Proton sensing GPCR modulators

Abstract

The present disclosure provides heterocyclic compounds and methods for their therapeutic use. Also provided are methods for preparing these compounds. Such compounds may have utility as therapeutic agents for treatment or prophylaxis of diseases or conditions mediated by proton-activated G protein-coupled receptors. The compounds may also be useful for manufacture of medicaments for treatment or prophylaxis of diseases or conditions mediated by proton-activated G protein-coupled receptors.

Description

PROTON SENSING GPCR MODULATORSRelated application data

[0001] The present application claims priority from Australian Patent Application No. 2024900224 entitled “Proton Sensing GPCR Modulators” filed on 1 February 2024, the entire contents of which is hereby incorporated by reference.Technical Field

[0002] The present disclosure relates to novel compounds useful as modulators of proton-activated G protein-coupled receptors. The present disclosure further relates to methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with proton-activated G protein- coupled receptors.Background

[0003] Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumour growth. Acidic pH is not merely a consequence of disease but contributes to recruitment and regulation of immune cells, modifies metabolism of parenchymal, immune and tumour cells, modulates fibrosis, vascular permeability, oxygen availability, and consumption, invasiveness of tumour cells, and impacts on cell survival. Thus, pH-sensing mechanisms are required in cells involved in these processes. These pH sensors play important roles in normal physiology and pathophysiology.

[0004] Among the pH-sensing mechanisms, the proton-activated G protein-coupled receptors (GPCRs), in particular GPR68 (OGR1), GPR4 (GPR4), and GPR65 (TDAG8), have emerged as important targets. These receptors are widely expressed, upregulated in inflammation and tumours, sense changes in extracellular pH in the range between pH 8 and 6, and are involved in modulating key pathological processes such as the genesis and progression of several inflammatory diseases (asthma, inflammatory bowel disease), tumour cell metabolism and invasiveness, and fibrosis(Silva et al., Am J Physiol Cell Physiol., l;323(2):C400, 2022; Silva and Wagner, Pflugers Arch., 474(5):487, 2022.).

[0005] There is a need for new therapies to ameliorate, treat and / or prevent diseases, disorders, or conditions associated with proton-activated GPCRs, such as inflammatory, proliferative or fibrotic disorders, or cancer.Summary

[0006] The present inventors have identified compounds effective for modulating, such as inhibiting, proton-activated G protein-coupled receptors, such as GPR68 (OGR1). The identified compounds are useful in the treatment, prevention and / or diagnosis of diseases, disorders, or conditions associated with proton-activated G protein-coupled receptors, such as inflammatory, fibrotic, or proliferative diseases, disorders or conditions, and / or cancer.

[0007] Accordingly, in one aspect of the present disclosure, there is provided a compound having the structure of Formula (I):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:Y is -O-, -CR92-, -S-, or -NR9-; each instance of X is independently C or N; each instance of Z is independently O, N, NH, or S; provided that at least one of Z is N;R1is -C(O)OR10, -C(O)R10, -C(O)NR9R10, -C(O)SR10, -S(O)R10, -S(O)2R10, - S(O)2NR9R10, -C(=NR10)R10, -C(=NR1O)NR9R10, -C(=NR10)OR10, -P(=O)(OR9)R10, - CF3, -CN, or halogen;each R9is independently selected from hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, C1-4haloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6carbocyclyl, optionally substituted C5-10aryl, optionally substituted 5-6 membered heteroaryl, and optionally substituted 5-6 membered heterocyclyl; each R10is independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C2-20alkoxyalkyl, C1-6haloalkyl, -C(O)R9, -OR9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, - S(O)2R9, and -S(O)2N(R9)2; wherein any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-10alkyl, halogen, -CN, -OR9, - SR9, -S(O)2R9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -NO2, =(O), =(S), =(N)R9, - C(O)R9, -C(O)OR9, -C(O)N(R9)2, or -C(O)SR9; each instance of R4and R5is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; p is an integer from 1 to 6; each instance of R2is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-10alkyl, optionally substituted C1-10heteroalkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C1-10alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, - CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)OR10, - C(O)SR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -C(S)R10, -C(S)N(R10)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and -B(OR10)2; wherein any two adjacent R2, when present, together with the atoms to which they are attached, may form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, - N(R10)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)N(R10)2, -C(O)SR10or - C(O)OR10; n is an integer from 0 to 4; each instance of R3is selected from halogen, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C5-6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -OR9, -SR9, -NR9R10, -C(O)R9, -C(O)OR9, -S(O)2R9, and -NO2; and m is an integer from 0 to 3.

[0008] In some embodiments, the compound as defined herein has the structure of Formula (II):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0009] In some embodiments, the compound as defined herein has the structure of Formula (Illa) or (Illb):(Illa) (Illb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0010] In some embodiments, Z is O or NH. In some embodiments, Z is O.

[0011] In some embodiments, the compound as defined herein has the structure of Formula (IVa) or (IVb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0012] In some embodiments, R4and R5are hydrogen.

[0013] In some embodiments, Y is -O-, -CH2-, -S-, or -NH-. In some embodiments, Y is -O- or -CH2-.

[0014] In some embodiments, R1is selected from -C(O)OR10, -C(O)R10, - C(O)NR9R10, -C(O)SR10,-C(=NR10)R10, -C(=NR1O)NR9R10, -C(=NR10)OR10, -CN, or halogen. In some embodiments, R1is -C(O)OR10, -C(O)NR9R10, -CN, halogen, or a 5 membered heteroaryl or a 5 membered heterocyclyl selected fromsome embodiments, R1is selected from -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, and halogen. In some embodiments, R1is -C(O)OH.

[0015] In some embodiments, the compound as defined herein has the structure of Formula (Va) or (Vb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0016] In some embodiments, Y is -O- or -CH2-. In some embodiments, Y is -O-.

[0017] In some embodiments, n is 0, 1 or 2.

[0018] In some embodiments, each R2, when present, is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-10alkyl, optionally substituted C1-10heteroalkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C1-10alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-6 carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, - C(O)OR10, -C(O)SR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -C(S)R10, -C(S)N(R1O)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and - B(OR10)2; wherein any two adjacent R2, when present, together with the atoms to which they are attached, may form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, -N(R10)2, -NO2, =(0), =(S), =(N)R10, -C(O)R10, -C(O)N(R10)2, -C(O)SR10or - C(O)OR10.

[0019] In some embodiments, each R2, when present, is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -NO2, -OR10, -SR10, -N(R10)2, - C(O)R10, -C(O)OR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, - N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and -B(OR10)2.

[0020] In some embodiments, each R2, when present, is independently selected from halogen, C1-6alkyl, C3-6carbocyclyl, and 3-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, halogen, -CN, -OR9, -SR9, -S(O)2R9, -NR9R10, -NO2, =(O), =(S), =(N)R9, =(N)R10, -C(O)R9, -C(O)NR9R10, -C(O)SR9or -C(O)OR9.

[0021] In some embodiments, each R2, when present, is independently selected from halogen, C1-6alkyl, and C1-6alkyl optionally substituted with one or more substituents selected from C1-6alkyl, optionally substituted C3-6carbocyclyl, halogen, -OR9, and - NR9R10.

[0022] In some embodiments, each R2, when present, is independently selected from halogen, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, cyclobutyl, and cyclopropyl.

[0023] In some embodiments, m is 0 or 1.

[0024] In some embodiments, R3, when present, is a halogen.

[0025] In some embodiments, each instance of X is C. In some embodiments, at least one X is N.

[0026] In some embodiments, the compound as defined herein is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0027] There is also provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0028] There is also provided a method of treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof, comprising administering to the subject an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein.

[0029] There is also provided a use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment and / or prevention of a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

[0030] There is also provided a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein, for use in the treatment and / or prevention of a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

[0031] In some embodiments, the proton-activated GPCR is a GPR68 (OGR1).

[0032] In some embodiments, the disease, disorder or condition is selected from the group consisting of: an inflammatory disease, disorder or condition; a fibrotic disease, disorder or condition; a proliferative disease, disorder or condition, or a cancer.

[0033] In some embodiments, the disease, disorder or condition is an inflammatory disease, disorder or condition. In some embodiments, the inflammatory disease, disorder or condition is selected from focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disorder (COPD), asthma, and cystic fibrosis.

[0034] In some embodiments, the inflammatory disease, disorder or condition is an autoimmune disease, disorder or condition. In some embodiments, the autoimmune disease, disorder or condition is selected from systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn’s disease, ulcerative colitis, graft versus host disease, multiple sclerosis, and rheumatoid arthritis.

[0035] In some embodiments, the disease, disorder or condition is a fibrotic disease, disorder or condition. In some embodiments, the fibrotic disease, disorder or condition is selected from renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, dermal fibrosis, pancreatic fibrosis, and liver fibrosis. In some embodiments, the fibrotic disease, disorder or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral artery disease, cerebrovascular disease, chronic kidney disease, diabetic nephropathy, systemicsclerosis (scleroderma), hypertrophic scars, keloids, idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosis cholangitis (PSC).

[0036] In some embodiments, the disease, disorder or condition is a proliferative disease, disorder or condition. In some embodiments, the proliferative disease, disorder or condition is selected from diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0037] In some embodiments, the disease, disorder or condition is a cancer. In some embodiments, the cancer is selected from a breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer and kidney cancer.

[0038] In some embodiments, the subject is a human.

[0039] There is also provided a method of inhibiting a proton-activated GPCR in a cell, comprising administering to the cell an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein.

[0040] There is also provided a use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the inhibition of a proton-activated GPCR in a cell.

[0041] There is also provided a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein, for use in the inhibition of a proton-activated GPCR in a cell.

[0042] In some embodiments, the proton-activated GPCR is a GPR68 (OGR1).

[0043] In some embodiments, the cell is a tumour cell.Detailed Description

[0044] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, cell culture, molecular biology and pharmacy).

[0045] All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise.

[0046] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0047] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Thus, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly indicates otherwise. For example, the term “an subject” means “one or more subjects” unless the context clearly indicates otherwise.

[0048] The term "about" as used herein refers to a range of + / -5% of the specified value.

[0049] Throughout this specification, various aspects and components of the disclosure can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.

[0050] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0051] The use of "or" or "and" means "and / or" unless stated otherwise.

[0052] The compounds of the present disclosure can exist as solvates. The term "solvate" refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0053] The compounds of the present disclosure can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound and which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0054] As used herein, “Cato Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1to C4alkyl” or “C1-4alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0055] The term “halogen” or “halo,” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0056] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as “C1-4alkyl” or similar designations. By way of example only, “C1-4alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0057] As used herein, “alkoxy” refers to the group alkyl as defined above which contains at least one O atom, where the at least one oxygen atom is at the position where the alkoxy group is attached to the remainder of the compound. By way of non- limiting example, suitable alkoxy groups include, e.g., methoxy (-O-CH3), ethoxy (-O- CH2-CH3), propoxy (-O-CH2-CH2-CH3(straight chain alkyl) or -O-CH-(CH3)2(branched chain alkyl)) and -O-CH2-CH2-O-CH3. The alkoxy may be substituted or unsubstituted. The alkoxy may be substituted or unsubstituted. In this regard, the term “haloalkoxy”, as used herein, refers to “alkoxy” substituted with one or more halo i.e. one or more of F, Cl, Br or I. An example of “haloalkoxy” is -OCF3.

[0058] As used herein, “alkylthio” refers to the formula -SR wherein R is an alkyl as is defined above, such as “C1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert- butylmercapto, and the like.

[0059] As used herein, “alkenyl” refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as “C2-4alkenyl” or similar designations. By way of example only, “C2-4alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl- ethen-1-yl, 2-methyl-propen-3-yl, buta- 1,3 -dienyl, buta- 1,2, -dienyl, and buta-l,2-dien- 4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.

[0060] As used herein, “alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” whereno numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be designated as “C2-4alkynyl” or similar designations. By way of example only, “C2-4alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

[0061] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as “C1-4heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0062] As used herein, “alkylene” means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as “C1-4alkylene” or similar designations. By way of example only, “C1-4alkylene” indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan- 1,1 -diyl, propylene, propan- 1,1 -diyl, propan-2, 2-diyl, 1-methyl-ethylene,butylene, butan- 1,1 -diyl, butan-2,2-diyl, 2-methyl-propan- 1,1 -diyl, 1 -methyl- propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1- ethyl-ethylene.

[0063] As used herein, “alkenylene” means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as “C2-4alkenylene” or similar designations. By way of example only, “C2-4alkenylene” indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen- 1,1 -diyl, propenylene, propen- 1,1 -diyl, prop- 2-en- 1,1 -diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-l,3-dienylene, buten- 1,1 -diyl, but-l,3-dien-l,l-diyl, but-2-en-l, 1-diyl, but-3-en-l, 1-diyl, 1-methyl- prop-2-en-l, 1-diyl, 2-methyl-prop-2-en- 1,1 -diyl, 1-ethyl-ethenylene, 1,2-dimethyl- ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2- methyl-propen- 1,1 -diyl, and 2,2-dimethyl-ethen-l,l-diyl.

[0064] The term “aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

[0065] As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may bedesignated as “C6-10aryl,” “C6or C10aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0066] As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, in which R is an aryl as is defined above, such as “C6-10aryloxy” or “C6-10arylthio” and the like, including but not limited to phenyloxy.

