General Procedure I (Ether Formation): Add NaHH (60% in mineral oil, 1.0 equivalent) to a stirred solution of alcohol (1.0 equivalent) in DMF. Stir the reaction mixture at 0°C under _N₂ for 0.5 h, then slowly add the bromine derivative (1.0 equivalent). Stir the reaction mixture at room temperature for 2 h until the reaction is complete. Dilute the suspension with NaCl (aqueous solution) and extract with EtOAc. Wash the organic layer with brine, dry over _{anhydrous Na₂SO₄} , filter, concentrate under vacuum, and purify by column chromatography to obtain the ether derivative.

General Procedure J (Oxidation of Alcohol to Aldehyde): Add DMP (1.2 equivalents) to a solution of alcohol (1.0 equivalents) in DCM at 0°C. Stir the mixture at 0°C for 30 min. Add saturated _NaHCO3 (aqueous solution) to the mixture and extract with DCM. Wash the combined organic layers with brine, dry over _{anhydrous Na2SO4} , filter, and concentrate under vacuum. Purify the crude substance by silica gel chromatography to obtain the aldehyde product.

General procedure K (Grignard addition to aldehyde): A Grignard reagent (1.2 equivalents) is added to a solution of aldehyde (1.0 equivalents) in THF at 0 °C. The mixture is stirred at room temperature for 1 h. Water is added and the mixture is extracted with EtOAc. The combined organic layers are dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The crude material is purified by silica gel chromatography to give the corresponding secondary alcohol product.

General Procedure L (Alkylation of Terminal Alkynes): n-BuLi (1.2 equivalents) was added to a suspension of terminal alkynes (1.0 equivalents) in THF at -78°C. The mixture was stirred for 1 hour, and HMPA containing a bromine derivative (1.0 equivalents) was added dropwise. The reaction mixture was heated to room temperature and stirred for another 16 hours. A 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 to obtain the desired alkylated product.

General procedure M (coupling): A terminal alkyne (1.1 equivalent), Pd( _PPh3 ) _2Cl2 ( _0.1 equivalent), CuI (0.1 equivalent), and TEA (3.0 equivalent) were added to a stirred solution of aryl halide (1.0 equivalent) in THF. The reaction mixture was stirred at 60 °C under nitrogen for 16 h. The mixture was filtered through a diatomaceous earth filter, followed by the addition of water and EA. The organic phase was collected and evaporated under reduced pressure, and purified by silica gel chromatography to obtain the coupling product.

General procedure N (cyclization to obtain indole/azaindole derivative): t-BuOK (1.4 equivalents) was added to a stirred solution of alkyne (1.0 equivalents) in DMF. The reaction mixture was stirred at 80°C under nitrogen for 0.5 h. The mixture was filtered through a diatomaceous earth mat and purified by preparative HPLC to obtain the indole/azaindole derivative.

Example 1: Synthesis of compound I-24

Synthetic scheme of compound I-24

1.1 Synthesis of intermediates 1-2

t-BuOK (135.7 g, 1.21 mol) was added to a suspension of (3-carboxypropyl)triphenylphosphonium bromide (207.6 g, 483.7 mmol) in THF (1600 mL) at 0 °C. The mixture was stirred for 30 min and THF (200 mL) containing 1-1 (68 g, 483.7 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 16 h. A saturated _NH4Cl solution was added at 0 °C, and 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 substance 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] ⁺ .

1.2 Synthesis of intermediates 1-3

10% Pd/C (8.0 g) was added to a stirred solution of 1-2 (71.0 g, 338.1 mmol) in EtOAc (500 mL) under a _H2 atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 8 h until the reaction was complete (according to LC-MS), and then filtered. The residue was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure to give 1-3 (71 g, 99%) as a colorless oil. LC-MS m/z: 213.1 [M+H] ⁺ .

1.3 Synthesis of intermediates 1-4

_LiAlH₄ (12.7 g, 334.9 mmol) was slowly added to a stirred solution of 1-3 (71 g, 334.9 mmol) in THF (500 mL) at -20 °C. The reaction mixture was heated to room temperature and stirred for 5 hours until the reaction was complete (according to LC-MS). The reactants were quenched by adding water (13 mL), NaOH (15% aqueous solution, 13 mL), and water (39 mL) dropwise at 0 °C. The mixture was filtered, and the filtrate was dried over anhydrous _Na₂SO₄ 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] ^⁺ .

1.4 Synthesis of intermediates 1-5

At 0 °C under an Ar atmosphere, methanesulfonic anhydride (63.6 g, 366 mmol) was added to a solution of 1-4 (60.6 g, 305 mmol) and TEA (61.6 g, 610 mmol) in THF (800 mL). The mixture was then heated to room temperature and stirred for 2 h. Saturated _NaHCO3 (aqueous solution, 80 mL) was added to the mixture and extracted with DCM (300 mL × 3). The combined organic layers were washed with brine (200 mL × 2 ₎ , dried over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give 1-5 (84.0 g, 91%) as a yellow oil. LC-MS m/z: 277.2 [M+H] ⁺ .

Synthesis of intermediates 1-6 (1.5)

LiBr (52.7 g, 606.9 mmol) was added to a solution of 1-5 (84.0 g, 303.5 mmol) in acetone (800 mL) at room temperature. The mixture was stirred under 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 under vacuum to give 1-6 (75.4 g, yield: 95%) as a yellow oil. LC-MS m/z: 263.1 [M+H] ^⁺ .

1.6 Synthesis of intermediates 1-7

PPh ₃ (151.0 g, 576.4 mmol) was added to a stirred solution of 1-6 (75.4 g, 288.2 mmol) in acetonitrile (600 mL). The reaction mixture was refluxed overnight at 80 °C. The solvent was evaporated under reduced pressure, and the crude substance 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] ⁺ .

1.7 Synthesis of intermediates 1-9

HATU (148.4 g, 390.6 mmol) and DIEA (155 mL, 937.5 mmol) were added to a stirred solution of 1–8 (50.0 g, 312.5 mmol) in DMF (600 mL) under ice bath conditions. 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. When the reaction was complete (according to 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 material was purified by silica gel chromatography (10–33% EtOAc/PE) and preparative HPLC. 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: liquid _CO2 containing 15% EtOH (35 °C and 2000 psi), flow rate: 2 mL/min, detector: 215 nm), yielding 1-9 as a yellow oil (t _R : 1.542 min, 18 g, yield: 23%). The t _R for 1-10 was 1.895 min.

1.8 Synthesis of intermediates 1-11

15% Pd/C (2.7 g) was added to a stirred solution of 1-9 (18.0 g, 71.6 mmol) in MeOH (200 mL) under a _H₂ atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 2 h until complete (according to LC-MS), followed by filtration. The residue was washed with EtOAc and the combined filtrates were concentrated under reduced pressure. The crude substance was purified by silica gel chromatography (PE solution of 24% EtOAc/0.1% formic acid) to give 1-11 (8.5 g, yield: 74%) as a pale yellow oil. LC-MS m/z: 161.2 [M+H] ^⁺ .

1.9 Synthesis of intermediates 1-12

The solution of 1-11 (200 mg, 1.25 mmol) in SOCl ₂ (1.5 mL) was stirred at 70 °C for 1 hour. The residue was concentrated under reduced pressure to obtain a crude substance, which was then co-distilled with DCM (2 × 10 mL) to obtain a yellow oily product 1-12 (190 mg, yield: 85%), which was used directly in the next step.

Synthesis of intermediates 1-14 (1.10)

Methyl iodine (7.2 g, 50.9 mmol) was added to a solution of 1-13 (5.0 _g , 25.4 mmol) and _K₂CO₃ (10.5 g, 76.3 mmol) in DMF (30 mL) under an Ar atmosphere. The mixture was then stirred overnight at room temperature until the reaction was complete (according to LCMS). The reaction mixture was slowly poured into cold water, the precipitate was collected and dried to give 1-14 (5.0 g, 88%) as a brown solid. ^¹H 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).

1.11 Synthesis of intermediates 1-15

_LiAlH₄ (848 mg, 22.3 mmol) was slowly added to a stirred solution of 1-14 (5.0 g, 22.3 mmol) in THF (50 mL) at -20 °C. The reaction mixture was heated to room temperature and stirred for 5 hours until the reaction was complete (according to LCMS). The reactants were quenched by adding water (0.9 mL), NaOH (15% aqueous solution, 2.7 mL), and water (0.9 mL) dropwise at 0 °C. The mixture was filtered, and the filtrate was dried over _{anhydrous Na₂SO₄} and evaporated under reduced pressure to give crude product 1-15 (3.1 g, 71%), which was used directly in the next step.

Synthesis of intermediates 1-16, 1.12

_MnO₂ (31.0 g, 356 mmol) was added to a mixture of 1-15 (3.1 g, 15.8 mmol) in DCM (25 mL). The reaction mixture was stirred at room temperature for 4 h until the reaction was complete (according to LCMS), followed by filtration. The residue was washed with EtOAc and the combined filtrates were concentrated under reduced pressure to give 1-16 (2.5 g, 80%) as a gray solid.

1.13 Synthesis of intermediates 1-17

LiHMDS (1.0 M in THF, 31.6 mL, 31.6 mmol) was added to a suspension of 1-16 (2.5 g, 12.6 mmol) in THF (100 mL) at -78 °C. The mixture was stirred for 30 min, followed by the dropwise addition of THF (100 mL) containing 1-7 (9.7 g, 50.3 mmol). The reaction mixture was heated to room temperature and stirred for 5 h. A 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 substance was purified by silica gel chromatography (5% EtOAc/hexane) to give 1-17 (2.9 g, 64%) as a pale yellow solid.