[0067] An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as “C7-14aralkyl” and the like, including but not limited to benzyl, 2-phenylethyl, 3 -phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4alkylene group).

[0068] As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0069] A heteroaryl group may, for example, be monocyclic or polycyclic (e.g. bicyclic). A polycyclic heteroaryl may for example contain fused rings. In a bicyclic heteroaryl group there may be one or more heteroatoms in each ring, or heteroatoms only in one of the rings. Examples of monocyclic heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, andpyrimidinyl. Examples of bicyclic heteroaryl groups include quinoxalinyl, quinazolinul, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.

[0070] A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2- thienylmethyl, 3 -thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4alkylene group).

[0071] As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro- connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as “C3-6carbocyclyl” or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro [4.4] nonany 1.

[0072] A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C4-10(carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0073] As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] As used herein, “cycloalkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0075] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms ), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3- dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2 / 7-1, 2-oxazinyl, trioxanyl, hexahydro- 1,3, 5-triazinyl, 1,3-dioxolyl, 1,3 -dioxolanyl, 1,3- dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro- 1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0076] A heterocyclyl group may, for example, be monocyclic or polycyclic (e.g. bicyclic). A polycyclic heterocyclyl may for example contain fused rings. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or heteroatoms only in one of the rings. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. In one example, the heterocyclyl group is of three to ten atoms (i.e. 3-10 membered heterocyclyl). Examples of monocyclic non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl. Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzoazepanyl.

[0077] A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0078] As used herein, “acyl” refers to -C(O)R, wherein R is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0079] An “O-carboxy” group refers to a “-OC(O)R” group in which R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0080] A “C-carboxy” group refers to a “-C(O)OR” group in which R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non- limiting example includes carboxyl (i.e., -C(O)OH).

[0081] A “cyano” group refers to a “-CN” group. A "cyanato" group refers to an "-OCN" group. An "isocyanato" group refers to a "-NCO" group. A "thiocyanato" group refers to a "-SCN" group. An " isothiocyanate" group refers to an "-NCS" group.

[0082] A “sulfinyl” group refers to an “-S(O)R” group in which R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0083] A “sulfonyl” group refers to an “-SO2R” group in which R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0084] An “S-sulfonamido” group refers to a “-SO2NRARB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0085] An “N-sulfonamido” group refers to a “-N(RA)SO2RB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0086] An “O-carbamyl” group refers to a “-OC(O)NRARB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0087] An “N-carbamyl” group refers to an “-N(RA)OC(O)RB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0088] An “O-thiocarbamyl” group refers to a “-OC(S)NRARB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0089] An “N-thiocarbamyl” group refers to an “-N(RA)OC(S)RB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0090] An “amino” group refers to a “-NRARB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH2).

[0091] An “aminoalkyl” group refers to an amino group connected via an alkylene group.

[0092] An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8alkoxyalkyl” and the like.

[0093] A "haloalkyl" refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.

[0094] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted,” it is meant that the group is substituted with one or more substituents independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C7carbocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), C3-C7-carbocyclyl- C1-C6-alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), aryl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl(C1- C6)alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), halo, cyano, hydroxy, C1-C6alkoxy, C1-C6alkoxy(C1-C6)alkyl(i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1- C6)alkoxy (e.g., -OCF3), C1-C6alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0095] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”

[0096] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where ring A is a heteroaryl ring containing the depicted nitrogen.

[0097] In another example, when adjacent R1groups are present in the following substructure:and R1is defined as selected from the group consisting of hydrogen and alkyl, or any two adjacent R1together with the atoms to which they are attached form a heterocyclyl, it is meant that R1can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where ring A is a heterocyclyl ring containing the depicted atoms carbon and nitrogen.

[0098] Similarly, when two “adjacent” R groups are said to form a ring “together with the atom to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R1and can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where A is an aryl ring or a carbocylyl containing the depicted double bond.

[0099] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers,including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0100] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

[0101] Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0102] The terms “modulate”, “modulator” and “modulation” of a proton-activated GPCR, as used herein, is intended to encompass antagonism, agonism, partial antagonism and / or partial agonism of an activity associated with a proton-activated GPCR. In various embodiments, “modulation” may inhibit or stimulate proton- activated GPCR activity. In certain embodiments, “modulation” refers to inhibition of proton-activated GPCR activity.

[0103] A “patient” or “subject” to be treated by the methods described herein may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease, disorder or condition. A subject regardless of whether a human or non-human animal may be referred to as an individual, subject, animal, host or recipient as well as patient.

[0104] The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.

[0105] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Oilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0106] A therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing" means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0107] "Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / ortherapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease, disorder or condition, but who is susceptible to, or otherwise at risk of, a particular disease, disorder or condition, whereby the treatment reduces the likelihood that the patient will develop the disease, disorder or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease, disorder or condition.

[0108] The term "at risk" as used herein, refers to a probability of developing a disease, disorder or condition described herein, that is higher than in the general population. Accordingly, treatment of an individual considered to be ""at risk" of a particular condition is designed to prevent a subject from the developing the disease, disorder or condition or at least to reduce the risk of developing the disease, disorder or condition to a level no higher than that found in general population as a whole.

[0109] As used herein, "an effective amount" is intended to mean an amount sufficient to prevent, reduce, or eliminate a disease, disorder or condition. In some embodiments an effective amount can range from nanomolar concentrations to micromolar concentrations, for example, from about 1 nM to about 1,000 μM. One skilled in the art will recognize that to achieve these concentrations in vivo there will be a particular dependence on the pharmacokinetics of the exact compound selected. Thus, in some embodiments, a dose may range from about 1 mg / kg to about 1,000 mg / kg, including all quantities in between, and from about 10 mg / kg to about 500 mg / kg in other embodiments, and from about 50 mg / kg to about 250 mg / kg in yet other embodiments.

[0110] The terms "co-administration" or the like, as used herein, are meant to encompass administration of a compound described herein and an additional therapeutic agents to a single patient, and are intended to include treatment regimens in which the compounds and agents are administered by the same or different route of administration or at the same or different time.

[0111] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and aplurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0112] Those skilled in the art will appreciate that the disclosure described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0113] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the disclosure, as described herein.

[0114] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.Compounds of the disclosure

[0115] This disclosure is directed, in part, to compounds that are modulators, such as inhibitors, of proton-activated GPCRs, for example GPR68 (OGR1), which allows the compounds to be useful in prophylaxis, amelioration, treatment and / or prevention of diseases, disorders, or conditions associated with proton-activated GPCRs, such as inflammatory, fibrotic, or proliferative diseases, disorders, or conditions, and / or cancer.

[0116] Accordingly, in one aspect, there is provided a compound of Formula (I):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:Y is -O-, -CR92-, -S-, or -NR9-; each instance of X is independently C or N; each instance of Z is independently O, N, NH, or S; provided that at least one of Z is N;R1is -C(O)OR10, -C(O)R10, -C(O)NR9R10, -C(O)SR10, -S(O)R10, -S(O)2R10, - S(O)2NR9R10, -C(=NR10)R10, -C(=NR1O)NR9R10, -C(=NR10)OR10, -P(=O)(OR9)R10, - CF3, -CN, or halogen; each R9is independently selected from hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, C1-4haloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6carbocyclyl, optionally substituted C5-10aryl, optionally substituted 5-6 membered heteroaryl, and optionally substituted 5-6 membered heterocyclyl; each R10is independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C2.2o alkoxyalkyl, C1-6haloalkyl, -C(O)R9, -OR9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, - S(O)2R9, and -S(O)2N(R9)2; wherein any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-10alkyl, halogen, -CN, -OR9, - SR9, -S(O)2R9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -NO2, =(O), =(S), =(N)R9, - C(O)R9, -C(O)OR9, -C(O)N(R9)2, or -C(O)SR9; each instance of R4and R5is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; p is an integer from 1 to 6; each instance of R2is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-io alkyl, optionally substituted C1-io heteroalkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C1-10alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, - CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)OR10, - C(O)SR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -C(S)R10, - C(S)N(R10)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and -B(OR10)2; wherein any two adjacent R2, when present, together with the atoms to which they are attached, may form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, - N(R10)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)N(R10)2, -C(O)SR10or - C(O)OR10; n is an integer from 0 to 4; each instance of R3is selected from halogen, hydroxy, optionally substituted C1- 6 alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C5-6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -OR9, -SR9, -NR9R10, -C(O)R9, -C(O)OR9, -S(O)2R9, and -NO2; and m is an integer from 0 to 3.

[0117] As defined generally above, Y is -O-, -CR92-, -S-, or -NR9-. In some embodiments, Y is -O-. In some embodiments, Y is -CR92- In certain embodiments, Y is -CH2-. In some embodiments, Y is -S-. In some embodiments, Y is or -NR9-. In certain embodiments, Y is or -NH-.

[0118] In some embodiments, Y is -O-, and the compound has the structure of Formula (la):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0119] As defined generally above, in the compound of Formula (I) or Formula (la) described herein, p is an integer from 1 to 6. In some embodiments, p is 6, 5, or 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1, and the compound has the structure of Formula (II) or (Ila):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0120] As defined generally above, in the compound of Formula (I), (la), (II), or (Ila) described herein, each instance of X is independently C or N. It is to be understood that in a compound structure such as those described herein a hydrogen atom may be explicitly disclosed or understood to be present in the compound. For example, reference herein to C encompasses aromatic CH and aromatic C positions. It is also tobe understood that each aromatic CH position independently may serve as a point of attachment of R2or R3as indicated in Formula (I), (la), (II), or (Ila) described herein.

[0121] In some embodiments, all X are C.

[0122] In some embodiments, at least one X is N. In some embodiments, at least twoX is N. In some embodiments, at least three or four X is N.

[0123] In some embodiments, at least onesome. In some embodiments,some embodiments,

[0125] In some embodiments, all

[0126] In some embodiments, at least one

[0127] In some embodiments, twoare N. In some embodiments,selected from

[0128] In some embodiments, at least twoembodiments, threeare N. In some embodiments, four X inN.

[0129] As defined generally above, in the compound of Formula (I), (la), (II), or (Ila) described herein, each instance of Z is independently O, N, NH, or S, provided that at least one of Z is N. That is, in the compound of Formula (I), (la), (II), or (Ila) described

[0130] Accordingly, in certain embodiments, the compound described herein has the structure of Formula (Illa) or (Illb) :or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0131] In some embodiments, Z is O. In some embodiments, Z is NH.

[0132] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa) or (Illb) described herein, Y is selected from -O-, -CR92-, -S-, or -NR9-. In some embodiments, Y is -O-, -CH2-, -S-, or -NH-. In some embodiments, Y is -O- or -CH2-.

[0133] In some embodiments, Y is -O-, and the compound has the structure of Formula (Illaa) or (Illbb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0134] In some embodiments, Z is O, and the compound has the structure of (IVa) or (IVb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0135] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), or (IVb) described herein, each instance of R4and R5is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl. In some embodiments, one of R4and R5is hydrogen, and the other of R4and R5is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl. In some embodiments, R4and R5are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, one of R4and R5is hydrogen, and the other of R4and R5is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, one of R4and R5is hydrogen, and the other of R4and R5is optionally substituted alkyl, such as optionally substituted C1-6alkyl. In some embodiments, R4and R5are independently selected from optionally substituted alkyl, such as optionally substituted C1-6alkyl. In some embodiments, R4and R5are hydrogen.

[0136] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)OR10, -C(O)R10, - C(O)NR9R10, -C(O)SR10, -S(O)R10, -S(O)2R10, -S(O)2NR9R10, -C(=NR10)R10, - C(=NR10)NR9R10, -C(=NR10)OR10, -P(=O)(OR9)R10, -CF3, -CN, or halogen.

[0137] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), or (IVb) described herein, each R9is independently selected from hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, C1-4haloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6carbocyclyl, optionally substituted C5-10aryl, optionally substituted 5-6 membered heteroaryl, and optionally substituted 5-6 membered heterocyclyl. In some embodiments, R9is selected from hydrogen or optionally substituted C1-6alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is optionally substituted C1-6alkyl. In some embodiments, R9is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R9is trifluoromethyl.

[0138] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), or (IVb) described herein, each R10is independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C2-20alkoxyalkyl, C1-6haloalkyl, -C(O)R9, -OR9, - N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -S(O)2R9, and -S(O)2N(R9)2; wherein any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-10alkyl, halogen, -CN, -OR9, -SR9, -S(O)2R9, -N(R9)2, NR9C(O)R9, - N(R9)S(O)2R9, -NO2, =(O), =(S), =(N)R9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, or - C(O)SR9.

[0139] In some embodiments, R10may be selected from hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is trifluoromethyl.

[0140] In some embodiments, R10may be selected from -C(O)R9, -OR9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -S(O)2R9, and -S(O)2N(R9)2. In some embodiments, R10is -C(O)R9. In some embodiments, R10is -C(O)Me. In some embodiments, R10is - OR9. In some embodiments, R10is -OH. In some embodiments, R10is -N(R9)2. In some embodiments, R10is -NHR9or -NH2.