1.14 Synthesis of intermediates 1-18

10% Pd/C (580 mg) was added to a stirred solution of 1-17 (2.9 g, 8.1 mmol) in EtOAc (30 mL) under a H2 atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 1 h until the reaction was complete (according to LCMS), followed by filtration. The residue was washed with EtOAc and the combined filtrates were concentrated under reduced pressure to give 1-18 (2.3 g, 79%) as a pale yellow solid.

Synthesis of intermediates 1-19 (1.15)

_Me₂AlCl (1.0 M in hexane, 1.0 mL, 1.0 mmol) was added to a stirred solution of 1-18 (360 mg, 1.0 mmol) in dichloromethane (15 mL) at 0 °C. After 45 _min , _CH₂Cl₂ (1 mL) containing 1-12 (1.4 g, 6.4 mmol) was added dropwise at room temperature, and the reaction mixture was stirred for another ₂ h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (30% EtOAc/Hex) to give 1-19 (320 mg, 64%) as a yellow oil.

1.16 Synthesis of Compound I-24

Lithium hydroxide (120 mg, 3.2 mmol) was added to a mixture of 1-19 (320 mg, 0.64 mmol) in THF/ _H₂O (10 mL/2 mL), and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete (according to LCMS). A saturated _NH₄Cl solution was added at 0 °C, and the mixture was acidified to pH 6.0 with HCl (1.0 M), followed by extraction with EtOAc. The combined organic layers were washed with brine, _dried over anhydrous _Na₂SO₄ , and evaporated under reduced pressure. The crude material was purified by preparative HPLC to give I-24 (130 mg, 42%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ12.18 (br, 1H), 8.37 (d, J = 2.0Hz, 1H), 8.32 (d, J = 2.0Hz, 1H), 7.31-7.26 (m, 2H), 7.22 (d, J = 7.6Hz, 1H), 7.16 (d, J=7.6Hz, 1H), 3.80 (s, 3H), 3.18 (t, J=7.6Hz, 2H), 3.04 (dd, J=16.4, 5.6Hz, 1H), 2.86 (d d, J=16.8, 7.6Hz, 1H), 2.58 (t, J=7.6Hz, 2H), 2.41 (d, J=5.6Hz, 1H), 2.37 (d, J=5.6Hz, 1H), 2.17 (dd, J=15.6, 8.0Hz, 1H), 1.60-1.56 (m, 4H), 1.46-1.41 (m, 2H), 1.38-1.34 (m, 2H), 0.96 (d, J=6.8Hz, 3H).

LC-MS m/z: 489.0 [M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 2 and 2a below.

Table 2: Characterization data of additional exemplary compounds

Table 2a: Additional characterization data for additional exemplary compounds

Compound numbering Rt(Min)(LCMS) Rt(Min)(HPLC) I-305 2.109 10.774

Example 2: Synthesis of Compound I-60

Synthetic scheme of compound I-60

2.1 Synthesis of intermediate 2-2

NaH (1.4 g, 34.1 mmol, 60% in mineral oil) was added to a stirred solution of propane-1,3-diol (25.9 g, 340.7 mmol) in DMF (150 mL). The reaction mixture was stirred at 0 °C under a _nitrogen atmosphere for 0.5 h, followed by the slow addition of 2-1 (7.0 g, 34.1 mmol), 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 _Na₂SO₄ , filtered, and concentrated under vacuum to give 2-2 (6.8 g, crude substance) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.32(s, 1H), 7.27-7.25(m, 2H), 7.21-7.19(m, 1H), 4.48(d, J=6.8Hz, 2H), 3.78 (t, J=6.0Hz, 2H), 3.65 (t, J=6.0Hz, 2H), 2.38 (s, 1H), 1.88-1.85 (m, 2H).

2.2 Synthesis of intermediates 2-3

At 0 °C, CBr ₄ (16.2 g, 48.7 mmol) and PPh ₃ (8.5 g, 48.7 mmol) were added to a stirred solution of 2-2 (6.5 g, 32.5 mmol) in DCM (100 mL). The reaction mixture was heated to room temperature and stirred for 2 hours until the reaction was complete. The solvent was evaporated under reduced pressure and the crude substance was purified by silica gel chromatography (PE/EA = 3/1) to give 2-3 (5.6 g, yield: 66%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.33 (s, 1H), 7.27-7.26 (m, 2H), 7.21 (d, J=0.8Hz, 1H), 4.49 (s, 2H), 3.61 (t, J=6.0Hz, 2H), 3.54 (t, J=6.4Hz, 2H), 2.14 (t, J=6.4Hz, 2H).

2.3 Synthesis of intermediates 2-4

PPh ₃ (11.1 g, 42.5 mmol) was added to a stirred solution of 2-3 (5.6 g, 21.3 mmol) in acetonitrile (100 mL). The reaction mixture was refluxed overnight at 80 °C. The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (15% MeOH/DCM) to give 2-4 (11.1 g, yield: 99%) as a colorless oil. LC-MS m/z: 445.0 [M-Br] ⁺ .

2.4 Synthesis of intermediates 2-5

LiHMDS (1.6 M in THF, 16 mL, 25.1 mmol) was added to a suspension of 2-4 (11.0 g, 20.9 mmol) in THF (100 mL) at -78 °C. The mixture was stirred for 30 min and THF (40 mL ₎ containing 1-11 (4.9 g, 25.1 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for another 16 h. A 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 substance was purified by silica gel chromatography (10% EtOAc/hexane) to give 2-5 (5.1 g, yield: 67%) as a yellow solid. LC-MS m/z: 360.0 [M+H] ^⁺ .

Synthesis of intermediates 2-6 (2.5)

10% Pd/C (500 mg) was added to a stirred solution of 2-5 (2.1 g, 5.6 mmol) in EtOAc (20 mL) under a _H2 atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 2 h until the reaction was complete (according to LC-MS), followed by filtration. The residue was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure to give crude product 2-6 (1.4 g, yield: 66%) as a colorless oil. LC-MS m/z: 362.0 [M+H] ⁺ .

2.6 Synthesis of intermediates 2-7

_Me₂AlCl (1.0 M in hexane, 1.7 mL, 1.66 mmol) was added dropwise to a stirred solution of 2-6 (300 mg, 0.83 mmol) in dichloromethane (5 mL) at -78 °C. After 30 min, 1 mL of dichloromethane containing 1-12 (222 mg, 1.24 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for another 0.5 _h . The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (40% EtOAc/Hex) to give 2-7 (350 mg, yield: 84%) as a colorless oil. LC-MS m/z: 504.0 [M+H] ^⁺ .

2.7 Synthesis of Compound I-60

Lithium hydroxide monohydrate (292 mg, 6.9 mmol) was added to a stirred solution of 2-7 (350 mg, 0.694 mmol) in MeOH/THF/ _H₂O (5 mL/5 mL/0.1 mL). The reaction mixture was stirred overnight at room temperature until complete (according to LCMS). A saturated _NH₄Cl solution was added at 0 °C, and the mixture was acidified to pH ~3.0 with HCl (1.0 M), followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and evaporated under reduced pressure. The crude material was purified by preparative HPLC to give I-60 (76 mg, yield: 22%) as a colorless semi-solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.86(d, J=1.6Hz, 1H), 7.30(s, 1H), 7.24-7.20(m, 4H), 7.19-7.17(m , 1H), 4.46 (s, 2H), 3.69 (s, 3H), 3.53 (t, J=6.0Hz, 2H), 3.23-3.19 (m, 2H ), 3.01-2.99 (m, 2H), 2.73-2.71 (m, 1H), 2.51 (dd, J=15.2, 5.6Hz, 1H), 2.36 (dd, J=14.8, 6.8Hz, 1H), 1.77-1.73 (m, 4H), 1.15 (d, J=6.8Hz, 3H). LC-MS m/z: 489.9 [M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and in this paper. Data for these compounds are provided in Table 3 below.

Table 3: Characterization data of additional exemplary compounds

Example 3: Synthesis of compound I-44

Synthetic scheme of compound I-44

3.1 Synthesis of Intermediate 3-1

t-BuOK (135.7 g, 275 mmol) was added to a suspension of (4-carboxybutyl)triphenylphosphine bromide (48.6 g, 110 mmol) in THF (800 mL) at 0 °C. The mixture was stirred for 30 min and THF (200 mL) containing 1-11 (21.2 g, 110.0 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 16 h. A saturated _NH4Cl solution was added at 0 °C, and 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 substance was purified by silica gel chromatography (5% MeOH/DCM) to give 3-1 (30.0 g, 98%) as a yellow oil. LC-MS m/z: 278.0 [M+H] ⁺ .

3.2 Synthesis of intermediate 3-2

10% Pd/C (6.0 g) was added to a stirred solution of 3-1 (30.0 g, 108.3 mmol) in EtOAc (500 mL) under a _H2 atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 8 h until the reaction was complete (according to LC-MS), and then filtered. The residue was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure to give 3-2 (28.0 g, 93%) as a colorless oil. LC-MS m/z: 279.7 [M+H] ⁺ .

3.3 Synthesis of intermediate 3-3

_LiAlH₄ (7.63 g, 200.8 mmol) was slowly added to a stirred solution of 3-2 (28.0 g, 100.4 mmol) in THF (500 mL) at -78 °C. The reaction mixture was heated to room temperature and stirred for 5 hours until the reaction was complete (according to LC-MS). The reactants were quenched by adding water (8 mL), NaOH (15% aqueous solution, 8 mL), and water ( ₂₄ mL) dropwise at 0 °C. The mixture was filtered, and the filtrate was dried over anhydrous _Na₂SO₄ and then evaporated under reduced pressure. The crude product was purified by silica gel chromatography (30% EtOAc/PE) to give 3-3 (17.5 g, 66%) as a yellow solid. LC-MS m/z: 266.0 [M+H] ^⁺ .