[0141] In some embodiments, any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-10alkyl, halogen, -CN, -OR9, -SR9, -S(O)2R9,-N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -NO2, =(0), =(S), =(N)R9, -C(O)R9, - C(O)OR9, -C(O)N(R9)2, or -C(O)SR9. In some embodiments, any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen and oxygen, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-10alkyl, halogen, -CN, -OR9, =(O), =(S), =(N)R9, -C(O)R9, -C(O)OR9, -C(O)N(R9)2, or -C(O)SR9. For example, any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5 membered heteroaryl or a 5 memberedembodiments, any two adjacent R10, when present, together with the atoms to which they are attached, form a 5 membered heteroaryl or a 5 membered heterocyclyl selected

[0142] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)SR10, -S(O)R10, -S(O)2R10, -S(O)2NR9R10, -C(=NR10)R10, -C(=NR1O)NR9R10, -C(=NR10)OR10, or - P(=O)(OR9)R10.

[0143] In some such embodiments, R9is selected from hydrogen or optionally substituted C1-6alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is optionally substituted C1-6alkyl. In some embodiments, R9is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R9is trifluoromethyl.

[0144] In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is trifluoromethyl.

[0145] In further such embodiments, R10may be selected from -C(O)R9, -OR9, - N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -S(O)2R9, and -S(O)2N(R9)2. In some embodiments, R10is -C(O)R9. In some embodiments, R10is -C(O)Me. In some embodiments, R10is -OR9. In some embodiments, R10is -OH. In some embodiments, R10is -N(R9)2. In some embodiments, R10is -NHR9or -NH2.

[0146] In some embodiments, R1is -C(O)SR10.

[0147] In some embodiments, R1is -S(O)R10or -S(O)2R10. In some embodiments, R1is -S(O)2R10. In some embodiments, R1is -S(O)2OR9or -S(O)2N(R9)2. In some embodiments, R1is -S(O)2OH or -S(O)2NH2.

[0148] In some embodiments, R1is S(O)2NR9R10. In some embodiments, R1is S(O)2NR9C(O)R9. In some embodiments, R1is S(O)2NHC(O)R9.

[0149] In some embodiments, R1is -C(=NR10)R10, -C(=NR10)NR9R10, or - C(=NR10)OR10.

[0150] In some embodiments, R1is -P(=O)(OR9)R10. In some embodiments, R1is - P(=O)(OR9)H or -P(=O)(OR9)OR9. In some embodiments, R1is -P(=O)(OH)H or - P(=O)(OH)OR9. In some embodiments, R1is -P(=O)(OH)OH.

[0151] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)OR10, -C(O)R10, -C(O)NR9R10, -C(=NR10)R10, -C(=NR10)NR9R10, -C(=NR10)OR10, -CN, or halogen. In some embodiments, R1is -S(O)R10, -S(O)2R10, or -S(O)2NR9R10. In some embodiments, R1is -C(=NR10)R10, -C(=NR10)NR9R10, or -C(=NR10)OR10. In some embodiments, R1is a 5 membered heteroaryl or a 5 membered heterocyclyl selected fromsome embodiments, R1is a 5 membered heteroaryl or a 5 membered heterocyclyl selected from

[0152] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)OR10, -C(O)R10, -C(O)NR9R10, - CN, or halogen.

[0153] In some such embodiments, R9is selected from hydrogen or optionally substituted C1-6alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is optionally substituted C1-6alkyl. In some embodiments, R9is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R9is trifluoromethyl.

[0154] In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is trifluoromethyl.

[0155] In further such embodiments, R10may be selected from -C(O)R9, -OR9, - N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -S(O)2R9, and -S(O)2N(R9)2. In some embodiments, R10is -C(O)R9. In some embodiments, R10is -C(O)Me. In some embodiments, R10is -OR9. In some embodiments, R10is -OH. In some embodiments, R10is -N(R9)2. In some embodiments, R10is -NHR9or -NH2.

[0156] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)OR10. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl.

[0157] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)R10. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl. In some embodiments, R10is trifluoromethyl.

[0158] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)NR9R10. In some such embodiments, each R9and R10may independently be selected from hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl. In some embodiments, each R9and R10is independently selected from hydrogen or C1-6alkyl. In some embodiments, R9and R10is independently selected from hydrogen, methyl, ethyl, propyl, or isopropyl. In some embodiments, R9and R10is hydrogen. In some embodiments, R9and R10is methyl.

[0159] In further such embodiments, R10may be selected from H, -C(O)R9, -OR9, — S(O)2R9, and -S(O)2N(R9)2. In some embodiments, R10is H. In some embodiments, R10is -C(O)R9. In some embodiments, R10is -C(O)Me. In some embodiments, R10is -OR9. In some embodiments, R10is -OH. In some embodiments, R10is — S(O)2R9. In some embodiments, R10is -S(O)2N(R9)2.

[0160] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is selected from -CF3, -CN, or halogen. In some embodiments, R1is -CF3. In some embodiments, R1is CN. In some embodiments, R1is halogen. In some embodiments, R1is iodine, fluorine, bromine or chlorine. In certain embodiments, R1is iodine or fluorine.

[0161] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), or (IVb) described herein, R1is -C(O)OH, and the compound has the structure of Formula (Va) or (Vb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0162] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), (IVb), (Va), or (Vb) described herein, Y is selected from -O-, - CR92-, -S-, or -NR9-. In some embodiments, Y is -O-, -CH2-, -S-, or -NH-. In some embodiments, Y is -O- or -CH2-. In some embodiments, Y is -O-.

[0163] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), (IVb), (Va), or (Vb) described herein, n is an integer from 0 to 4. In some embodiments, n is 0. In some embodiments, n is at least 1. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0164] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), (IVb), (Va), or (Vb) described herein, each instance of R2is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-10alkyl, optionally substituted C1-10heteroalkyl, optionally substituted C2-10alkenyl,optionally substituted C2-10alkynyl, optionally substituted C1-10alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, -CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)OR10, -C(O)SR10, -C(O)N(R10)2, -S(O)R10, - S(O)2R10, -S(O)2N(R10)2, -C(S)R10, -C(S)N(R1O)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and -B(OR10)2; wherein any two adjacent R2, when present, together with the atoms to which they are attached, may form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, -N(R1O)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, - C(O)N(R10)2, -C(O)SR10or -C(O)OR10.

[0165] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, each R2, when present, is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-10alkyl, optionally substituted C1-10heteroalkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C1-10alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)OR10, -C(O)SR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, - S(O)2N(R10)2, -C(S)R10, -C(S)N(R1O)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, - N(R10)S(O)2N(R10)2, and -B(OR10)2.

[0166] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, any two adjacent R2, when present, together with the atoms to which they are attached, form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionallysubstituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, -N(R1O)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, - C(O)N(R10)2, -C(O)SR10or -C(O)OR10.

[0167] In some embodiments, any two adjacent R2, when present, together with the atoms to which they are attached, form an optionally substituted fused 5-6 membered heteroaryl. In some embodiments, the optionally substituted fused 5-6 membered heteroaryl is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, or pyrimidinyl, each of which may be optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, - S(O)2R10, -N(R1O)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)N(R10)2, -C(O)SR10or -C(O)OR10. In some such embodiments, the one or more optional substituent may be selected from the group consisting of optionally substituted C1-6alkyl, halogen, -CN, - NO2, -OR10, =(O), =(S), and =(N)R10, wherein R10may be H or optionally substituted C1-6alkyl. In some embodiments, the one or more substituent is optionally substituted C1-6alkyl, =(O), or -OR10. In some embodiments, the one or more substituent is methyl, ethyl, propyl, isopropyl, =(O), or OCH3.

[0168] In some embodiments, any two adjacent R2, when present, together with the atoms to which they are attached, form an optionally substituted fused 5-6 membered heterocyclyl. In some embodiments, the optionally substituted fused 5-6 membered heterocyclyl is pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which may be optionally substituted with one or more substituents selected from optionallysubstituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, -N(R10)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)N(R10)2, -C(O)SR10or -C(O)OR10. In some such embodiments, the one or more optional substituent may be selected from the group consisting of optionally substituted C1-6alkyl, halogen, -CN, -NO2, -OR10, =(O), =(S), and =(N)R10, wherein R10may be H or optionally substituted C1-6alkyl. In some embodiments, the one or more substituent is optionally substituted C1-6alkyl, =(O), or - OR10. In some embodiments, the one or more substituent is methyl, ethyl, propyl, isopropyl, =(O), or OCH3.

[0169] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, each R2, when present, is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, optionally substituted 5-6 membered heteroaryl, -CN, - NO2, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)OR10, -C(O)N(R10)2, -S(O)R10, - S(O)2R10, -S(O)2N(R10)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, or -B(OR10)2. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl.

[0170] In some embodiments, each R2, when present, is independently deuterium, halogen, or hydroxy. In some embodiments, each R2, when present, is independently iodine, fluorine, bromine or chlorine. In certain embodiments, R2is iodine or fluorine.

[0171] In some embodiments, each R2, when present, is independently selected from optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, or optionally substituted C2-10alkoxyalkyl. In some such embodiments, the one or more optional substituent may be selected from the group consisting of optionally substituted C1-6alkyl, C3-6carbocyclyl, halogen, hydroxy, -CN, -NO2, -OR10, -N(R10)2, =(O), =(S), =(N)R10, - C(O)R10, or -C(O)OR10. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl.

[0172] In some embodiments, each R2, when present, is independently selected from optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R2is optionally substituted C3-6carbocyclyl. In certain embodiments, R2is optionally substituted cyclopropyl or optionally substituted cyclobutyl. In certain embodiments, R2is optionally substituted cyclopropyl. In some embodiments, R2is optionally substituted C6aryl. In some embodiments, R2is optionally substituted 3-6 membered heterocyclyl or optionally substituted 5-6 membered heteroaryl. In certain embodiments, R2is optionally substituted oxetanyl, azetidinyl, furanyl, isoxazolyl, pyrazolyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3- dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2 / 7-1,2-oxazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro- 1,4- thiazinyl, thiamorpholinyl, tetrahydroquinoline. In certain embodiments, R2is optionally substituted oxetanyl, azetidinyl, furanyl, isoxazolyl, or pyrazolyl.

[0173] In some embodiments, each R2, when present, is independently -CN, -NO2, - OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)OR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, - S(O)2N(R10)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, or -B(OR10)2. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl.

[0174] In certain embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, each R2, when present, is independently selected from halogen, C1-6alkyl, C3-6carbocyclyl, and 3-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C3-6carbocyclyl. halogen, -CN, -OR9, -SR9, -S(O)2R9, -NR9R10, -NO2, =(O), =(S), =(N)R9, =(N)R10, - C(O)R9, -C(O)NR9R10, -C(O)SR9or -C(O)OR9. In some such embodiments, each R9and R10may be selected from hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, each R9and R10is hydrogen. In some embodiments, each R9and R10is independently unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, each R9and R10is independently methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, each R9and R10is methyl. In some such embodiments, the optionally substituted C3-6carbocyclyl is optionally substituted cyclopropyl.

[0175] In some embodiments, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, each R2, when present, is independently selected from halogen, C1-6alkyl, or C1-6alkyl optionally substituted with one or more substituents selected from C1-6alkyl, optionally substituted C3-6carbocyclyl, halogen, -OR9, or -NR9R10. In some such embodiments, each R9and R10may be selected from hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, each R9and R10is hydrogen. In some embodiments, each R9and R10is independently unsubstituted C1-6alkyl or substitutedC1-6alkyl. In some embodiments, each R9and R10is independently methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, each R9and R10is methyl. In some such embodiments, the optionally substituted C3-6carbocyclyl is optionally substituted cyclopropyl.

[0176] In some embodiments, each R2is independently halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, wo-butyl, sec-butyl, tert-butyl, -CH2F, - CHF2, -CF3, cyclobutyl, or cyclopropyl. In some embodiments, each R2is independently halogen, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, cyclobutyl, or cyclopropyl. In some embodiments, each R2is independently iodine, fluorine, bromine or chlorine. In certain embodiments, R2is iodine or fluorine.

[0177] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, m is an integer from 0 to 3. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1. In some embodiments, m is 0.

[0178] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, each instance of R3is selected from halogen, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C5-6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -OR9, -SR9, -NR9R10, - C(O)R9, -C(O)OR9, -S(O)2R9, and -NO2.

[0179] In some embodiments, each R2, when present, is independently halogen or hydroxy. In some embodiments, R2is halogen. In some embodiments, each R2is independently iodine, fluorine, bromine or chlorine. In certain embodiments, R2is iodine or fluorine. In certain embodiments, R2is fluorine.

[0180] In some embodiments, each R2, when present, is independently selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, or optionally substituted C2-8alkoxyalkyl. In some such embodiments, the one or more optional substituent maybe selected from the group consisting of optionally substituted C1-6alkyl, C3-6carbocyclyl, halogen, hydroxy, -CN, -NO2, -OR10, -N(R10)2, =(O), =(S), =(N)R10, - C(O)R10, or -C(O)OR10. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl.

[0181] In some embodiments, each R2, when present, is independently selected from optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C5-6aryl, or optionally substituted 5-6 membered heteroaryl. In some such embodiments, the one or more optional substituent may be selected from the group consisting of optionally substituted C1-6alkyl, C3-6carbocyclyl, halogen, hydroxy, -CN, -NO2, -OR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, or - C(O)OR10. In some such embodiments, R10may be selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R10is hydrogen. In some embodiments, R10is unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, R10is methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R10is methyl.

[0182] In some embodiments, each R2, when present, is independently -CN, -OR9, - SR9, -NR9R10, -C(O)R9, -C(O)OR9, -S(O)2R9, or -NO2. In some such embodiments, each R9and R10may be selected from hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, each R9and R10is hydrogen. In some embodiments, each R9and R10is independently unsubstituted C1-6alkyl or substituted C1-6alkyl. In some embodiments, each R9and R10is independently methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, each R9and R10is methyl.

[0183] As defined generally above, in the compound of Formula (I), (la), (II), (Ila), (Illa), (Illb), (IVa), (IVb), (Va), or (Vb) described herein, each instance of X is independently C or N. It is to be understood that in a compound structure such as thosedescribed herein a hydrogen atom may be explicitly disclosed or understood to be present in the compound. For example, reference herein to C encompasses aromatic CH and aromatic C positions. It is also to be understood that each aromatic CH position independently may serve as a point of attachment of R2or R3as indicated in Formula (I), (la), (II), (Ila), (Illa), (IIIb), (IVa), (IVb), (Va), or (Vb) described herein.

[0184] In some embodiments, all X are C.

[0185] In some embodiments, at least one X is N. In some embodiments, at least two X is N. In some embodiments, at least three or four X is N.

[0186] In some embodiments, at least onesome,

[0189] In some embodiments, at least one

[0190] In some embodiments, twoembodiments,selected from

[0191] In some embodiments, at least twoembodiments, threeare N. In some embodiments, four X inN.

[0192] In some embodiments, the present disclosure provides a compound selected from the following structures:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.Preparation of the compounds

[0193] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.Pharmaceutical and compositions and administration

[0194] While it is possible for compounds of the present disclosure to be administered as a raw chemical, it is also possible to present them as a pharmaceutical formulation.

[0195] Accordingly, the present disclosure provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, prodrug or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes, for example.

[0196] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route depends upon for example the condition and disorder of the recipient. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art. All methods include the step of bringing into association a compound of the present disclosure or a pharmaceutically acceptable salt, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0197] Formulations of the present disclosure suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste.

[0198] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0199] The compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can bestored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

[0200] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0201] In addition to the formulations described above, the compounds of the present disclosure can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0202] The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. The compounds can also be formulated in vaginal compositions as gels, suppositories, or as dendrimers conjugates.

[0203] Compounds of the present disclosure can be administered topically, that is by non-systemic administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin such as gels, liniments, lotions, creams, ointments or pastes.

[0204] Gels for topical or transdermal administration of compounds of the present disclosure can include a mixture of volatile solvents, nonvolatile solvents, and water. The volatile solvent component of the buffered solvent system can preferably include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. More preferably, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound can crystallize due to evaporation of volatile solvent, while an excess will result in a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system can be selected from any buffer commonly used in the art; preferably, water is used. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.

[0205] Lotions or liniments for application to the skin can also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and / or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

[0206] Creams, ointments or pastes according to the present disclosure are semi-solid formulations of the active ingredient for external application. They can be made by mixing the active ingredient in finely -divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base can comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, com, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or amacrogel. The formulation can incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, can also be included.Methods of use

[0207] Without being bound by theory, the compounds of the present disclosure were found to modulate, optionally to inhibit, proton-activated GPCRs such as GPR68 (OGR1).

[0208] Accordingly, in one aspect, the present disclosure provides a method of treating and / or preventing a disease, disorder or condition mediated by a proton- activated GPCR in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as disclosed herein, to the subject. The methods may include identifying a subject at risk for or having a disease, disorder or condition mediated by a proton-activated GPCR, and administering a compound to the subject in an effective amount for therapeutic treatment or prophylactic treatment.

[0209] In some embodiments, the proton-activated GPCR is GPR68 (OGR1). In other embodiments, the proton-activated GPCR is selected from GPR68 (OGR1), GPR4 (GPR4), GPR65 (TDAG8), and GPR132 (G2A).

[0210] The proton-activated GPCRs, such as GPR68 (OGR1), GPR4 (GPR4) and GPR65 (TDAG8), are involved in modulating key processes in inflammation, tumour biology, and fibrosis.

[0211] Accordingly, in some embodiments, the disease, disorder or condition mediated by a proton-activated GPCR is an inflammatory, fibrotic, or proliferative disease, disorder or condition. In certain embodiments, the disease, disorder or condition is a cancer.

[0212] In some embodiments, the compounds and methods provided herein are useful in the treatment of an inflammatory disease, disorder or condition.

[0213] Generally, inflammatory diseases, disorders or conditions treatable with the compounds disclosed herein relate to any diseases, disorders or condition characterized by an abnormal, irregular, excessive, rogue or unwarranted inflammatory response.

[0214] In some embodiment, the inflammatory disease, disorder or condition is the result of an injury to a tissue. In some embodiments, the inflammatory disease, disorder or condition is the result of an autoimmune condition, while in further embodiment, the inflammatory disease, disorder or condition is the result of a bacterial or viral infection or the presence of a toxin.

[0215] The compounds provided herein can have anti-inflammatory activity and / or immunomodulatory activity and can be useful in the treatment of diseases including but not limited to septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T- cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and / or bronchitis. The compounds and methods provided herein may be useful in treating one or more of these diseases, disorders or conditions.

[0216] In some embodiments, the inflammatory disease or disorder or condition is at least one inflammatory disease or disorder or condition selected from the group consisting of inflammatory bowel disease, celiac disease, colitis, irritable bowel syndrome, intestinal hyperplasia, metabolic syndrome, obesity, diabetes, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0217] In some embodiments, the inflammatory disease, disorder or condition is arthritis, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, diabetic retinopathy, retinal inflammation, retinitis, Sjogren's syndrome, macular degeneration, gout, pseudogout, pericarditis, or uveitis.

[0218] In some embodiments, the inflammatory disease, disorder or condition is focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disorder (COPD), asthma, or cystic fibrosis.

[0219] In some embodiments, the inflammatory disease, disorder or condition is an autoimmune disease, disorder or condition. In some embodiments, the autoimmune disease, disorder or condition treatable by the compounds and methods provided herein is systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn’s disease, ulcerative colitis, graft versus host disease, multiple sclerosis, or rheumatoid arthritis.

[0220] In some embodiments, the compounds and methods provided herein are useful in the treatment of a fibrotic disease, disorder or condition.

[0221] A "fibrotic condition", "fibrotic disease", and "fibrotic disorder", are used interchangeably to refer to a condition, disease or disorder that is characterized by dysregulated proliferation or activity of fibroblasts and / or abnormal accumulation of fibronectin and / or pathologic or excessive accumulation of collagenous tissue. Fibrotic disorders include, but are not limited to, renal fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis (e.g., hepatic fibrosis associated with chronic active hepatitis), and pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology.

[0222] In some embodiments, the fibrotic disease, disorder or condition is renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, dermal fibrosis, pancreatic fibrosis, or liver fibrosis.

[0223] In some embodiments, the fibrotic diseases, disorders or conditions suitable for treatment by the methods provided herein include, but are not limited to, kidney disease, such as progressive glomerular kidney disease, glomerulonephritis, and diabetic nephropathy; lung disease, such as pulmonary fibrosis; fibrotic skin disorders, such as keloids, hypertrophic scars and scleroderma; heart disease, such as heart failure due to ischaemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; and liver disease, such as fibrosis of the liver.

[0224] In certain embodiments, the fibrotic disease, disorder or condition is kidney disease. In some embodiments, the kidney disease may include, but is not limited to, a progressive glomerular kidney disease including without limitation diabetic nephropathy (e.g., as a consequence of Type I or Type II diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis) or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephropathy). In some embodiments, the kidney disease may include progressive kidney diseases with origins primarily in the tubulointerstitium. In some embodiments, the kidney disease may include, e.g., chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0225] In some embodiments, the fibrotic diseases, disorders or conditions suitable for treatment by the methods provided herein include, but are not limited to, diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral artery disease, cerebrovascular disease, chronic kidney disease, diabetic nephropathy, systemic sclerosis (scleroderma), hypertrophic scars, keloids, idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosis cholangitis (PSC).

[0226] In some embodiments, the compounds and methods provided herein are useful in the treatment of a proliferative disease, disorder or condition.

[0227] Generally, proliferative diseases, disorders or conditions treatable with the compounds disclosed herein relate to any diseases, disorders or condition characterized by aberrant cell proliferation. Cell proliferation may be self-propagating and includes an inappropriate or excessive wound healing response. The cellular proliferation can increase the influx of inflammatory cytokines and inflammatory cells, and thus be associated with inflammation and / or degeneration.

[0228] Proliferative diseases, disorders or conditions treatable with the compounds disclosed herein include, but are not limited to, various retinopathies.

[0229] In some embodiments, the proliferative diseases, disorders or conditions suitable for treatment by the methods provided herein include, but are not limited to, diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0230] Proliferative diseases, disorders or conditions treatable with the compounds disclosed herein further include, but are not limited to, various tumours and cancers, benign or malignant, metastatic or non-metastatic.

[0231] Cancers treatable with the compounds disclosed herein include a variety of cancers, including, among others, breast cancer, skin cancer, ovarian cancer, renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.

[0232] In some embodiments, the cancer is a cancer that is characterized by the presence of one or more tumours in the subject. Examples of cancers suitable for treatment by the compounds and methods provided herein include, but are not limited to, metastatic melanoma, metastatic prostate cancer, metastatic breast cancer, triple negative breast cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, head and neck cancer, squamous cell lung cancer, non-small lung cell cancer, Merkel cell carcinoma, sarcoma, hepatocellular cancer, multiple myeloma, pancreatic cancer, colorectal carcinoma, cervical cancer, gastric carcinoma, kidney cancer, metastatic renal cell carcinoma, leukemia, ovarian cancer, and malignant glioma. In certainembodiments, the cancer is metastatic melanoma, metastatic prostate cancer , or metastatic breast cancer. In some embodiments, the subject has received an allogeneic tissue graft associated with treatment for cancer, e g, after hematopoietic stem cell transplantation used for treatment of a leukemia.

[0233] In some embodiments, the cancer suitable for treatment by the compounds and methods provided herein is a breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer, or kidney cancer.

[0234] In some embodiments, the subject is a human.

[0235] The term "therapeutically effective amount," as used herein, refers to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, the assays disclosed in the following examples. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0236] For any compound, the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0237] Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED50 / LD50. Pharmaceutical compositionsthat exhibit large therapeutic indices are preferred. However, pharmaceutical compositions that exhibit narrow therapeutic indices are also within the scope of the invention. The data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0238] The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0239] An effective amount of the compounds of the present disclosure for modulating, such as inhibiting, a proton-activated GPCR such as GPR68 (OGR1) includes an amount that can establish a concentration between about 1 nm and about 1,000 μM in one embodiment, between about 1 nM to about 250 μM in another embodiment, between about 1 nM to about 100 μM in another embodiment, between about 1 nM to about 50 μM in yet another embodiment. In some embodiments, an effective amount of the compounds of the present disclosure for modulating, such as inhibiting, a proton-activated GPCR such as GPR68 (OGR1) is an amount that can establish a concentration of about between about 1 μM to about 100 μM, about 1 μM to about 50 μM, or about 1 μM to about 20 μM. In some embodiments, an effective amount of the compounds of the present disclosure for modulating, such as inhibiting, a proton-activated GPCR such as GPR68 (OGR1) is an amount that can establish a concentration of about 100 μM, about 90 μM, about 80 μM, about 70 μM, about 60 μM, about 50 μM, about 40 μM, about 30 μM, about 20 μM, about 10 μM, or about 1 μM. In certain embodiments, an effective amount of the compounds of the presentdisclosure for modulating, such as inhibiting, a proton-activated GPCR such as GPR68 (0GR1) is an amount that can establish a concentration of about between about 1 μM to about 20 μM, about 1 μM to about 15 μM, about 1 μM to about 10 μM, or about 1 μM to about 5 μM. As will be clear to a skilled artisan, the exact amount of the compound can depend on a variety of factors including weight, age, sex. An effective amount of compounds of the present disclosure can include dosing regimens according to the pharmacokinetics / metabolism of the compounds and can also vary depending on the stage or severity of the disease, condition or disorder when the disease, condition or disorder is already established. Dosing and quantities are also influenced by mode of administration, such as oral versus intravenous administration.

[0240] In some embodiments, treating a disease, disorder or condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days. An increase in survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. In an another preferred aspect, an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0241] In some embodiments, treating a disease, disorder or condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone. In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In a further aspect, treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof. Preferably, the mortality rate isdecreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%. In a preferred aspect, a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. In another preferred aspect, a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In another preferred aspect, a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.

[0242] In certain embodiments, treating a disease, disorder or condition described herein results in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0243] In another aspect, treating a disease, disorder or condition described herein results in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. In a preferred aspect, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. In another preferred aspect, the proportion of proliferating cells is equivalent to the mitotic index.

[0244] In another aspect, treating a disease, disorder or condition described herein results in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, the size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.

[0245] The methods described herein may include identifying a subject in need of treatment. In a preferred embodiment, the methods include identifying a mammal in need of treatment. In a highly preferred embodiment, the methods include identifying a human in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing, or any other means known to one of skill in the art, including any combination of means for identification.

[0246] As described elsewhere herein, the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition. A preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the embodiments can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.