3.4 Synthesis of intermediates 3-4

DMP (33.6 g, 79.2 mmol) was added to a solution of 3-3 (17.5 g, 66.0 mmol) in DCM (500 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Saturated _NaHCO3 (aqueous solution, 50 mL) was added to the mixture and extracted with DCM (300 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over _{anhydrous Na2SO4} , filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (20% EtOAc/PE) to give 3-4 (5.0 g, 29%) as a yellow solid. LC-MS m/z: 264.1 [M+H] ⁺ .

Synthesis of intermediate 3-5

Magnesium (3-chlorophenyl) bromide (1M in THF, 23.0 mL, 23.0 mmol) was added to a solution of 3-4 (5.0 g, 19.0 mmol) in THF (200 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (30% EtOAc/PE) to give 3-5 (4.5 g, 63%) as a white solid. LC-MS m/z: 376.0 [M+H] ^⁺ .

3.6 Synthesis of intermediates 3-6

_Me₂AlCl (0.9M in hexane, 2.0mL, 2.0mmol) was added to a stirred solution of 3-5 (300mg, 0.8mmol) in dichloromethane (15mL) at 0°C. After 30 min, _CH₂Cl₂ ( _2mL ) containing 1-12 (284.8mg, 1.6mmol) was added dropwise, and the reaction mixture was stirred at room temperature for another 1 _h . The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (30% EtOAc/Hex) to give 3-6 (180mg, 44%) as a colorless oil.

3.7 Synthesis of Compound I-44

Lithium hydroxide (147.0 mg, 3.5 mmol) was added to a mixture of 3-6 (180 mg, 0.35 mmol) in THF/ _H₂O (10 mL/2 mL). The reaction mixture was stirred at room temperature for 4 h until the reaction was complete (according to LCMS). A saturated _NH₄Cl solution was added at 0 °C, and the mixture was acidified to pH ~3.0 with HCl (1.0 M). The mixture was then extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and evaporated under reduced pressure. The crude material was purified by preparative HPLC to give I-44 (73.9 mg, 42%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ 12.11 (br, 1H), 7.95 (d, J = 1.2Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.36-7.31 (m, 2H), 7.27-7.23 (m , 3H), 5.32-5.21 (m, 1H), 4.53 (t, J=6.0Hz, 1H), 3.74 (s, 3H), 3.11 (t, J=8.0Hz, 2H), 2.98 (dd, J =16.4, 5.6Hz, 1H), 2.84 (dd, J = 16.4, 7.6Hz, 1H), 2.48-2.45 (m, 1H), 2.38 (dd, J = 15.6, 5.6Hz, 1 H), 2.17 (dd, J=15.2, 8.0Hz, 1H), 1.59-1.54 (m, 4H), 1.41-1.23 (m, 4H), 0.96 (d, J=5.2Hz, 3H). LC-MS m/z: 504.0[M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 4 and 4a below.

Table 4: Characterization data of additional exemplary compounds

Table 4a: Additional characterization data for additional exemplary compounds

Example 4: Synthesis of compound I-68

Synthetic scheme of compound I-68

4.1 Synthesis of intermediate 4-1

CBr ₄ (945 mg, 2.9 mmol) and PPh ₃ (746 mg, 2.9 mmol) were added to a stirred solution of 3-3 (505 mg, 1.9 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The solvent was evaporated under reduced pressure and the crude substance was purified by silica gel chromatography (PE/EA = 1/0 to 1/1) to give 4-1 (410 mg, yield: 66%) as a colorless oil. LC-MS m/z: 328.0 [M+H] ⁺ .

4.2 Synthesis of intermediate 4-2

n-BuLi (2.5 M in THF, 0.5 mL, 1.3 mmol) was added to a suspension of 3-methylbut-1-yne (73 mg, 1.1 mmol) in THF (3 mL) at -78 °C. The mixture was stirred for 1 h, and HMPA (1 mL) containing 4-1 (350 mg, 1.1 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for another 16 h. A 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 substance was purified by silica gel chromatography (0% to 33% EtOAc/hexane) to give 4-2 (280 mg, yield: 83%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.47 (s, 1H), 7.15 (d, J = 8.8Hz, 1H), 7.08 (d, J = 8.8Hz, 1H), 6.18 (s, 1H), 3.64 (s, 3H), 2.71 (t, J = 7.6Hz , 2H), 2.52-2.50 (m, 1H), 2.16-2.14 (m, 2H), 1.72-1.70 (m, 2H), 1.49-1.47 (m, 6H), 1.13 (d, J=6.8Hz, 6H).

4.3 Synthesis of intermediate 4-3

_Me₂AlCl (1.0 M in hexane, 0.9 mL, 0.87 mmol) was added to a stirred solution of 4-2 (200 mg, 0.44 mmol) in dichloromethane (3 mL) at 0 °C, and the mixture was stirred for 30 min. Then, a solution of 1-12 (117 mg, 0.66 mmol) in dichloromethane (1 mL) was added dropwise at 0 °C, and the reaction mixture was heated to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _{anhydrous Na₂SO₄} . The solvent was evaporated under reduced pressure to give 4-3 (280 mg, crude substance) as a colorless oil, which was used directly in the next step.

4.4 Synthesis of Compound I-68

Lithium hydroxide monohydrate (257 mg, 6.1 mmol) was added to a stirred solution of 4-3 (280 mg, 0.61 mmol) in MeOH/THF/ _H₂O (2 mL/2 mL/0.2 mL). The reaction mixture was stirred overnight at room temperature until complete (according to LCMS). A saturated _NH₄Cl solution was added at 0 °C, and the mixture was acidified to pH ~3.0 with HCl (1.0 M), followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and evaporated under reduced pressure. The crude substance was purified by preparative HPLC to give I-68 (112 mg, yield: 41%) as a white semi-solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.88 (s, 1H), 7.23-7.22 (m, 1H), 7.20 (dd, J=8.8, 1.6Hz, 1H), 3.70 (s, 3H), 3.18-3.14 (m, 2H), 3.00-2.96 (m, 2H), 2.73-2.71 (m, 1H), 2.53-2.51(m, 2H), 2.35(dd, J=15.6, 7.2Hz, 1H), 2.14-2.13(m, 2H), 1.60-1.58(m, 2H), 1.48-1.46(m, 6H), 1.14-1.11(m, 9H). LC-MSm/z: 444.0[M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 5 and 5a below.

Table 5: Characterization data of additional exemplary compounds

Table 5a: Additional characterization data for additional exemplary compounds

Example 5: Synthesis of compound I-139

Synthetic scheme of compound I-139

5.1 Synthesis of Intermediate 5-1

To a stirred solution of 5-chloro-3-iodopyridin-2-amine (15.0 g, 58.8 mmol) in THF (70 mL), but-3-yn-1-ol (4.5 g, 64.8 mmol), Pd( _{PPh3 )2Cl2 (} 750 mg), CuI (1.5 g), and TEA (18.0 g, 176.7 mmol) were added. The reaction mixture was stirred at 60 °C under nitrogen for 16 h. The mixture was filtered through a diatomaceous earth mat, followed by the addition of _H2O (250 mL) and EA (250 mL), and the organic phase was collected and evaporated under reduced pressure to give a yellow oily 5-1 (16.8 g, crude substance).

5.2 Synthesis of Intermediate 5-2

t-BuOK (11.3 g, 100.9 mmol) was added to a stirred solution of 5-1 (14.0 g, 72.1 mmol) in DMF (100 mL). The reaction mixture was stirred at 80 °C under nitrogen for 0.5 h. The mixture was filtered through a diatomaceous earth mat and purified by preparative HPLC (MeCN/water: 5% to 95%) to give 5-2 (7.3 g, yield: 52%) as a yellow solid.

5.3 Synthesis of intermediate 5-3

MeI (5.8 g, 40.9 mmol) and _Cs₂CO₃ (13.3 g, 40.9 mmol) were added to a stirred solution of 5-2 (7.3 _g , 37.2 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 4 h until the reaction was complete (according to LCMS), followed by the addition of _H₂O (100 mL) and EA (100 mL), and the organic phase was collected and evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (EA/PE: 0:1 to 1:0) to give 5-3 (3.0 g, yield: 38%) as a yellow solid.

5.4 Synthesis of intermediate 5-4

NaH (60% dispersion in mineral oil, 1.2 g, 29.7 mmol) was added to a stirred solution of 5-3 (2.5 g, 11.9 mmol) and 2-bromoacetic acid (3.3 g, 23.7 mmol) in DMF (25 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of _H₂O (75 mL) and EA (75 mL). The organic phase was washed with brine and evaporated under reduced pressure to give 5-4 (1.5 g, yield: 47%) as a yellow oil.

Synthesis of intermediate 5-5

_LiAlH₄ (848 mg, 22.3 mmol) was added to a stirred solution of 5-4 (1.5 g, 5.6 mmol) in THF (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h until the reaction was complete (according to LCMS), followed by the dropwise addition of _H₂O (1 mL) and NaOH (15% aqueous solution, 1 mL) at 0 °C to quench the reactants. The mixture was filtered, and the filtrate was dried over anhydrous _{Na₂SO₄ and} evaporated under reduced pressure to give a crude product 5-5 (1.1 g, yield: 77%) as a yellow oil, which was used directly in the next step.