[0247] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament fortreating and / or preventing a disease, disorder or condition mediated by a proton- activated GPCR.

[0248] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein, with an additional medicament. By "co-administration," it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In some embodiments, the agents are administered simultaneously. In some such embodiments, administration in combination is accomplished by combining the agents in a single dosage form. In some embodiments, the agents are administered sequentially. In some embodiments the agents are administered through the same route, such as orally. In some other embodiments, the agents are administered through different routes, such as one being administered orally and another being administered by i.v. Thus, for example, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.

[0249] For example, the compounds and / or pharmaceutical compositions described herein may be co-administered with an additional medicament or therapy for treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR. In some embodiments, the compounds and / or pharmaceutical compositions described herein may be co-administered with a medicament or therapy for the treatment and / or prevention of an inflammatory, fibrotic, or proliferative disease, disorder or condition. In certain embodiments, the compounds and / or pharmaceuticalcompositions described herein may be co-administered with a medicament or therapy for the treatment and / or prevention of a cancer.

[0250] Further embodiments of the present disclosure provide a method of inhibiting a proton-activated GPCR in a cell, comprising administering to the cell an effective amount of compounds of the present disclosure. The cell may be in a cell culture. The cell may be present in or otherwise comprise a tissue. The tissue may be a human tissue.

[0251] In some embodiments, the proton-activated GPCR is a GPR68 (OGR1).

[0252] In some embodiments, the cell is a tumour cell. The tumour cell may be a tumour cell of the pancreas, a tumour cell of the head and neck, a tumour cell of the lung, a tumour cell of the kidney, a tumour cell of the breast, a tumour cell of the colon, a tumour cell of the ovary, a tumour cell of a lymph node, a tumour cell of the stomach, a tumour cell of the esophagus, a tumour cell of the skin, a tumour cell of the brain, a tumour cell of the oral cavity, a tumour cell of the pharynx, a tumour cell of the thyroid, a tumour of the adrenal gland, a leukemia cell, a sarcoma cell, a tumour cell of the testes, a tumour cell of the bladder, or a tumour cell of the prostate gland. The tumour cell may be in a cell culture. The cell may be present in or otherwise comprise a tumour tissue.

[0253] The present disclosure is further described by the following examples, which are not intended to limit the scope of the claims.Example 1. Experimental preparative and analytical conditionsAbbreviations

[0254] Chloroform-d (deuterated chloroform); DMSO-d6(deuterated dimethylsulfoxide); Methanol-d4 (deuterated methanol); DMF (N,N- dimethylformamide); DCM (dichloromethane); PE (petroleum ether); ESI (electrospray atmospheric pressure ionization); TEA (triethylamine); TFA (trifluoroacetic acid); dioxane (1,4-dioxane); THF (tetrahydrofuran); EtOH (ethanol); H2O (water); MeCN (Acetonitrile); EtOAc (ethyl acetate); g (gram); h (hour); nm (nanometer);NMR (proton nuclear magnetic resonance); Hz (hertz); LC-MS (liquid chromatography-massspectrometry); MS (mass spectrometry); mg (milligrams); MHz (megahertz); min (minutes); mL (millilitres), mmol (millimoles); ppm (parts per million); Rt(retention time); RT (room temperature); TLC (thin layer chromatography); v / v (volume / volume); m / z (mass charge ratio); HOAc (acetic acid); ( CH3)3SnOH (Trimethyltin hydroxide); PPSE (Trimethylsilyl polyphosphate); DCE (1,2-Dichloroethane); HATU (O-(7- Azabenzotriazol-1-yl)-N,N,N',N'-tetraMethyluroniuM hexafluorophosphate) ; (COC1)2(Oxalyl chloride); CS2CO3(Cesium carbonate); NH4CI (ammonium chloride); SOCI2(Thionyl chloride); DIPEA (N,N-diisopropylethylamine); MW (microwave); NH4CI (Ammonium chloride); DMAP (4 -Dimethylaminopyridine); LiOH (Lithium hydroxide); NaH (Sodium hydride); Aq (aqueous); HPLC: high performance liquid chromatography; M: molar, molecular ion; UV: ultraviolet; UPLC: ultra performance liquid chromatography.General experimental

[0255] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Reaction mixtures were magnetically stirred and reactions performed at room temperature (ca. 20 °C) unless otherwise indicated.

[0256] Column chromatography was performed on an automated flash chromatography system, such as a Biotage Isolera Rf system, using pre-packed silica (40 μm) cartridges, unless otherwise indicated.

[0257] 1H NMR spectra were recorded using a Bruker AVANCE 400 MHz spectrometer. Data for1H are reported as chemical shift (ppm) and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. The spectra were recorded at 298 K unless otherwise indicated.

[0258] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system, equipped with ACQUITY PDA Detector and ACQUITY QDa Mass Detector, running one of the analytical methods described below.

[0259] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below.Preparative HPLC Generic Methods:

[0260] HPLC Instruments: Shimadzu 20AP UV detector: SPD-20A. UV wavelength: 214 nm and 254 nm.

[0261] Conditions 1: Mobile phase A: water; Mobile phase B: acetonitrile.

[0262] Conditions 2: Mobile phase A: water with 0.1% trifluoroacetic acid; Mobile phase B: acetonitrile.

[0263] Conditions 3: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile.

[0264] Conditions 4: Mobile phase A: water with 0.1% ammonium hydroxide; Mobile phase B: acetonitrile.

[0265] Column: Agilent 10 Prep-C18 250 x 21.2 mm. Column temperature: Ambient

[0266] LC gradient: 20% to 85% in 20 min; then 85% to 100% in 0.01 min; then hold 100% for 5 min; then 100 % to 20% in 0.01 min; hold at 20% for 5 min.

[0267] LC Flow rate: 20 mL / min binary pump.

[0268] Nomenclature of structures was generated using ‘ Structure to Name’ conversion from ChemDraw® Professional 17 (PerkinElmer).Analytical Methods:Method 1 - Acidic method (Shimadzu 3 min)

[0269] Column: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6x50 mm column.

[0270] Detection: 2020, Quadrupole LC / MS, Ion Source: API-ESI, TIC: 100-900 m / z, Drying gas flow: 15 L / min, Nebulizer pressure: 1.5 L / min, Drying gas temperature: 250 °C, Vcap: 4500V. Samples were dissolved in methanol at 1-10μg / mL, then filtered through a 0.22 gm filter membrane. Injection volume: 1—10 pL. Detector: 214 nm, 254 nm. Detection wavelength: 214 nm, 254 nm.

[0271] Solvents: A: 0.05% v / v Formic acid in water, B: 0.05% v / v Formic acid in MeCN.

[0272] Gradient:Method 2 - Acidic 5 min method (Shimadzu 5 min)

[0273] Column: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6^50 mm column.

[0274] Detection: 2020, Quadrupole LC / MS, Ion Source: API-ESI, TIC: 100-900 m / z, Drying gas flow: 15 L / min, Nebulizer pressure: 1.5 L / min, Drying gas temperature: 250 °C, Vcap: 4500V. Samples were dissolved in methanol at 1-10 μg / mL, then filtered through a 0.22 μm filter membrane. Injection volume: 1—10 pL. Detection wavelength: 214 nm, 254 nm.

[0275] Solvents: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v).

[0276] Gradient:Method 3 - Acidic method (Waters QDa 3 min)

[0277] Column: Waters QDa, Binary Pump, Diode Array Detector. Waters CORTECS UPLC, Cl 8, 1.6 μm, 2.1 x50 mm column.

[0278] Detection: QDa, Quadrupole LC / MS, Ion Source: API-ES, TIC: 70-900 m / z, Fragmentor: 70, Drying gas flow: 12 L / min, Nebulizer pressure: 36 psi, Drying gas temperature: 350 °C, Vcap: 3000V. Samples were dissolved in methanol at 1-10 μg / mL, then filtered through a 0.22 μm filter membrane. Injection volume: 1—10 pL. Detector: 214 nm, 254 nm.

[0279] Solvents: A: 0.05% Formate in water (v / v), B: 0.05% Formate in MeCN (v / v).

[0280] Gradient:Method 4 - Acidic method (Agilent 3 min)

[0281] Column: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Agilent EclipsePlus RRHD C18, 1.8μm, 3.0x50 mm.

[0282] Detection: G6120A, Quadrupole EC / MS, Ion Source: API-ES, TIC: 70-1000 m / z, Fragmentor: 70, Drying gas flow: 12 L / min, Nebulizer pressure: 36 psi, Drying gas temperature: 350 °C, Vcap: 3000V. Samples were dissolved in methanol at 1-10 μg / mL, then filtered through a 0.22 μm filter membrane. Injection volume: 1—10 pL. Detector: 214 nm, 254 nm.

[0283] Solvents: A: 0.05% Formate in water (v / v), B: 0.05% Formate in MeCN (v / v).

[0284] Gradient:Example 2. Compound synthesis

[0285] The compounds of the present disclosure may be prepared by methods well known to those skilled in the art, and / or as described in the synthetic experimental procedures shown below.

[0286] The synthesis of the compounds disclosed herein may follow a general scheme according to Scheme 1:PhenolReagents: (a) MeCN, CS2CO3, KI, Molecular sieve, 60 °C.

[0287] The synthesis of various suitable phenol intermediates is described below.

[0288] Phenol 1. 2-hydroxy-5-methylbenzonitrileZn(CN)2Step 1

[0289] Step 1: 2-hydroxy-5-methylbenzonitrile: A mixture solution of 2-bromo-4- methylphenol (9.3 g, 50.0 mmol), Zn(CN)2(3.22 g, 27.5 mmol), Pd(Xantphos)C12 (1.9 g, 2.5 mmol) and DIPEA (9.68 g, 75.0 mmol) in DMA (300 mL) was stirred at 85°C overnight under N2 atmosphere. The mixture reaction was filtered and purified by Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, contained 0.1% HCOOH) to give the title compound (5.2 g, 39.1 mmol, 78% yield) as a yellow solid. UPLC-MS (Method 3) m / z 132.0, (M-H)’ at 1.259 min.

[0290] Phenol 2. 2-hydroxy-5-propionylbenzonitrileStep 1 Step 2

[0291] Step 1: l-(3-bromo-4-hydroxyphenyl)propan-l-one: A mixture solution of 1- (4-hydroxyphenyl)propan-1-one (3.0 g, 19.97 mmol), NBS (4.26 g, 23.97 mmol), I2 (505 mg, 1.99 mmol) in MeCN (50 mL) was stirred at RT overnight under darkness.The reaction solution was filtered and concentrated under vacuum to afford the crude product, the crude product was purified by silica gel chromatography (eluting with 1 / 5 EtOAc / PE) to afford the title compound (3.0 g, 13.1 mmol, 66 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.5, 2.1 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 2.96 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).

[0292] Step 2: 2-hydroxy-5-propionylbenzonitrile: To a solution of l-(3-bromo-4- hydroxyphenyl)propan-1-one (2.0 g, 8.77 mmol) in NMP (8 mL) at RT was added CuCN (1.17 g, 13.16 mmol). The resulting solution was stirred at 130 °C overnight. The mixture solution was filtered and purified by Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, contained 0.1% HCOOH) to give the title compound (1.05 g, 6.0 mmol, 68% yield) as a yellow solid. UPLC-MS (Method 3) m / z 174.26, (M-H)- at 1.371 min.

[0293] Phenol 3. 2-hydroxy-5-isopropoxybenzonitrileStep 1 Step 2

[0294] Step 1: 2-fluoro-5-isopropoxybenzonitrile: A mixture solution of 2-fluoro-5- hydroxybenzonitrile (1.0 g, 7.3 mmol), 2-iodopropane (1.5 g, 8.76 mmol), KS2CO3(14.6 g, 4.75 mmol) in MeCN (10 mL) was stirred at RT overnight. The mixture solution was filtered and concentrated under vacuum to afford the title compound (1.2 g, 6.7 mol, 92% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, J =5.2, 3.1 Hz, 1H), 7.40 (t, J = 9.1 Hz, 1H), 7.29 (ddd, J = 9.1, 4.5, 3.1 Hz, 1H), 4.63 (p, J = 6.0 Hz, 1H), 1.24 (d, J = 6.0 Hz, 6H).

[0295] Step 2: 2-hydroxy-5-isopropoxybenzonitrile: To a solution of 2-fluoro-5- isopropoxybenzonitrile (500 mg, 2.79 mmol) and 2-(methylsulfonyl)ethan-1-ol (346 mg, 2.79 mmol) in DMF (5 mL) at 0 °C was added NaH (223.2 mg, 5.58 mmol). The resulting solution was stirred at RT for 1 hour. The mixture reaction was quenched with water and EtOAc. The solution was extracted with EtOAc (100 ml*3), washed by brine (100 mL*3) and dried over Na2SO4. The organic phase was concentrated in vacuum and purified by silica gel column chromatography (PE / EtOAc = 1 / I) to afford the title compound (250.0 mg, 1.41 mol, 51% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.14 (d, J = 3.1 Hz, 1H), 7.09 (dd, J = 9.0, 3.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 4.49 (p, J = 6.0 Hz, 1H), 1.22 (d, 7 = 6.0 Hz, 6H).