5.6 Synthesis of intermediates 5-6

DEAD (1.5 g, 8.6 mmol), PPh ₃ (2.3 g, 8.6 mmol), and 5-5 (1.1 g, 4.3 mmol) were added to a stirred solution of 2,2,2-trifluoro-N-(pyridin-3-yl)acetamide (1.6 g, 8.6 mmol) in THF (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 64 hours until the reaction was complete (according to LCMS). The reactants were quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _{anhydrous Na₂SO₄} . The solvent was evaporated under reduced pressure, followed by purification by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to give 5-6 as a yellow oil (290 mg, yield: 16%).

5.7 Synthesis of intermediates 5-7

_AlCl₃ (312 mg, 2.3 mmol) was added to a stirred solution of 5-6 (200 mg, 0.47 mmol) in dichloromethane (5 mL) at 0 °C. After 10 min, 1.0 mL of dichloromethane containing 300 mg, 2.3 mmol of 4-methyldihydro-2H-pyran-2,6(3H)-dione was added dropwise, and the reaction mixture was stirred at room temperature for another 1 _h . The reaction mixture was quenched by adding water (1 mL) and extracted with EtOAc (15 mL × 3). The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure and purified by preparative HPLC to give 5-7 (45 mg, yield: 17%) as a yellow oil.

5.8 Synthesis of Compound I-139

Add NaOH (0.2 mL 1 M aqueous solution, 0.2 mmol) to a stirred solution of 5-7 (40 mg crude substance, 0.072 mmol) in MeOH (2 mL). Stir the reaction mixture at 0 °C for 3 h until the reaction is complete (according to LCMS). Add saturated _NH₄Cl solution at 0 °C and acidify the mixture to pH ~4.0 with HCl (1.0 M), then extract with EtOAc. Wash the combined organic layers with brine, dry over anhydrous _Na₂SO₄ and evaporate _under reduced pressure. Purify the crude substance by preparative HPLC to give I-139 (6 mg, yield: 18%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ8.35 (d, J=2.0Hz, 1H), 8.28 (d, J=2.0Hz, 1H), 7.89 (t, J=1.6Hz, 1H), 7.73 (d, J=5.6Hz, 1H), 7.28-7.25 (m, 1H), 7.22-7.18 (m, 1H), 4.50-4.47 (m, 2H), 3.89-3.8 4(m, 4H), 3.77(s, 3H), 3.53-3.45(m, 2H), 3.08(dd, J=15.6, 5.2Hz, 1H), 2.78(dd, J=15.6, 8.4Hz, 1H), 2.62-2.52 (m, 1H), 2.24-2.20 (m, 2H), 1.05 (d, J=6.4Hz, 3H).

LC-MS m/z: 458.9 [M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Table 6 below.

Table 6: Characterization data of additional exemplary compounds

Example 6: Synthesis of compound I-147

Synthetic scheme of compound I-147

6.1 Synthesis of Intermediate 6-1

TEA (565 mg, 5.6 mmol) was added to a solution of 1-18 (200 mg, 0.56 mmol) in DCM (10 mL) at 0 °C, followed by dropwise addition of TFAA (1.17 g, 5.6 mmol). The reaction mixture was heated to room temperature and stirred for 16 h. A saturated _NaHCO3 solution was added at 0 °C, and the mixture was extracted with DCM (10 mL × 2). The combined organic layers were washed with brine, dried over anhydrous _{Na2SO4 ,} and evaporated under reduced pressure to give a yellow oily crude substance 6-1 (230 mg, 91%), which was used directly in the next reaction.

6.2 Synthesis of intermediate 6-2

NaOH (5.0 M, 1 mL, 5 mmol) was added to a solution of 6-1 (230 mg, 0.5 mmol) in dioxane (9 mL) and EtOH (1 mL) at 0 °C. The reaction mixture was then heated to room temperature and stirred at 95 °C for 2 h. The mixture was acidified to pH ~3.0 with HCl (3.0 M), followed by extraction with EtOAc (20 mL × ₃ ). The combined organic layers were washed with brine, dried over anhydrous _Na₂SO₄ , and evaporated under reduced pressure. The crude substance was purified by silica gel chromatography (14% MeOH/DCM) to give 6-2 (200 mg, 98%) as a yellow solid.

6.3 Synthesis of intermediate 6-3

HATU (209 mg, 0.5 mmol) and DIEA (194 mg, 1.5 mmol) were added to a solution of 6-2 (200 mg, 0.5 mmol) in DMF (5 mL) at 0 °C. The mixture was stirred for 15 min, followed by the addition of (S)-methylpyrrolidine-3-carboxylate (83 mg, 0.5 mmol). The reaction mixture was heated to room temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (10 mL × 3). The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure _, and the crude substance was purified by silica gel chromatography (18% MeoH/DCM) to give 6-3 (98 mg, 38%) as a white solid.

6.4 Synthesis of Compound I-147

NaOH (2.0 M, 0.95 mL, 1.9 mmol) was added to a mixture of 6-3 (98 mg, 0.19 mmol) and MeOH (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH ~3.0 with HCl (1.0 M) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, _dried over anhydrous _Na₂SO₄ and evaporated under reduced pressure. The crude material was purified by preparative HPLC to give I-147 (30 mg, 32%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₊ )δ12.47 (s, 1H), 8.25 (d, J = 2.4Hz, 1H), 7.92 (s, 1H), 7.30-7.20 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 3.77 (s, 3H), 3.59-3.42 (m , 4H), 3.07 (s, 1H), 2.90 (t, J=7.2Hz, 2H), 2.56 (t, J=7.6Hz, 2H), 2.10-2.04 (m, 2H), 1.61-1.51 (m, 4H), 1.31-1.30 (m, 4H). LC-MS m/z: 502.3[M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 7 and 7a below.

Table 7: Characterization data of additional exemplary compounds

Table 7a: Additional characterization data for additional exemplary compounds

Example 7: Synthesis of Compound I-13

Synthetic scheme of compound I-13

7.1 Synthesis of Intermediate 7-1

A mixture of I-2 (250 mg, 0.51 mmol), ammonium acetate (60 mg, 0.77 mmol), HATU (195 mg, 0.51 mmol), and DIEA (199 mg, 1.54 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was quenched by adding water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _{anhydrous Na₂SO₄} . The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (20% EtOAc/Hex) to give 7-1 (160 mg, 64%) as a yellow solid.

7.2 Synthesis of Intermediate 7-2

Pyridine (53 mg, 0.66 mmol) was added dropwise to a solution of 7-1 (160 mg, 0.33 mmol) and trifluoroacetic anhydride (104 mg, 0.50 mmol) in DCM (10 mL). The mixture was then stirred at room temperature for 2 h until the reaction was complete (according to LCMS). The reactants were quenched with water and extracted with DCM. The organic layers were combined, washed with brine, and dried over _{anhydrous Na₂SO₄} . The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (40% EtOAc/Hex) to give 7-2 (110 mg, 71%).

7.3 Synthesis of Compound I-13

A mixture of 7-2 (110 mg, 0.24 mmol) and dimethylamine hydrochloride (192 mg, 2.35 mmol) in DMF was added, followed by the addition of sodium azide (153 mg, 2.35 mmol) under Ar protection. The reaction mixture was stirred at 120 °C for 3 days until the reaction was complete (according to LCMS). The reactants were quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _{anhydrous Na₂SO₄} . The solvent was evaporated under reduced pressure, and the crude material was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19*250 mm; flow rate: 20 mL/min; solvent system: MeCN/(0.2% formic acid/water) gradient; MeCN: 50%–95%; collection wavelength: 214 nm). The preparative HPLC fraction was concentrated under reduced pressure at 35 °C to remove MeCN, and the residue was lyophilized to give I-13 (90 mg, 75%) as a brown solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.94 (d, J=2.0Hz, 1H), 7.57 (d, J=8.4Hz, 1H), 7.20-7.30 (m, 5H), 7.15 (d, J=7.6Hz, 1H), 3.74 (s, 3H), 3.04-3.12 (m, 3H), 2.71-2.8 0 (m, 3H), 2.57 (t, J=7.6Hz, 2H), 2.51-2.52 (m, 1H), 1.50-1.59 (m, 4H), 1.39-1.44 (m, 2H), 1.31-1.36 (m, 2H), 0.90 (d, J=6.8Hz, 3H). LC-MS m/z: 511.9 [M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 8 and 8a below.

Table 8: Characterization data of additional exemplary compounds

Table 9a: Characterization data of additional exemplary compounds

Example 8: Synthesis of Compound I-14

Synthetic scheme of compound I-14

A mixture of I-2 (250 mg, 0.51 mmol), methanesulfonamide (96 mg, 0.61 mmol), EDCI (57 mg, 0.30 mmol), and DMAP (61 mg, 0.50 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _{anhydrous Na₂SO₄} . The solvent was evaporated under reduced pressure, and the crude substance was purified by preparative HPLC to give I-14 (27 mg, 10%) as a white solid. ^¹H NMR (400 MHz, DMSO- _d₆) was then performed. )δ7.95 (d, J=2.0Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.21-7.31 (m, 5H), 7.16 (d, J=7.6Hz, 1H) , 3.75 (s, 3H), 3.31 (s, 1H), 3.11-3.16 (m, 5H), 2.96 (dd, J=16.4Hz, 5.6Hz, 1H), 2.84 (dd, J=16.4Hz, 7.6Hz, 1H), 2.58 (t, J=7.6Hz, 2H), 2.33-2.40 (m, 1H), 2.20 (dd, J=14.8Hz, 7.6 Hz, 1H), 1.52-1.62 (m, 4H), 1.40-1.48 (m, 2H), 1.32-1.37 (m, 2H), 0.95 (d, J=6.8Hz, 3H). LC-MSm/z: 564.8[M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 10 and 10a below.

Table 10: Characterization data of additional exemplary compounds

Table 10a: Additional characterization data for additional exemplary compounds

Example 9: Synthesis of Compound I-23

Synthetic scheme of compound I-23

9.1 Synthesis of intermediate 9-2

n-BuLi (2.5 M in THF, 13 mL, 32.6 mmol) was added to a solution of 9-1 (5.0 g, 29.6 mmol) in 100 mL of THF at -78 °C. The mixture was stirred at -78 °C for 1 h and 20 mL of THF containing DMF (4.6 mL, 59.2 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 h. A saturated _NH4Cl solution was added at 0 °C, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na2SO4 ,} and evaporated under reduced pressure. The crude substance was purified by silica gel chromatography (PE/EA = 9/1) to obtain 9-2 (5.5 g, yield: 95%) as a pale yellow solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 10.11 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 8.8 Hz, 2.0 Hz, 1H).

9.2 Synthesis of intermediate 9-3

LiHMDS (1.0 M in THF, 23 mL, 23 mmol) was added to a suspension of 1-7 (12.0 g, 23.1 mmol) in THF (100 mL) at -78 °C. The mixture was stirred for 30 min and THF (20 mL) containing 9-2 (3.0 g, 15.4 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. A saturated _NH4Cl solution was added at 0 °C, and the mixture was acidified to pH ~3 with HCl (1.0 M), extracted with EtOAc, washed with brine, dried over _{anhydrous Na2SO4} and evaporated under reduced pressure. The crude substance was purified by silica gel chromatography (5%–10% EtOAc/PE) to give 9-3 (4.3 g, yield: 78%) as a pale yellow oil.

Synthesis of intermediate 9-4 (9.3)

10% Pd/C (500 mg) was added to a stirred solution of 9-3 (4.3 g, 12.1 mmol) in EtOAc (100 mL) under a _H2 atmosphere (1.0 atm). The reaction mixture was stirred at room temperature for 1 h until the reaction was complete (according to LCMS), followed by filtration. The residue was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE/EA = 100/1) to give 9-4 (3.9 g, yield: 88%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.62-7.66 (m, 2H), 7.14-7.22 (m, 4H), 7.03 (d, J=7.2Hz, 1H), 6.91 (s, 1H), 2.88 (t, J=7. 2Hz, 2H), 2.57 (t, J=7.6Hz, 2H), 1.71-1.75 (m, 2H), 1.59-1.63 (m, 2H), 1.26-1.43 (m, 4H).

Synthesis of intermediate 9-5 (9.4)

_AlCl₃ (373 mg, 2.8 mmol) was added to a stirred solution of 9-4 (500 mg, 1.4 mmol) in dichloromethane (10 mL) at 0 °C. After 45 _min , _CH₂Cl₂ (5 mL) containing 1-12 (167.0 mg, 0.9 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for another 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and _dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure, and the crude substance was purified by silica gel chromatography (15% EtOAc/Hex) to give 9-5 (300 mg, 63%) as a yellow oil. LC-MS m/z: 505.3 [M] ^⁺ .

9.5 Synthesis of Compound I-23

Lithium hydroxide (139 mg, 3.3 mmol) was added to a stirred solution of 9-5 (280 mg, 0.6 mmol) in MeOH/THF/ _H₂O (5 mL/2 mL/1 mL). The reaction mixture was stirred at room temperature for 2 h until the reaction was complete (according to LCMS). A saturated _NH₄Cl solution was added at 0 °C, and the mixture was acidified to pH ~3.0 with HCl (1.0 M), followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and evaporated under reduced pressure. The crude material was purified by preparative HPLC (column: Waters X-Bridge C18OBD 10 μm 19*250 mm; flow rate: 20 mL/min; solvent system: MeCN/(0.2% formic acid/water) gradient; MeCN: 50%–95%; collection wavelength: 214 nm). The preparative HPLC fraction was concentrated under reduced pressure at 35 °C to remove MeCN, and the residue was lyophilized to give I-23 (100 mg, yield: 37%) as a yellow oil. ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 12.14 (s, 1H), 7.99–8.01 (m, 2H), 7.42 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.21–7.30 (m, 3H), 7.14 (d, J = 7.2 Hz, 1H), 3.04–3.10 (m, 3H), 2.88 (dd, J = 16.8 Hz, 8.0 Hz, 1H), 2 .49-2.58(m, 4H), 2.36(dd, J＝15.6Hz, 4.0Hz, 1H), 2.19(dd, J＝15.6Hz, 8.0Hz, 1H) , 1.67-1.71 (m, 2H), 1.53-1.57 (m, 2H), 1.29-1.42 (m, 4H), 0.96 (d, J=6.8Hz, 3H). LC-MS m/z: 492.8[M+H] ⁺ .

Additional exemplary compound I-21 was prepared using a method substantially similar to that described above and in this document.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.39 (dd, J = 8.8, 2.4Hz 1H), 7.30-7.20 (m, 1H), 7.14 (d, J=7.2Hz, 3H), 3.13 (t, J=7.6Hz, 2H), 3.06 (dd , J=17.2, 6.0Hz, 1H), 2.90 (dd, J=17.2, 7.6Hz, 1H), 2.56 (t, J=7.6Hz, 2H), 2.4 8-2.46 (m, 1H), 2.38 (dd, J=15.6, 6.0Hz, 1H), 2.19 (dd, J=15.6, 8.0Hz, 1H), 1. 74-1.69 (m, 2H), 1.57-1.52 (m, 2H), 1.40-1.30 (m, 4H), 0.97 (d, J=6.4Hz, 3H). LC-MSm/z: 475.0[M+H] ⁺ .

Example 10: Synthesis of Compound I-162

Synthetic scheme of compound I-162

Synthesis of intermediate 10-2 (10.1)

1-(bromomethyl)-3-chlorobenzene (30.6 g, 149.9 mmol) and KOH (15.8 g, 281.9 mmol) were added to a solution of tetrahydro-2H-pyran-2-one (5.0 g, 50.0 mmol) in toluene (50 mL) at room temperature. The reaction mixture was stirred at 125 °C for 16 h. After stirring, the mixture was cooled to room temperature and quenched with ice water (200 mL). After standing for a few minutes, the organic layer was separated and the aqueous phase was washed with MTBE (30 mL × 3). The aqueous phase was then cooled to 0 °C and adjusted to pH 3–4 with HCl (3 M). The suspension was extracted with EtOAc (60 mL × ₄ ), dried over anhydrous _Na₂SO₄ , and concentrated under reduced pressure to give 10⁻² (10.7 g, yield: 83%) as a pale yellow oil.

10.2 Synthesis of intermediate 10-3

(COCl) _₂ (10.4 g, 82.6 mmol) and anhydrous DMF (0.1 mL) were added to a stirred solution of 10⁻² (10.0 g, 41.3 mmol) in anhydrous THF (110 mL) at 0 °C. The mixture was allowed to reach room temperature and stirred for another 2 h. It was then concentrated under reduced pressure, dissolved in anhydrous DCM, and added at 0 °C to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.95 g, 41.3 mmol) and pyridine (6.5 g, 82.6 mmol) in anhydrous DCM (110 mL). The reaction mixture was stirred at room temperature for 16 h. The solution was acidified with 0.5 M HCl, extracted with EtOAc (50 mL × 3), dried over _{Na₂SO₄ ,} and concentrated to a yellow oil. EtOH (120 mL) was added, and the solution was stirred at 78 °C for 16 h. After completion, it was cooled to room temperature, evaporated under reduced pressure, and purified by silica gel chromatography (PE/EA~10/1) to obtain 10-3 (9.7 g, yield: 75%) as a yellow oil.

Synthesis of intermediate 10-4 (10.3)

At room temperature, _NH₄OH (8 mL, 53.8 mmol, 28% aqueous solution) and 2-chloroacetaldehyde (1.2 mL, 6.7 mmol, 40% aqueous solution) were added to a stirred solution of 10⁻³ (2.1 g, 6.7 mmol) in EtOH (6 mL). The reaction mixture was heated to 70 °C and stirred for 20 h. After the reaction was complete (according to LCMS), the mixture was cooled to room temperature and adjusted to pH 4 with aqueous HCl _. The suspension was washed with water (100 mL), extracted with EtOAc (50 mL × 3), dried over anhydrous _Na₂SO₄ and evaporated under reduced pressure to give the crude product. The crude oil was purified by silica gel chromatography (PE/EA～4/1) to give 10⁻⁴ (1.05 g, 46%) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₊ )δ11.19 (s, 1H), 7.39-7.32 (m, 3H), 7.28-7.26 (m, 1H), 6.61 (t, J = 2.4Hz, 1H), 6.32 (t, J = 2.8Hz, 1H), 4.44 (s, 2H), 4.13 (q, J = 14.0, 6.8Hz, 2H), 3.43 (t, J=6.0Hz, 2H), 2.86 (t, J=7.2Hz, 2H), 1.67-1.59 (m, 2H), 1.57-1.50 (m, 2H), 1.23 (t, J=7.2Hz, 3H).

Synthesis of intermediate 10-5 (10.4)

_CH₃I (425 mg, 3.0 mmol) was added to a solution of 10⁻⁴ (200 mg, 0.6 mmol) and _Cs₂CO₃ (855 mg, 2.6 mmol) in DMF (4 mL) at 0 ° _C under a _N₂ atmosphere. The mixture was then heated to room temperature and stirred for 2 h. Water (40 mL) was added to the mixture and extracted with EtOAc (15 mL × 3). The organic layer was washed with brine (30 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum to give a yellow oily 10⁻⁵ (150 mg, yield: 70%).