[0296] Phenol 4. 2-hydroxybenzonitrile-5-dStep 1

[0297] Step 1: 2-hydroxybenzonitrile-5-d: To a solution of 5-bromo-2- hydroxybenzonitrile (1.0 g, 5.07 mmol) in THF (10 mL) at -78 °C was added n-BuLi (2.5 M, 4.06 mL, 10.15 mmol). The resulting solution was stirred at -78 °C for 0.5 hour, then added D2O (ImL). The resulting solution was warmed to RT for 2 hours. The mixture reaction was poured into water and extracted with EtOAc (100 ml*3), washed by brine (100 mL*2) and dried over Na2SO4. The organic phase was concentrated in vacuum to give the title compound (420 mg, 3.5 mmol, 69% yield) as a yellow oil.1H NMR (400 MHz, DMSO-76) δ 11.04 (s, 1H), 7.60 (td, J = 3.9, 3.5, 1.7 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H).

[0298] Phenol 5. 2-hvdroxy-5-(2-methoxyethoxy)benzonitrileStep 1 Step 2

[0299] Step 1: 2-fluoro-5-(2-methoxyethoxy)benzonitrile: A mixture solution of 2- fluoro-5-hydroxybenzonitrile (800.0 mg, 5.83 mmol), l-bromo-2-methoxy ethane (966 mg, 7.0 mmol), K2CO3(1.68 g, 11.66 mmol) in MeCN (10 mL) was stirred at 60 °C overnight. The mixture solution was filtered and concentrated under vacuum to afford the title compound (800 mg, 4.1 mol, 70% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 4.39 (t, J = 5.3 Hz, 2H), 3.29 (t, J = 5.3 Hz, 2H), 2.33 (s, 3H).

[0300] Step 2: 2-hydroxy-5-(2-methoxyethoxy)benzonitrile: Using the procedure outlined in Step 2 of Phenol 3 Starting with 2-fluoro-5-(2-methoxyethoxy)benzonitrile (600.0 mg, 3.08 mmol). The title compound was obtained (330 mg, 1.7 mmol, 55% yield) as a yellow oil. UPLC-MS (Method 3) m / z 200.10, (M-H)’ at 1.067 min.1H NMR (400 MHz, DMSO-76) δ 10.55 (s, 1H), 7.29 - 7.08 (m, 1H), 6.95 (d, 7 = 9.1 Hz, 1H), 5.78 (s, 1H), 4.20 - 4.02 (m, 2H), 3.74 - 3.59 (m, 2H), 3.31 (s, 3H).

[0301] Phenol 6. 5-(tert-butyl)-2-hydroxybenzonitrileZnCN2, G3PdStep 1

[0302] Step 1: 5-(tert-butyl)-2-hydroxybenzonitrile: A mixture solution of 2-bromo- 4-(tert-butyl)phenol (1.0 g, 3.47 mmol), Zn(CN)2(815 mg, 6.94 mmol), G3Pd (276 mg, 0.347 mmol) in the mixture solution of THF / H2O (v / v=5 / l, 12 mL) was stirred at 50°C overnight under N2 atmosphere. The mixture reaction was filtered and the crude product was purified by silica gel chromatography (eluting with 1 / 5 EtOAc / PE) to afford the title compound (240.0 mg, 1.37 mmol, 39% yield) as a white solid.1H NMR (400 MHz, DMSO-76) δ 10.83 (s, 1H), 7.59 - 7.51 (m, 2H), 7.00 - 6.93 (m, 1H), 1.26 (s, 9H).

[0303] Phenol 7. 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxybenzonitrile

[0304] Step 1: 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenol: A mixture solution of 2-bromo-5-(hydroxymethyl)phenol (5.0 g, 24.6 mmol), tert- butylchlorodimethylsilane (3.89 g, 25.8 mmol), imidazole (2.17 g, 32.0 mmol) in DMF (10 mL) was stirred at RT for 1 hour. The mixture reaction was filtered and the crude product was purified by silica gel chromatography (eluting with 1 / 20 EtOAc / PE) to afford the title compound (4.3 g, 13.6 mmol, 55% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 2.2 Hz, 1H), 6.66 - 6.57 (m, 1H), 4.60 (s, 2H), 0.90 (s, 9H), 0.07 (s, 6H).

[0305] Step 2: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxybenzonitrile: Using the procedure outlined in Step 1 of Phenol 1 Starting with 2-bromo-5-(((tert- butyldimethylsilyl)oxy)methyl)phenol (300.0 mg, 0.95 mmol). The title compound was obtained (110 mg, 0.42 mmol, 44% yield) as a yellow solid. UPLC-MS (Method 3) m / z 262. 0, (M-H)- at 2.410 min.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.3 Hz, 1H), 6.90 - 6.80 (m, 1H), 4.72 (s, 2H), 0.94 (s, 9H), 0.11 (s, 6H).

[0306] Phenol 8. 2-hydroxy-4-(methoxymethyl)benzonitrileStep 1 Step 2

[0307] Step 1: 2-bromo-5-(methoxymethyl)phenol: To a solution of 2-bromo-5- (hydroxymethyl)phenol (2.0 g, 9.85 mmol) in THF (10 mL) at 0 °C was added NaH (60%, 985 mg, 24.6 mmol). The resulting solution was stirred at 0 °C for 0.5 hour, then added Mel (1.4 g, 9.85 mmol). The resulting solution was warmed to RT for 2 hours. The mixture reaction was poured into water and extracted with EtOAc (100 ml*3),washed by brine (100 mL*2) and dried over Na2SO4. The organic phase was concentrated in vacuum to give crude product, which was purified by silica gel chromatography (eluting with 1 / 3 EtOAc / PE) to afford the title compound (800.0 mg, 3.7 mmol, 38% yield) as a coloress oil.1H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H), 4.39 (s, 2H), 3.38 (s, 3H).

[0308] Step 2: 2-hydroxy-4-(methoxymethyl)benzonitrile: A mixture solution of 2- bromo-5-(methoxymethyl)phenol (300.0 mg, 1.39 mmol), CuCN (249 mg, 0.28 mmol), Cui (319 mg, 1.67 mmol) and KI (300 mg, 1.8 mmol) in DMF (5 mL) was stirred at 130°C overnight in sealed tube. The mixture solution was filtered and purified by Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, contained 0.1% HCOOH) to give the title compound (70 mg, 0.43 mmol, 31% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 6.96 (s, 1H), 6.84 (dd, J = 8.0, 1.4 Hz, 1H), 4.40 (s, 2H), 3.30 (s, 3H).

[0309] Phenol 9. 6-hydroxy-2,3-dimethylbenzonitrileStep 3

[0310] Step 1: 2,6-dibromo-3,4-dimethylphenol: To a solution of 3,4-dimethylphenol (6.1 g, 50.0 mmol) in the mixture solution of HOAC / H2O (v / v-1 / 1, 50 mL) at 0 °C was added Bn (8.0 mL, 50.0 mmol). The resulting solution was stirred at °C for 2 hours. The mixture reaction was added Na2S20s(aq) and extracted with EtOAc (100 ml*3), washed by brine (100 mL*2) and dried over Na2SO4. The organic phase was concentrated in vacuum to give the crude product, which was purified by BiotageIsolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, contained 0.1% HCOOH) to give the title compound (5.8 g, 20.7 mmol, 41% yield) as a white solid.1H NMR (400 MHz, Chloroform-d) 8 7.350 (s, 1H), 2.43 (s, 3H), 2.36 (s, 3H).

[0311] Step 2: 2-bromo-3,4-dimethylphenol: To a solution of 2,6-dibromo-3,4- dimethylphenol (1.0 g, 3.57 mmol) in MeOH (34 mL) at RT was added Pd / C (10% wet, 100.0 mg), the resulting solution was stirred at RT 2 hours under H2atmosphere. The mixture solution was filtered and concentrated under vacuum to afford the title compound (237.0 mg, 1.18 mol, 33% yield) as a coloress oil.1H NMR (400 MHz, Chloroform-d) 8 6.97 (dd, J = 8.2, 3.3 Hz, 1H), 6.77 (dd, J = 8.6, 3.3 Hz, 1H), 2.33 (d, 7 = 3.1 Hz, 3H), 2.24 (s, 3H).

[0312] Step 3: 6-hydroxy-2,3-dimethylbenzonitrile: Using the procedure outlined in Step 1 of Phenol 1 Starting with 2-bromo-3,4-dimethylphenol (200.0 mg, 1.0 mmol). The title compound was obtained (125 mg, 0.85 mmol, 85% yield) as a grey solid. UPLC-MS (Method 3) m / z 146. 0, (M-H)’ at 2.256 min.

[0313] The synthesis of a suitable chloride intermediate is described below.

[0314] Intermediate 1. 2-(chloromethyl)benzo[d]oxazole-6-carboxylic addStep 1 Intermediate 1

[0315] Step 1: 2-(chloromethyl)benzo[d]oxazole-6-carboxylic acid; A mixture solution of 4-amino-3-hydroxybenzoic acid (5.0 g, 32.7 mmol) and 2-chloro- 1,1,1 - trimethoxyethane (5.0 g, 32.7 mmol) in EtOH (150 mL) was stirred at 75°C overnight. The solvent was removed under pressure and purified by silica gel column chromatography (PE / EtOAc = 30 / 1 to 10 / 1) to afford the title compound (5 g, 22.2 mol, 68 % yield) as a white solid.1H NMR (400 MHz, DMSO-76) 8 8.25 (d, J = 1.4 Hz, 1H), 8.00 (dd, J = 8.3, 1.5 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 5.09 (s, 2H).Example 3. Synthetic route to compound 3Step 1Compound 3

[0316] Step 1: 2-((2-cyano-4-methylphenoxy)methyl)benzo[d]oxazole-6-carboxylic acid: A mixture solution of 2-hydroxy-5-methylbenzonitrile (Phenol 1, 127 mg, 0.96 mmol), 2-(chloromethyl)benzo[d]oxazole-6-carboxylic acid (Intermediate 1, 302.7 mg, 1.43 mmol), CS2CO3(777.9 mg, 2.39 mmol), KI (79.26 mg, 0.48 mmol) and molecular sieve (300 mg) in MeCN (10 mL) was stirred at 60 °C overnight. The mixture solution was filtered and concentrated under vacuum to afford the crude product, the crude product was purified by prep-HPLC (eluting with 10 % to 90 % MeCN / H2O, contained 0.1% HCOOH) to afford the title compound (70.0 mg, 0.22 mmol, 23% yield) as a white solid. UPLC-MS (Method 2) m / z 309.15, (M+H)+at 3.683 min.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 1.5 Hz, 1H), 8.01-7.99 (dd, J = 8.3, 1.6 Hz, 1H), 7.88-7.86 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.48-7.46 (d, J = 8.5 Hz, 1H), 7.31-7.29 (dd, J = 8.6, 1.8 Hz, 1H), 5.69 (s, 2H), 2.26 (s, 3H).Example 4. Synthetic route to compound 102

[0317] Step 1: 2-((2-cyano-4-propionylphenoxy)methyl)benzo[d]oxazole-6- carboxylic acid: Using the procedure outlined in Step 1 of Example 1 Starting with 2- hydroxy-5-propionylbenzonitrile (300.0 mg, 1.71 mmol). The title compound wasobtained (300.0 mg, 0.85 mmol, 50% yield) as a white solid. UPLC-MS (Method 3) m / z 349.27, (M+H)+at 1.630 min.

[0318] Step 2: 2-((2-cyano-4-(l-hydroxypropyl)phenoxy)methyl)benzo[d]oxazole-6- carboxylic acid: To a solution of 2-((2-cyano-4- propionylphenoxy)methyl)benzo[d]oxazole-6-carboxylic acid (200.0 mg, 0.57 mmol) in mixture solution of THF (5 mL) and water (1 mL) was added NaBH4 (64.8 mg, 1.71 mmol). The resulting solution was stirred at R.T 2 hours. The solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 6 with IM HC1. The mixture was extracted with EtOAc (10 mL x 3), dried over Na2SO4and concentrated under vacuum to afford the crude product. The crude product was purified by prep-HPLC to give the title compound (17.0 mg, 0.048 mmol, 8% yield) as a white solid. UPLC-MS (Method 2) m / z 353.20, (M+H)+at 3.050 min.1H NMR (400 MHz, DMSO-76) δ 8.28 (d, J = 1.4 Hz, 1H), 8.01 (dd, 7 = 8.3, 1.5 Hz, 1H), 7.88 (d, 7 = 8.3 Hz, 1H), 7.67 (d, 7 = 2.2 Hz, 1H), 7.60 (dd, 7 = 8.8, 2.2 Hz, 1H), 7.37 (d, 7 = 8.8 Hz, 1H), 5.73 (s, 2H), 5.33 - 5.17 (m, 1H), 4.48 - 4.42 (m, 1H), 1.58 (p, 7 = 7.2 Hz, 2H), 0.79 (t, 7 = 7.3 Hz, 3H).Example 5. Synthetic route to compound 67Compound 67

[0319] Step 1: 2-((5-(((tert-butyldimethylsilyl)oxy)methyl)-2- cyanophenoxy)methyl)benzo[d]oxazole-6-carboxylic acid: Using the procedure outlined in Step 1 of Example 1 Starting with 4-(((tert-butyldimethylsilyl)oxy)methyl)- 2-hydroxybenzonitrile (200.0 mg, 0.76 mmol). The title compound was obtained (210.0mg, 0.48 mmol, 63% yield) as a white solid. UPLC-MS (Method 3) m / z 437.0, (M-H)’ at 2.487 min.