Synthesis of intermediate 10-6 (10.5%)

At room temperature, KOH (120 mg, 2.15 mmol), NaOH (150 mg, 3.87 mmol), and H₂O (1 mL) were added to a solution of 10⁻⁵ (150 mg, 0.4 mmol) in dioxane (1 mL) and EtOH ( _0.3 mL). The mixture was stirred at 100 °C for 36 h. The pH was then adjusted to 3 with 3N HCl aqueous solution, and the mixture was extracted with EtOAc (15 mL × ₃ ). The combined organic layers were dried over anhydrous _Na₂SO₄ and concentrated under vacuum to give a crude, yellow, oily substance, 10⁻⁶ (230 mg, 111%).

Synthesis of intermediate 10-7 (10.6)

HATU (373 mg, 0.98 mmol) was added to a stirred solution of 10⁻⁶ (210 mg, 0.65 mmol) in anhydrous DMF (6 mL). The mixture was stirred at room temperature for 10 min, and a solution of (S)-methylpyrrolidine-3-carboxylate (119 mg, 0.72 mmol) and DIPEA (675 mg, 5.23 mmol) in anhydrous DMF (4 mL) was added. The reaction mixture was stirred at 35 °C for 6 h. After completion, ice water (150 mL) was added, and the suspension was extracted with EtOAc (15 mL × ₃ ), dried over _Na₂SO₄ and evaporated under reduced pressure to give 10⁻⁷ (330 mg, yield: 106%) as a crude yellow oil.

10.7 Synthesis of Compound I-162

MeOH (3.4 mL) and NaOH (270 mg in 1.7 mL _H₂O , 6.94 mmol) were added to a solution of 10⁻⁷ (300 mg, 0.69 mmol) in 6 mL THF at 0 °C. The mixture was stirred at room temperature for 2.5 h. Then, water (10 mL) was added, and the pH was adjusted to 3–4 with HCl (2N). The suspension was extracted with EtOAc (15 mL × ₃ ), dried over anhydrous _Na₂SO₄ , and the solvent was concentrated under reduced pressure. The crude substance was purified by preparative HPLC (ACN/ _H₂O ) to give I-162 (106.91 mg, yield: 34%) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.42 (br., 1H), 7.39-7.33 (m, 3H), 7.28-7.27 (m, 1H), 6.61 (d, J = 2.0Hz, 1H), 6.16 (d, J = 2.0Hz, 1H), 4.44 (s, 2H), 3.65- 3.63 (m, 2H), 3.51 (s, 3H), 3.43-3.41 (m, 4H), 3.05-2.99 (m, 1H), 2.78-2.75 (m, 2H), 2.09-1.94 (m, 2H), 1.58-1.46 (m, 4H). LC-MS m/z: 419.2[M+H] ⁺ .

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Table 11 below.

Table 11: Characterization data of additional exemplary compounds

Example 11: Synthesis of compounds I-105 and I-106

Synthetic schemes for compounds I-105 and I-106

11.1 Synthesis of Intermediate 11-2

To a stirred solution of 6-amino-5-iodonicotinonitrile (11-1, 30.0 g, 122.4 mmol) in THF (200 mL) and TEA (100 mL), hexane-5-yn-1-ol (13.2 g, 134.7 mmol), _{Pd(PPh3)2Cl2 ( 4.3} g, 6.1 mmol), and CuI (1.2 g, 6.1 mmol) were added. The reaction mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was filtered through a diatomaceous earth filter, followed by the addition of _H2O (500 mL) and EA (500 mL), and the organic phase was collected and evaporated under reduced pressure to give 11-2 (28.0 g, crude substance) as a yellow oil.

11.2 Synthesis of intermediate 11-3

t-BuOK (29.2 g, 260.2 mmol) was added to a stirred solution of 11-2 (28.0 g, 130.1 mmol) in DMF (200 mL). The reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 1 h, followed by the addition of _H₂O (800 mL) and EA (800 mL). The organic phase was washed with brine and evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM: 0:1 to 1:10) to give 11-3 (16 g, yield: 57%) as a yellow solid.

11.3 Synthesis of intermediate 11-4

MeI (12.6 g, 89.3 mmol) and _Cs₂CO₃ (48.5 g, 148.8 mmol) were added to a stirred solution of 11-3 (16 g, 74.4 mmol) in DMF (120 _mL ). The reaction mixture was stirred at room temperature for 16 h until the reaction was complete (according to LCMS), followed by the addition of _H₂O (500 mL) and EA (500 mL), and the organic phase was collected and evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (EA/PE: 0:1 to 1:0) to give 11-4 (9.5 g, yield: 56%) as a yellow solid.

Synthesis of intermediate 11-5 (11.4)

NaH (60% dispersion in mineral oil, 4.4 g, 109.2 mmol) was added to a stirred solution of 11-4 (12.5 g, 54.6 mmol) and (bromomethyl)benzene (10.3 g, 60.0 mmol) in DMF (100 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of _H₂O (400 mL) and EA (350 mL), and the organic phase was washed with brine and evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (EA/PE: 0:1 to 1:2) to give 11-5 (14.5 g, yield: 83%) as a yellow solid.

Synthesis of intermediate 11-6 (11.5)

_Me₂AlCl (1M in hexane, 87.7mL, 87.7mmol) was added to a stirred solution of 11⁻⁵ (14.0g, 43.8mmol) in dichloromethane (100mL) at 0°C. After 5 min, _CH₂Cl₂ ( _10mL ) containing S-2rac (11.7g, 65.7mmol) was added dropwise, and the reaction mixture was stirred at room temperature for another 3 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under _reduced pressure, and the crude substance was purified by silica gel chromatography (50% EtOAc/Hex) to give 11⁻⁶ (2.2g, 11%) as a yellow oil.

11.6 Synthesis of compounds I-105 and I-106

Lithium hydroxide (2.0 g, 47.6 mmol) was added to a mixture of 11-6 (2.2 g, 4.8 mmol) in THF/MeOH/ _H₂O (20 mL/4 mL/6 mL), and the reaction mixture was stirred at room temperature for 5 h until the reaction was complete (according to LCMS). The mixture was acidified to pH ~5.0 with HCl (1.0 M), followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and evaporated under reduced pressure to give I-104. The crude product was purified sequentially by preparative HPLC and SFC to give I-105 and I-106 (590 mg, 27%) as white solids.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Tables 12 and 12a below.

Table 12: Characterization data of additional exemplary compounds

Table 12a: Additional characterization data for additional exemplary compounds

Example 12: Synthesis of compounds I-456 and I-457

Synthetic schemes for compounds I-456 and I-457

12.1 Synthesis of Intermediate 12-2

NaOH (5.0 M, 30 mL) was added to a solution of 12-1 (2.1 g, 0.5 mmol) in dioxane (36 mL) and EtOH (4 mL) at 0 °C. The reaction mixture was then heated to 95 °C and maintained for 2 h. The mixture was acidified to pH ~3.0 with HCl (3.0 M), followed by extraction with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and evaporated under reduced pressure. The crude substance was purified by silica gel chromatography (MeOH/DCM: 13%) to give 12-2 (1.2 g, yield: 64%) as a yellow solid.

12.2 Synthesis of Intermediate 12-3

HATU (250 mg, 0.66 mmol) and TEA (181 mg, 1.8 mmol) were added to a solution of 12-2 (270 mg, 0.60 mmol) in DMF (3 mL) at 0 °C. The mixture was stirred for 15 min, followed by the addition of (S)-pyrrolidine-3-nitrile hydrochloride (87 mg, 0.66 mmol). The reaction mixture was heated to room temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (50 mL) and extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The solvent was evaporated under reduced pressure _, and the crude substance was purified by silica gel chromatography (EtOAc/PE: 50%) to give 12-3 (283 mg, yield: 86.5%) as a yellow oil.

Synthesis of intermediate 12-4 (12.3)

To a stirred solution of 12-3 (230 mg, 0.44 mmol) in EtOH (10 mL) _{, NH₂OH} ·HCl (62 mg, 0.89 mmol) and DIEA (57 mg, 0.44 mmol) were added. The reaction mixture was stirred at room temperature under nitrogen for 16 _h . The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with brine, and dried over _Na₂SO₄ . The mixture was evaporated under reduced pressure and then purified by silica gel chromatography (PE/EA: 70%) to give 12-4 as a yellow solid (151 mg, yield: 60%).

12.4 Synthesis of Compound I-457

CDI (60 mg, 0.37 mmol) was added to a mixture of DBU (53 mg, 0.34 mmol) and dioxane (3 mL), and 12-4 (140 mg, 0.25 mmol) was added to the reaction mixture. The reaction mixture was stirred at 105 °C under nitrogen for 16 h until the reaction was complete (according to LCMS). The reactants were quenched by adding water (30 mL) and extracted with EtOAc (30 mL × ₃ ). The organic layers were combined, washed with brine, dried over _Na₂SO₄ , and evaporated under reduced pressure. The mixture was evaporated under reduced pressure and then purified by silica gel column chromatography (PE/EA: 40%) to give I-457 (85 mg, 58%) as a yellow oil. ¹ H NMR (400MHz, DMSO-d6) δ12.32 (br., 1H), 8.32 (d, J = 2.4Hz, 1H), 8.06 (d, J = 2.4Hz, 1H), 3.77 (s, 3H), 3.60-3.33 (m, 5H) ), 2.96-2.82(m, 5H), 2.57-2.51(m, 1H), 2.48-2.42(m, 1H), 2.30-2.05(m, 4H), 1.63-1.51(m, 2H), 1.44-1.27(m, 6H). LC-MS m/z: 590.0&592.0[( ⁷⁹ Br& ⁸¹ Br)M+H] ⁺ . HPLC purity (214nm): >99.9%; _tR = 9.685min.