[0320] Step 2: 2-((2-cyano-5-(hydroxymethyl)phenoxy)methyl)benzo[d]oxazole-6- carboxylic acid: To a solution of 2-((5-(((tert-butyldimethylsilyl)oxy)methyl)-2- cyanophenoxy)methyl)benzo[d]oxazole-6-carboxylic acid (100.0 mg, 0.23 mmol) in DMF (2 mL) was added CsF (51.9 mg, 0.34 mmol). The resulting solution was stirred at R.T overnight. The mixture was treated with water, and extracted with EtOAc (20 mL x 3), dried over Na2SO4and concentrated under vacuum to afford the crude product. The crude product was triturated with EtOH to give the title compound (20.0 mg, 0.06 mmol, 26% yield) as a white solid. UPLC-MS (Method 2) m / z 325.20, (M+H)+at 2.750 min.1H NMR (400 MHz, DMSO-de) δ 8.13 (s, 1H), 7.97 (dd, J = 8.3, 1.4 Hz, 1H), 7.71 (t, J = 8.2 Hz, 2H), 7.37 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 5.67 (s, 2H), 4.54 (s, 2H).Example 6. Analytical data for example compounds synthesised according to methods described in Examples 3 to 5

[0321] The following example compounds were prepared by methods described in Examples 3 to 5 hereinabove; or by methods analogous to the methods described hereinabove, substituting appropriate starting materials and intermediates where necessary.

[0322] Step 1: 2-hydroxy-5-methylbenzonitrile: Using the procedure outlined in Step 2 of Phenol 2 Starting with 2-bromo-4-methylphenol (500 mg, 2.6 mmol). The title compound was obtained (150 mg, 1.12 mmol, 43% yield) as a white solid. UPLC-MS (Method 3) m / z 132. 0, (M-H)’ at 1.273 min.

[0323] Step 2: ethyl 2-(2-cyano-4-methylphenoxy)acetate: To a solution of 2- hydroxy-5-methylbenzonitrile (130 mg, 1.0 mmol) in MeCN (10 mL) at RT was added CS2CO3(650 mg, 2.0 mmol) and ethyl 2-bromoacetate (180 mg, 1.1 mmol). The mixture solution was stirred at 60 °C for 12 hours. The reaction solution was filtered and concentrated under vacuum to afford the crude product, the crude product was purified by silica gel chromatography (eluting with 1 / 10 EtOAc / PE to 13 EtOAc / PE) to afford the title compound (200 mg, 0.91 mmol, 91 % yield) as a yellow solid. UPLC- MS (Method 3) m / z 220. 0, (M+H)+at 1.704 min.

[0324] Step 3: 2-(2-cyano-4-methylpheoxy)acetic acidn: A mixture of ethyl 2-(2- cyano-4-methylphenoxy)acetate (200.0 mg, 0.9 mmol) and LiOH (80.0 mg, 1.8 mmol) in THF (5 mL) and water (2 mL) was stirred at R.T for 2 hours. The solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 6 with IM HC1. The mixture was extracted with EtOAc (20 mL x 3), dried over Na2SO4and concentrated under vacuum to afford the crude product. The crude product was washed with EtOH, then the filter cake was dried under vacuum to give the title compound (150 mg, 0.78 mmol, 86% yield) as a white solid. UPLC-MS (Method 3) m / z 190. 0, (M-H)’ at 1.210 min.

[0325] Step 4: 2-((2-cyano-4-methylphenoxy)methyl)benzo[d]oxazole-5-carboxylic acid: A mixture of 2-(2-cyano-4-methylphenoxy)acetic acid (100 mg, 0.52 mmol), 3-amino-4-hydroxybenzoic acid (80.0 mg, 0.52 mmol) and PPSE (1 mL) was stirred at 120 °C in sealed tube for 12 hours. The mixture reaction was poured into ice-water and the pH of the aqueous solution was adjusted to 3 with 2M HC1. The mixture was extracted with DCM (50 mL x 3), dried over Na2SO4and concentrated under vacuum to afford the crude product. The crude product was purified by prep-HPLC (eluting with 10 % to 90 % MeCN / H2O) to give the title compound (57 mg, 0.16 mmol, 12% yield) as a white solid. UPLC-MS (Method 2) m / z 309.20, (M+H)+at 3.717 min.1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.03 (dd, J = 8.5, 1.2 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.51 - 7.46 (m, 1H), 7.31 (d, J = 8.7 Hz, 1H), 5.65 (s, 2H), 2.26 (s, 3H).Example 8. Synthetic route to compound 13p

[0326] Step 1: methyl (E)-3-(2-cyanophenyl)acrylate: To a solution of methyl 2- (dimethoxyphosphoryl) acetate (2.78 g, 15.0 mmol) in THF (30 mL) at 0 °C was added n-BuLi (2,5 mol / L, 7.2 mL, 18.0 mmol) and stirred at the same temperature for 0.5 hour. The mixture solution was added 2-formylbenzonitrile (2.0 g, 15.0 mmol), the resulting solution was stirred at RT for 12 hours. The mixture was quenched with NH4CI (aq), and extracted with EtOAc (100 ml*3), washed by brine (100 mL*3) and dried over Na2SO4. The organic phase was concentrated in vacuum to give the crude product. And the crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / I) to afford the title compound (2.0 g, 10. 7 mmol, 71% yield) as a white solid. UPLC-MS (Method 3) m / z 188. 0, (M-H)’ at 1.653 min.Ill

[0327] Step 2: (E)-3-(2-cyanophenyl)acrylic acid: Using the procedure outlined in Step 3 of Example 4 Starting with methyl (E)-3-(2-cyanophenyl)acrylate (500 mg, 2.67 mmol). The title compound was obtained (450 mg, 2.6 mmol, 97% yield) as a white solid. UPLC-MS (Method 3) m / z 172. 0, (M-H)’ at 1.153 min.

[0328] Step 3: 3-(2-cyanophenyl)propanoic acid: Using the procedure outlined in Step 2 of Phenol 9 Starting with (E)-3-(2-cyanophenyl)acrylic acid (450 mg, 2.6 mmol). The title compound was obtained (450 mg, 2.28 mmol, 88% yield) as a white solid. UPLC-MS (Method 3) m / z 174. 0, (M-H)’ at 1.112 min.

[0329] Step 4: methyl 2-(2-cyanophenethyl)benzo[d]oxazole-6-carboxylate: Using the procedure outlined in Step 4 of Example 4 Starting with 3-(2- cyanophenyl)propanoic acid (100 mg, 0.57 mmol). The title compound was obtained (30 mg, 0.1 mmol, 17% yield) as a white solid. UPLC-MS (Method 3) m / z 307. 0, (M+H)+at 2.193 min.

[0330] Step 5: 2-(2-cyanophenethyl)benzo[d]oxazole-6-carboxylic acid: Using the procedure outlined in Step 3 of Example 4 Starting with methyl 2-(2- cyanophenethyl)benzo[d]oxazole-6-carboxylate (30 mg, 0.1 mmol). The title compound was obtained (20 mg, 0.068 mmol, 68% yield) as a white solid. UPLC-MS (Method 2) m / z 293.15, (M+H)+at 3.250 min.1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.95 (dd, J = 8.3, 1.6 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.65 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 3.39 (s, 4H).Example 9. Analytical data for example compounds synthesised according to methods described in Examples 7 and 8

[0331] The following example compounds were prepared by methods described in Examples 7 and 8 hereinabove.Example 10. Biological testingGPR68 cAMP GloSensor Assay Protocol

[0332] The assay was developed to provide a quick screen assay to determine the potency and EC50s / IC50s of compounds against the GPR68 receptor with transient transfection cell.Assay Design Principle

[0333] GPR68 senses extracellular pH. Levels of cyclic adenosine monophosphate (cAMP), a secondary messenger associated with activation of GPCRs in the cAMP- dependent pathway, were found to be elevated in neutral to acidic extracellular pH (pH 7.0-6.5) in cells expressing GPR68. The pH-sensing ability of GPR68 was further tested and confirmed, as it was found that cAMP levels increased when GPR68 was stimulated by pH values less than pH 7.2.

[0334] To determine the compound activity in GPR68 inhibition, an GPR68 dependent cAMP assay was developed and validated. Principle of this method: Expression of GPR68 in HEK293T cells by transient transfection of a GPR68- expression vector and a cAMP-sensing reporter vector (GloSensor, Promega). The transfected cells as a pool will be re -plated uniformly in assay plates, to minimize the in-experiment variation. The GPR68 receptor signal will be measured via Gs to cAMP increase as indicated by the Luc activation under basal (pH8.4 or pH7.4) or activated (pH6.5 or pH6.0) states.Reagent ListGloSensor™ cAMP Reagent (Promega, Cat # E1291) human GPR68 NM_001177676.2_pcDNA3.1(+) (Genscript) The GloSensor™-22F cAMP Reporter Vector (Promega, Cat# E2301) DMEM (Gibco, Cat #11995065)FBS, Qualified, New Zealand origin (Gibco, Cat# 10091148) Penicillin-Streptomycin (Gibco, Cat# 15140122) 0.25% Trypsin-EDTA (Gibco, Cat# 25200056) PBS (Gibco, Cat# 10010049) lx HBSS (Gibco, Cat# 14175079) HEPES (Gibco, Cat# 15630080) MES (Sigma, Cat# M2933-25G) TAPS (Sigma, Cat# T5316-25G) NaOH (Sigma, Cat#221465) BSA (Sigma, Cat# B2064-50G) Opti-MEM (Gibco, Cat# 31985070) DMSO (Sigma, Cat# D5879-1L)FuGene HD Transfection Reagent (Promega, Cat # E2311)Consumables / Supplies List96 well plate (Corning, Cat#3610) 6-well plate (Corning, Cat#3516) 96 well V bottom plate (Greiner Bio-one, Cat# 651201) Cell culture dish 100mm (Coming, Cat#CLS430167)Equiμment & SettingsLiquid handler: Echo (LABCYTE Echo550), BRAVO (Agilent)Incubator (Grant-bio Thermo-shaker PHMP)Plate Centrifuge (Eppendorf 591 OR)Plate reader: Envision (PE).Experimental ProceduresCell Culture procedures

[0335] 1. Thawing cells

[0336] 1) Quickly thawed frozen cells at 37°C water bath with a gently continuous agitation.

[0337] 2) Gently added the cells, drop by drop, to a 15 ml centrifuge tube containing 10 ml of fresh pre-warmed complete medium. Then centrifuged the cells at 1000 rμm for 5 minutes.

[0338] 3) Discarded the supernatant medium and resuspended the cell pellet in 10 ml of fresh pre-warmed complete medium. Transferred cells to a 10 cm dish and incubated at 37°C with 5% CO2until the cells reach >90% confluence. The recovery rate for frozen cells was usually 80% or above.

[0339] 2. Subculturing

[0340] This cell line was normally split twice every 1-2 days at a 1:3 to 1:5 ratio dilutions. The fresh cells typically needed 1-2 days to grow to 85% confluence.

[0341] 1) Carefully aspirated all the media, washed the cell monolayer with 5mL pre- warmed PBS for 10cm dish gently, rinsed the cell layer with appropriate amount (gently 1 mL for 10 cm dish) of 0.2% trypsin-EDTA, and then aspirated it off.

[0342] 2) Added 5-fold of trypsin volume culture medium to stop the trypsin, harvested cells by centrifuged at 1000 rpm for 5 min at RT.

[0343] 3) Resuspended cells with appropriate amount of complete medium, and split cells as desired.

[0344] 3. Changing medium

[0345] 1) Gently aspirated off the medium.

[0346] 2) Transferred fresh warm complete medium (37°C) into the 10 cm dish.

[0347] 4. Freezing cells

[0348] 1) Repeated subculturing steps 1-3.

[0349] 2) Centrifuged down the cells at 1000 rpm for 5 min.

[0350] 3) Aspirated off the supernatant and resuspended the cells in fresh freezing medium at a density of 1-2 x 106cells / ml. Added 1 ml cells per Cryogenic Vial.

[0351] 4) Put the Cryogenic Vial of cells into Cryo Freezing Container followed by transferring the container into -80°C and staying overnight.

[0352] 5) Transferred Cryogenic Vial into liquid nitrogen (-196°C).Assay procedures

[0353] Step 1: Seeded cells in 6- well plate

[0354] 1) Detached cells with 0.25% Trypsin when the cell confluence was about 80%.

[0355] 2) Resuspended the detached cells in 3 ml fresh cell culture medium. Counted the cell number and diluted the cells to proper density.

[0356] 3) Seeded 1.5 x 10A6 cells into 6-well plate (Cat. #3516) in 2ml per well contained the need to transfection well so that the cells were 80-85% confluent at the time of transfection.

[0357] 4) Incubated the cells at 37°C in a CO2incubator for 6 hours.

[0358] Step 2: Transfected in 6-well plate

[0359] 5) Gently aspirated off the DMEM medium. Then added the Opti-MEM® Medium without serum into 6-well plate.

[0360] 6) Added 2.5μg GPR68 and 2.5p.g GloSensor-22F in 1:1 ratio and 12pl FuGeneHD into 120μl of Opti-MEM® Medium without serum. Mixed gently and incubated for 15 min at room temperature.