Synthesis of Compound I-456, 12.5

Zn(CN) _₂ (52 mg, 0.44 mmol), Xant-PHOS (41 mg, 0.07 mmol), and Pd(OAC) _₂ (44 mg, 0.19 mmol) were added to a mixture of I-457 (52 mg, 0.09 mmol) and DMA (2 mL). The reaction mixture was stirred at 150 °C for 1.2 h until the reaction was complete (according to LCMS). The reactants were quenched by adding water (30 mL) and extracted with EtOAc (30 mL × ₃ ). The organic layers were combined, washed with brine, dried over _Na₂SO₄ , and evaporated under reduced pressure. The crude material was purified by preparative HPLC to give I-456 (1.20 mg, 3%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.33 (s, 1H), 8.66 (d, J = 1.6Hz, 1H), 8.41 (d, J = 1.6Hz, 1H), 3.83 (s, 3H), 3.76-3.33 (m, 5H), 3.02-2.81 ( m, 5H), 2.56-2.51 (m, 2H), 2.28-2.17 (m, 1H), 2.15 (t, J=5.6Hz, 3H), 1.64-1.53 (m, 2H), 1.44-1.27 (m, 6H). LC-MS m/z: 537.2[M+H] ⁺ . HPLC purity (214nm): 98.65%; t _R =9.108min.

Example 13: Synthesis of Additional Compounds

The following compounds were prepared using a procedure based on the method described above.

Table of additional characterization data for additional exemplary compounds

Example 14: Neutrophil calcium flux assay

After separation, neutrophils were resuspended at a concentration of 5 × 10⁶ cells/ml in calcium- and magnesium-free PBS (PBS-/-). 2 μl of Indo-1 (1 mM) was added per ml of cells. After incubation at 37°C for 30 min, the cells were washed twice with PBS-/- and resuspended at 5 × 10⁶ cells/ml in assay buffer (1× HBSS and 1 M HEPES containing calcium and magnesium). 100 μL of neutrophils was dispensed into each well of a 96-well black optically clear plate. After incubation at 37°C for 5 min, 50 μL of assay buffer or 3× antagonist was added, and the plate was incubated for 5 min in a Tecan Spark plate reader (Tecan, Morrisville, NC). Baseline measurements were taken for 30 seconds (wavelength settings: excitation: 331 nm and emission: 410 nm). When the baseline stabilized, 50 μl of 200 nM (4X) 5-oxo-ETE or HBSS was added to the appropriate well. Fluorescence was measured every 5 seconds for 30 cycles. Results are expressed as net fluorescence (FLU minus background and injection peak). All data were analyzed using GraphPad Prism version 9 for Windows (GraphPad, San Diego, CA).

Results: Table 13 below provides results for exemplary compounds. The symbol “***” indicates an IC ₅₀ less than 100 nM. The symbol “**” indicates an IC ₅₀ in the range of 100 nM to 300 nM. The symbol “*” indicates an IC ₅₀ greater than 300 nM.

Table 13.

Example 15: BRET Measurement

Background – The following assays can be used to determine OXER1 activation in live HEK293 cells. GPCR signaling is tightly regulated by endocytosis, receptor targeting of endosomes, and their sorting to lysosomes or recycling back to the plasma membrane. Early endosome (EE) transport assay (Namkung et al., Monitoring G protein-coupled receptor and β-arrest intrafficking in live cells using enhanced bystander BRET, Nat Commun 2016, 7:12178) used Rluc8-labeled OXER1 and Renilla GFP (rGFP), which is attached to the FYVE domain of protein 16 containing the human endosome/zinc finger FYVE domain, which binds to phosphatidylinositol 3-phosphate in the EE. Agonist stimulation of OXER1-Rluc8 leads to receptor transport to the EE, and subsequently, an increase in donor concentration relative to the rGFP-FYVE receptor anchored in the same cellular compartment, resulting in increased BRET signaling.

The plasmid-human OXER1 VersaClone cDNA was obtained from R&D Systems. A fragment of the Rluc8 (A55T, C124A, S130A, K136R, A143M, M185V, M253L, and S287L variants of Renilla reniformis luciferase) gBlocks gene (Integrated DNA Technologies, IA) was inserted along with a linker within the C-terminal frame of OXER1. The FYVE domain (residues Q739 to K806) from human endothelial cells was attached in a frame to the C-terminus of humanized RenillaGFP (rGFP) to synthesize the gBlocks gene fragment.

Bioluminescent resonance energy transfer (BRET) measurement - HEK293 cells were transfected with OXER1-Rluc8 and rGFP-FYVE. The next day, transiently transfected cells were seeded in 96-well white clear-bottom microplates coated with poly-D-lysine and cultured for 24 hours. Cells were washed once with Tyrode's buffer (140 mmol/L NaCl, ₁ mmol/L CaCl2, 2.7 mmol/L KCl, 0.49 mmol/L _MgCl2 , _0.37 mmol/L _NaH2Pv4 , 5.6 mmol/L glucose, 12 mmol/L NaHCO3, and 25 mmol/L HEPES, pH 7.5) and then measured in Tyrode's buffer. The test compound was incubated with cells at 37°C for 15 min, followed by incubation at 37°C with 600 mmol/L of the OXER1 agonist 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE). Rluc8 substrate coelentrin 400A (Prolume, Lakeside, AZ) was added to a final concentration of 5 μmol/L, and BRET readings were collected using a Spark or Infinite M1000 microplate reader (Tecan, Morrisville, NC). ^BRET readings between Rluc8 and rGFP were collected by sequential integration of signals detected in the 370–450 nm (Rluc8) and 510–540 nm (rGFP) windows. The BRET signal was calculated as the ratio of light emitted by the receptor (rGFP) to light emitted by the donor (Rluc8). The net BRET value induced by ligand is calculated by subtracting the net BRET induced by the mediator from the net BRET induced by the ligand.

Results: Table 14 below provides results for exemplary compounds. The symbol “***” indicates an IC ₅₀ less than 100 nM. The symbol “**” indicates an IC ₅₀ in the range of 100 nM to 300 nM. The symbol “*” indicates an IC ₅₀ greater than 300 nM.

Table 14

While we have described several embodiments of the invention, it will be apparent that our embodiments can be modified to provide other embodiments utilizing the compounds and methods of the invention. Therefore, it should be understood that the scope of the invention is defined by the appended claims, and not by the specific embodiments shown by way of example.

Claims (78)