[0361] 7) After the 15-minute incubation, added 137j_il of DNA-Transfection Reagent complexes to each well containing cells and medium. Mixed gently by rocking the plate back and forth.

[0362] 8) Incubated the cells at 37°C in a co2 incubator for 19 h until they were ready to assay for transgene expression.

[0363] Step 3: Re-seeded cells in 96- well plate

[0364] Seeded 40000 cells / well, 100 pl / well in 96-well plate (Cat. #3610) with complete DMEM medium; incubated overnight.

[0365] Step 4: Test compounds

[0366] 1. Prepared different pH buffers.

[0367] 2. Prepared Compounds

[0368] 1) Compounds were solubilized in 100% DMSO to a concentration of 50 mM.

[0369] 2) Prepared compound DMSO solutions in 384 LDV echo plate: top concentration was 10 mM, 3-fold, 10 dose-response, so intermediate concentrations were created by serially diluting by (1:2) beginning from the 10000 μM. 5 pL testedintermediate compounds + lOpl DMSO solutions were transferred to 384 LDV echo plate. Centrifuged the echo plate at 1000 rpm for 30s before Echo procedure.Compounds were transferred 180 nL volume by Echo550 to a 96-assay plate (corning, Cat # 3599), to make compound 10 concentration points in duplicate (the final top concentration was 10 μM, 3-fold, 10 dose-response, in duplicate). Final DMSO concentration is 0.1%.

[0370] 3) For the Low control wells and High control wells, 180 nL DMSO were transferred by ECHO.

[0371] 4) Layout of assay plate 180 nL / well of compounds in 100% DMSO 180 nL / well DMSO in Low control wells and High control wells was as shown below. Compounds were prepared into assay plate at 100X working concentration in 100% DMSO, the assay volume was 150 pL, and final DMSO concentration was 0.1%.High control: pH 6.0 + 0.1% DMSOLow control: pH 8.4 + 0.1% DMSOCompound: pH 6.0 buffer + Compound

[0372] 3. Luciferin loading

[0373] 1) Removed culture medium, added 100 pL / well GloSensor (50X) to cells, then incubated for 2h at room temperature.Stock (mg / mL) Final (mg / mL) Fold Add (pL)GloSensor 30 0.6 50 220Buffer 4 (pH 8.4) 10780Total(pl) 11000

[0374] 2) Pre-read Luminescence at -5min for background after 2h incubation.

[0375] 4. Compound addition and Lum signal collection

[0376] 1) Compounds were diluted with assay buffer to 10 μM top as below:• ECHO-Transferred 180 nL compounds / DMSO to 96-well plate (corning, Cat # 651201).• Added 150 pL different pH buffers to compound plate. Mixed well.

[0377] 2) Removed 80 pL GloSensor from the cell plate, added pH buffer with or without compound, 100 pL / well to cell plate.

[0378] 3) Transferred the cell plate into plate reader immediately.

[0379] 4) Read and collected Luminescence signal from 0 min to 30 min on Envision.

[0380] The map of compounds plate and pH activationHigh control: pH 6.0 + 0.1% DMSOLow control: pH 8.4 + 0.1% DMSOCompound: pH 6.0 buffer +CompoundData Analysis

[0381] The percent (%) inhibition at each concentration of compound was calculated based on and relative to the signal in the High and Low control wells contained within each assay plate. The High control wells as 0% inhibition (pH 6.0), and the low control wells as 100% inhibition (pH 8.4).

[0382] Inhibition rate of the compound was calculated according to the formula:Inhibition% = [CTL pH6.0 - CPD pH6.0] / [CTL pH6.0 - CTL pH8.4] *100

[0383] The concentrations and % inhibition values for tested compounds were plotted and the concentration of compound required for 50% inhibition (IC50) was determined with a four-parameter logistic dose response equation.

[0384] The endpoint value (IC50) for the reference peptide / compound was evaluated in each experiment as a quality control measure. If the endpoint value was within 3-fold of the expected value, then the experiment was deemed acceptable.Results

[0385] The results of the described GPR68 cAMP GloSensor assay, given as IC50 values, indicated the concentration of test compound required for 50% inhibition. The results for this assay for sample compounds of the present disclosure are provided in Table 1 below.Table 1. GPR68 cAMP Giosensor assay results

Claims

CLAIMS:

1. A compound having the structure of Formula (I):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:Y is -O-, -CR92-, -S-, or -NR9-; each instance of X is independently C or N; each instance of Z is independently O, N, NH, or S; provided that at least one of Z is N;R1is -C(O)OR10, -C(O)R10, -C(O)NR9R10, -C(O)SR10, -S(O)R10, -S(O)2R10, - S(O)2NR9R10, -C(=NR10)R10, -C(=NR1O)NR9R10, -C(=NR10)OR10, -P(=O)(OR9)R10, - CF3, -CN, or halogen; each R9is independently selected from hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, C1-4haloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6carbocyclyl, optionally substituted C5-10aryl, optionally substituted 5-6 membered heteroaryl, and optionally substituted 5-6 membered heterocyclyl; each R10is independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C2.2o alkoxyalkyl, C1-6haloalkyl, -C(O)R9, -OR9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, - S(O)2R9, and -S(O)2N(R9)2; wherein any two adjacent R10, when present, together with the atoms to which they are attached, may form a 5-6 membered heteroaryl or a 5-6membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-io alkyl, halogen, -CN, -OR9, - SR9, -S(O)2R9, -N(R9)2, NR9C(O)R9, -N(R9)S(O)2R9, -NO2, =(O), =(S), =(N)R9, - C(O)R9, -C(O)OR9, -C(O)N(R9)2, or -C(O)SR9; each instance of R4and R5is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; p is an integer from 1 to 6; each instance of R2is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-io alkyl, optionally substituted C1-io heteroalkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C1-io alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, - CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)OR10, - C(O)SR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -C(S)R10, - C(S)N(R10)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and -B(OR10)2; wherein any two adjacent R2, when present, together with the atoms to which they are attached, may form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, - N(R10)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)N(R10)2, -C(O)SR10or - C(O)OR10; n is an integer from 0 to 4;each instance of R3is selected from halogen, hydroxy, optionally substituted C1- 6 alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C5-6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -OR9, -SR9, -NR9R10, -C(O)R9, -C(O)OR9, -S(O)2R9, and -NO2; and m is an integer from 0 to 3.

2. The compound according to claim 1, having the structure of Formula (II):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. The compound according to claim 1 or claim 2, having the structure of Formula (Illa) or (IIIb):(Illa) (Illb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

4. The compound according to claim 3, wherein Z is O or NH.

5. The compound according to claim 3, wherein Z is O.

6. The compound according to any one of claims 1 to 5, having the structure ofFormula (IVa) or (IVb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

7. The compound according to any one of claims 1 to 6, wherein R4and R5are hydrogen.

8. The compound according to any one of claims 1 to 7, wherein Y is -O-, -CH2-, -S-, or -NH-.

9. The compound according to any one of claims 1 to 8, wherein Y is -O- or - CH2-.

10. The compound according to any one of claims 1 to 9, wherein R1is selected from -C(O)OR10, -C(O)R10, -C(O)NR9R10, -C(O)SR10,-C(=NR10)R10, - C(=NR10)NR9R10, -C(=NR10)OR10, -CN, or halogen.

11. The compound according to any one of claims 1 to 10, wherein R1is -C(O)OR10, -C(O)NR9R10, -CN, halogen, or a 5 membered heteroaryl or a 5 membered heterocyclyl selected from12. The compound according to any one of claims 1 to 11, wherein R1is selected from -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, and halogen.

13. The compound according to any one of claims 1 to 12, wherein R1is -C(O)OH.

14. The compound according to any one of claims 1 to 13, having the structure ofFormula (Va) or (Vb):or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

15. The compound according to any one of claims 1 to 14, wherein Y is -O- or -CH2-16. The compound according to any one of claims 1 to 15, wherein Y is -O-.

17. The compound according to any one of claims 1 to 16, wherein n is 0, 1 or 2.

18. The compound according to any one of claims 1 to 17, wherein each R2, when present, is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-io alkyl, optionally substituted C1-io heteroalkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C1-10alkylthio, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -NO2, -OR10, -SR10, -N(R10)2, =(O), =(S), =(N)R10, -C(O)R10, -C(O)OR10, -C(O)SR10, -C(O)N(R10)2, -S(O)R10, - S(O)2R10, -S(O)2N(R10)2, -C(S)R10, -C(S)N(R1O)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, -N(R10)S(O)2N(R10)2, and -B(OR10)2; wherein any two adjacent R2, when present, together with the atoms to which they are attached, may form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkylthio, optionally substituted C2-8alkoxyalkyl, optionally substituted C3-10carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, halogen, -CN, -OR10, -SR10, -S(O)2R10, -N(R1O)2, -NO2, =(O), =(S), =(N)R10, -C(O)R10, - C(O)N(R10)2, -C(O)SR10or -C(O)OR10.

19. The compound according to any one of claims 1 to 18, wherein each R2, when present, is independently selected from deuterium, halogen, hydroxy, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C2-10alkoxyalkyl, optionally substituted C3-6carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C6aryl, optionally substituted 5-6 membered heteroaryl, -CN, -NO2, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)OR10, -C(O)N(R10)2, -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -N(R10)C(O)R10, -N(R10)S(O)2R10, - N(R10)S(O)2N(R10)2, and -B(OR10)2.

20. The compound according to any one of claims 1 to 19, wherein each R2, when present, is independently selected from halogen, C1-6alkyl, C3-6carbocyclyl, and 3-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from optionally substituted C1-6alkyl, halogen, -CN, -OR9, -SR9, -S(O)2R9, -NR9R10, -NO2, =(O), =(S), =(N)R9, =(N)R10, -C(O)R9, -C(O)NR9R10, - C(O)SR9or -C(O)OR9.

21. The compound according to any one of claims 1 to 20, wherein each R2, when present, is independently selected from halogen, C1-6alkyl, and C1-6alkyl optionally substituted with one or more substituents selected from C1-6alkyl, optionally substituted C3-6carbocyclyl, halogen, -OR9, and -NR9R10.

22. The compound according to any one of claims 1 to 21, wherein each R2, when present, is independently selected from halogen, methyl, ethyl, propyl, isopropyl, - CH2F, -CHF2, -CF3, cyclobutyl, and cyclopropyl.

23. The compound according to any one of claims 1 to 22, wherein m is 0 or 1.

24. The compound according to any one of claims 1 to 23, wherein R3, when present, is a halogen.

25. The compound according to any one of claims 1 to 24, wherein each instance of X is C.

26. The compound according to any one of claims 1 to 24, wherein at least one X is N.

27. The compound according to any one of claims 1 to 26, selected from the group consisting of:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

29. A method of treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 28.

30. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 28, in the manufacture of a medicament for the treatment and / or prevention of a disease, disorder or condition mediated by a proton- activated GPCR in a subject in need thereof.

31. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 28, for use in the treatment and / or prevention of a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

32. The method according to claim 29, the use according to claim 30, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 31, wherein the proton- activated GPCR is a GPR68 (OGR1).

33. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to any one of claims 29 to 32, wherein the disease, disorder or condition is selected from the group consisting of: an inflammatory disease, disorder or condition; a fibrotic disease, disorder or condition; a proliferative disease, disorder or condition, or a cancer.

34. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 33, wherein the disease, disorder or condition is an inflammatory disease, disorder or condition.

35. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 34, wherein the inflammatory disease, disorder or condition is selected from focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disorder (COPD), asthma, and cystic fibrosis.

36. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 34, wherein the inflammatory disease, disorder or condition is an autoimmune disease, disorder or condition.

37. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 36, wherein the autoimmune disease, disorder or condition is selected from systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn’s disease, ulcerative colitis, graft versus host disease, multiple sclerosis, and rheumatoid arthritis.

38. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 33, wherein the disease, disorder or condition is a fibrotic disease, disorder or condition.

39. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 38, wherein the fibrotic disease, disorder or condition is selected from renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, dermal fibrosis, pancreatic fibrosis, and liver fibrosis.

40. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 38, wherein the fibrotic disease, disorder or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral artery disease, cerebrovascular disease, chronic kidney disease, diabetic nephropathy, systemic sclerosis (scleroderma), hypertrophic scars, keloids, idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosis cholangitis (PSC).

41. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 33, wherein the disease, disorder or condition is a proliferative disease, disorder or condition.

42. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 41, wherein the proliferative disease, disorder or condition is selected fromdiabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

43. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 33, wherein the disease, disorder or condition is a cancer.

44. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 43, wherein the cancer is selected from a breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer and kidney cancer.

45. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to any one of claims 29 to 44, wherein the subject is a human.

46. A method of inhibiting a proton-activated GPCR in a cell, comprising administering to the cell an effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 28.

47. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 28, in the manufacture of a medicament for the inhibition of a proton-activated GPCR in a cell.

48. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 28, for use in the inhibition of a proton-activated GPCR in a cell.

49. The method according to claim 46, the use according to claim 47, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to claim 48, wherein the proton- activated GPCR is a GPR68 (0GR1).

50. The method, use, or the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition for use according to any one of claims 46 to 49, wherein the cell is a tumour cell.

51. The steps, features, integers, compositions and / or compounds disclosed herein or indicated in the specification of this application individually or collectively, and any and all combinations of two or more of said steps or features.

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