1. A compound of formula I: Or its N-oxide or pharmaceutically acceptable salt, 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 a phenyl ring. ^L1 is one of the following: (a) A _C1-5 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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 bond; Each R is independently hydrogen, or a group optionally substituted from the following: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The two R groups on the same nitrogen may optionally form a 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring with 0-3 independently selected heteroatoms other than nitrogen, oxygen and sulfur. Each -Cy- is independently a divalent ring that is optionally substituted, selected from 4-7 membered saturated or partially unsaturated heterocyclic alkenyl groups having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl alkenyl groups; 3-7 membered saturated or partially unsaturated carbocyclic alkenyl groups; or 5-6 membered heteroaryl alkenyl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; ^L2 is one of the following: (a) A _C1-7 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally substituted 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 bond; ^R1 is selected from (i) -C(O)OR, -C(O)N(R)S(O) _2R , -C(O)N(R)OR, -C(O) _NR2 , -CN, -OH and hydrogen; (ii) a 5-6 membered partially unsaturated oxoheterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n ^R5 ; and (iii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n ^R5 ; ^R2 is one of the following: (a) Phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by p R6; or (b) C _1-7 aliphatic groups, -C≡CR, -C(O)OR, or -C(O)R; each of which is replaced by p R ⁶ groups; or (c) Hydrogen; ^R3 is one of the following: (a) _C1-6 aliphatic groups optionally substituted with one or more -OH or -N(R) ₂ groups; (b)-CD ₃ ; (c) Hydrogen; or (d) Does not exist; Each ^R4 is independently hydrogen, deuterium, Rz, -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)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 The two ^R4 groups may optionally form =O together; or The two ^R4 groups, together with their intermediary atoms, can optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. Each ^R5 and ^R6 is independently hydrogen, deuterium, ^Rz , 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)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 The two ^R5 groups can optionally be combined to form =O; The two ^R6 groups can optionally be combined to form =O; The two ^R5 groups, together with their intermediary atoms, optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur; or The two ^R6 groups, together with their intermediary atoms, can optionally form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. Each R ^z is independently selected from optionally substituted groups, said groups being selected from _C1-6 aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3 or 4; The condition is that if ^L1 - ^{R1 is a hexyl group} and the ring A and its ^R3 and ^R4 substituents are hexyl groups, then ^L2 - ^R2 is not a n-hexyl group, and The condition is that if ^L1 - ^R1 is a hexyl group and the ring A and its ^R3 and ^R4 substituents are hexyl groups, then ^L2 - ^R2 is not a hexyl group. 2. The compound of claim 1, wherein the ring A substituted with ( ^R4 ) _m , ^R3 , -C(O) ^-L1 - ^R1 and ^-L2 - ^R2 is 3. The compound of claim 1 or 2, wherein the compound has any one of formula I-a-1, I-a-2, I-a-3 or I-a-4: Or its N-oxide or pharmaceutically acceptable salt. 4. The compound of claim 3, wherein the compound has any one of formula I-a-1 or I-a-2: Or its N-oxide or pharmaceutically acceptable salt. 5. The compound of claim 4, wherein the compound has formula I-a-2: Or its N-oxide or pharmaceutically acceptable salt. 6. The compound according to any one of claims 1-5, wherein ^L1 is a _C1-5 divalent straight-chain or branched saturated hydrocarbon chain. 7. The compound of claim 6, wherein ^L1 is 8. The compound of any one of claims 1-5, wherein ^L1 is a _C1-5 divalent straight-chain or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is substituted with -Cy-, wherein Cy is a divalent ring selected from 4-7 membered saturated heterocyclic alkenyl groups having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 9. The compound of claim 8, wherein ^L1 is 10. The compound according to any one of claims 1-5, wherein ^L1 is 11. The compound of claim 10, wherein ^L1 and R1 are ^... 12. The compound of claim 11, wherein ^L1 and R1 are ^... 13. The compound of claim 11, wherein ^L1 and R1 are ^... 14. The compound according to any one of claims 1-13, wherein ^L2 is a _C1-7 divalent straight-chain or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is substituted with -O-. 15. The compound according to any one of claims 1-13, wherein ^L2 is -( _CH2 ) _3-4 -O-( _CH2 ) _1-2- . 16. The compound according to any one of claims 1-13, wherein ^L2 is -( _CH2 ) _{3-4 -} O-(C(H)( _CH3 ))-. 17. The compound according to any one of claims 1-13, wherein ^L2 is a _C1-7 divalent straight-chain or branched unsaturated hydrocarbon chain. 18. The compound according to any one of claims 1-13, wherein ^L2 is a _C1 divalent straight-chain unsaturated hydrocarbon chain. 19. The compound according to any one of claims 1-13, wherein ^L2 is 20. The compound of claim 19, wherein ^L2 and R2 are ^... 21. The compound of claim 19, wherein ^L2 and R2 are ^... 22. The compound of claim 19, wherein ^L2 and R2 are ^... 23. The compound of claim 19, wherein ^L2 and R2 are ^... 24. The compound according to any one of claims 1-23, wherein ^R1 is 25. The compound of claim 24, wherein ^R1 is 26. The compound of claim 24, wherein ^R1 is 27. The compound according to any one of claims 1-26, wherein ^R2 is 28. The compound of claim 27, wherein ^R2 is 29. The compound of claim 27, wherein ^R2 is 30. The compound of claim 27, wherein ^R2 is 31. The compound according to any one of claims 1-26, wherein ^R2 is -C≡CR. 32. The compound according to any one of claims 1-26, wherein ^R2 is -C≡C- (a 3-7 member saturated monocyclic carbon ring substituted with one or two halogen groups). 33. The compound according to any one of claims 1-26, wherein ^R2 is -C≡C- (a cyclobutyl group substituted with one or two halogen groups). 34. The compound according to any one of claims 1-22, wherein ^R3 is hydrogen, _-CH3 , or is absent. 35. The compound of claim 34, wherein ^R3 is _-CH3 . 36. The compound according to any one of claims 1-35, wherein ^R4 is hydrogen, -Cl, _-CF3 , _-OCH3 , _-OCF3 , -CN, or 37. The compound of claim 36, wherein ^R4 is -Cl or -CN. 38. The compound of claim 37, wherein ^R4 is -CN. 39. The compound according to any one of claims 1-38, wherein m is 1. 40. The compound according to any one of claims 1-35, wherein m is 0. 41. The compound of claim 1, wherein the compound has any one of formula I-i-1, I-i-2, I-i-3, I-i-4, I-i-5 or I-i-6:                  Or its N-oxide or pharmaceutically acceptable salt. 42. The compound of claim 41, wherein the compound has any one of formula I-i-4, I-i-5 or I-i-6: Or its N-oxide or pharmaceutically acceptable salt. 43. The compound of claim 1, wherein the compound has any one of formula I-j-1, I-j-2, I-j-3, I-j-4, I-j-5 or I-j-6: Or its N-oxide or pharmaceutically acceptable salt. 44. The compound of claim 43, wherein the compound has any one of formula I-j-4, I-j-5 or I-j-6: Or its N-oxide or pharmaceutically acceptable salt. 45. The compound of claim 1, wherein 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: Or its N-oxide or pharmaceutically acceptable salt. 46. The compound of claim 45, wherein the compound has any one of formula I-j-10, I-j-11 or I-j-12: Or its N-oxide or pharmaceutically acceptable salt. 47. The compound of claim 1, wherein the compound has any one of formula I-k-1, I-k-2, I-k-3, I-k-4, I-k-5 or I-k-6: Or its N-oxide or pharmaceutically acceptable salt. 48. The compound of claim 47, wherein the compound has any one of formula I-k-4, I-k-5, or I-k-6: Or its N-oxide or pharmaceutically acceptable salt. 49. The compound of claim 1, wherein the compound has any one of formula I-q-1, I-q-2, I-q-3, I-q-4, I-q-5 or I-q-6: Or its N-oxide or pharmaceutically acceptable salt. 50. The compound of claim 49, wherein the compound has any one of formula I-q-4, I-q-5, or I-q-6: Or its N-oxide or pharmaceutically acceptable salt. 51. The compound of claim 1, wherein the compound has any one of formula I-q-7, I-q-8, I-q-9 or I-q-10: Or its pharmaceutically acceptable salt. 52. The compound of claim 1, wherein the compound has the formula I-q-11: Or its pharmaceutically acceptable salt. 53. The compound of claim 1, wherein the compound has any one of formula I-r-1, I-r-2, I-r-3, I-r-4, I-r-5 or I-r-6: Or its N-oxide or pharmaceutically acceptable salt. 54. The compound of claim 53, wherein the compound has any one of formula I-r-4, I-r-5, or I-r-6:              Or its N-oxide or pharmaceutically acceptable salt. 55. The compound of claim 1, wherein the compound has any one of formula I-r-7, I-r-8, and I-r-9: Or its pharmaceutically acceptable salt. 56. The compound of claim 1, wherein the compound has the formula I-r-10: Or its pharmaceutically acceptable salt. 57. The compound of claim 1, wherein the compound has any one of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5 or I-f-6: Or its N-oxide or pharmaceutically acceptable salt. 58. The compound of claim 57, wherein the compound has any one of formula I-f-4, I-f-5, or I-f-6: Or its N-oxide or pharmaceutically acceptable salt. 59. The compound of claim 1, wherein the compound has any one of formula I-g-1, I-g-2, I-g-3, I-g-4, I-g-5 or I-g-6: Or its N-oxide or pharmaceutically acceptable salt. 60. The compound of claim 59, wherein the compound has any one of formula I-g-4, I-g-5, or I-g-6: Or its N-oxide or pharmaceutically acceptable salt. 61. The compound of claim 1, wherein 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: Or its N-oxide or pharmaceutically acceptable salt. 62. The compound of claim 61, wherein the compound has any one of formula I-h-4, I-h-5 or I-h-6: Or its N-oxide or pharmaceutically acceptable salt. 63. The compound according to any one of claims 57-62, wherein ^R4 and ^R6, each when appearing, independently represent hydrogen, halogen, or _C1-6 aliphatic group. 64. The compound of claim 1, wherein the compound is selected from the compounds shown in Table 1 or their N-oxides or pharmaceutically acceptable salts. 65. A pharmaceutical composition comprising a compound as described in any one of claims 1-64, or its N-oxide or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, adjuvant, or mediator. 66. The compound of any one of claims 1-64 or the pharmaceutical composition of claim 62, used as a drug. 67. A method for antagonizing OXER1 in a biological sample, the method comprising contacting the sample with a compound as described in any one of claims 1-64, or its N-oxide or pharmaceutically acceptable salt, or a pharmaceutical composition as described in claim 65. 68. A method of treating a patient with an OXER1-mediated condition, disease, or disorder, the method comprising administering to the patient in need a compound as described in any one of claims 1-64 or its N-oxide or pharmaceutically acceptable salt, or a pharmaceutical composition as described in claim 65. 69. The method of claim 68, wherein the condition, disease, or ailment is a condition, disease, or ailment related to inflammation or cancer. 70. The method of claim 69, wherein the condition, disease, or disorder is an inflammation-driven disease, including skin, respiratory, and gastrointestinal diseases. 71. The method of claim 70, wherein the disease, ailment, or disorder is asthma, severe eosinophilic asthma, late-stage inflammatory asthma, chronic obstructive pulmonary disease (COPD), eosinophilic syndrome (HES), nasal polyps, allergic inflammation, allergic rhinitis, atopic dermatitis, chronic spontaneous urticaria, psoriasis, acne, idiopathic pulmonary fibrosis, eosinophilic gastritis, eosinophilic esophagitis (EoE), eosinophilic gastroenteritis, arthritis, atherosclerosis, or acute myocardial infarction. 72. The method of claim 71, wherein the disease, ailment, or disorder is asthma. 73. The method of claim 71 or 72, further comprising simultaneously administering a second agent to the subject, wherein the second agent is an analgesic, an anti-inflammatory agent, or an anti-allergic agent. 74. The method of claim 73, wherein the second agent is an NSAID, a bronchodilator, a glucocorticoid, a cysLT1 antagonist, or a leukotriene modifier. 75. The method of claim 73, wherein the compound and the second agent are administered simultaneously. 76. The method of claim 73, wherein the compound and the second agent are administered sequentially. 77. The method of claim 73, wherein the condition, disease, or ailment is cancer. 78. The method of claim 77, wherein the cancer is prostate cancer, triple-negative breast cancer, or ER-breast cancer.