Heterocyclic compounds and their uses

Abstract

The present disclosure relates to compounds useful as modulators of proton-activated G protein-coupled receptors, and pharmaceutical compositions comprising the same. The disclosure also relates to methods of using such compounds and pharmaceutical compositions for the treatment and / or prevention of diseases, disorders, or conditions mediated by proton-activated G protein-coupled receptors.

Description

[Technical Field]

[0001] The present disclosure relates to novel compounds useful as modulators of proton-activated G protein-coupled receptors. The disclosure further relates to methods of making such compounds, pharmaceutical compositions and medicaments containing 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 technology]

[0002] Local acidification is a common feature of many disease processes, such as inflammation, infarction, or solid tumor growth. Acidic pH is not simply a consequence of disease; it contributes to immune cell recruitment and regulation, alters the metabolism of parenchymal, immune, and tumor cells, and modulates fibrosis, vascular permeability, oxygen availability and consumption, tumor cell invasiveness, and cell survival. Therefore, pH-sensing mechanisms are required in cells involved in these processes. These pH sensors play an important role in normal physiology and pathophysiology.

[0003] Among pH-sensing mechanisms, proton-activated G protein-coupled receptors (GPCRs), particularly GPR68 (OGR1), GPR4 (GPR4), and GPR65 (TDAG8), have emerged as key targets. These receptors are widely expressed and upregulated in inflammation and tumors. They sense changes in extracellular pH in the range of 8–6 and are involved in regulating important pathological processes such as the development and progression of several inflammatory diseases (asthma, inflammatory bowel disease), tumor cell metabolism and invasiveness, and fibrosis (Silva et al., Am J Physiol Cell Physiol., 1;323(2):C400, 2022; Silva and Wagner, Pflugers Arch., 474(5):487, 2022).

[0004] 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 of the Invention

[0005] The present inventors have identified compounds that are effective in the modulation, such as inhibition, of proton-activated G protein-coupled receptors, such as GPR68 (OGR1). The identified compounds are useful for 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.

[0006] Thus, in one aspect of the present disclosure, a compound of the structure of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, X is N and NR 1 is selected from Y is N and NR 2 is selected from R 1 and R 2 However, independently, H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR9 R 10 , -C(O)SR 9 , or -C(O)OR 9 or C 3-6 one or more substituents selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 optionally substituted with one or more substituents selected from Alternatively, R 1 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is optionally substituted C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from Each R 9 are independently H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl; Each R 10 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and -C(O)R 9 is selected from R 3 is H, halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 5-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 -NO2, and -NO2; or R 3 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from q is an integer of 0 to 3, R 4is halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 6-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 and -NO2; R 5 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-6 Carbocyclyl, optionally substituted C 5-10 selected from aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 5- to 6-membered heterocyclyl; L is a bond or -C(O)N(R 9 a linker selected from -S(O)-, -S(O)2-, -C(O)-, or -C(O)O-, or an optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, -OC 1-4 Alkylene or -OC 2-4 a linker selected from alkenylene, each of which is —O—, —S—, —NR 9 -, -NR 10 -, -C(O)N(R 9 )-, -N(R 9 )C(O)-, -S(O)2-, -N(R 9 )S(O)2-, -S(O)2N(R9 a linker interrupted by -C(O)-, -C(O)-, -C(O)O-, or -O(O)C-; R 6 But C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 3-10 Carbocyclyl, C 1-10 Alkyl, C 2-10 Alkenyl, or C 2-10 alkynyl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl; or R 6 and R 5 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C 1-10 Alkyl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and optionally substituted with one or more substituents optionally selected from Each R 11 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkyni, optionally substituted C 5-10 Aryl, optionally substituted C 2-20 Alkoxyalkyl, C1-C6 haloalkyl, -C(O)R 9 , -OR 9 , -S(O)2R 9 , and -S(O)N(R 9 )2 is selected, R 7 and R 8 However, independently, H, C 1-6 Alkyl, C 5-10 Aryl, 5- to 10-membered heteroaryl, and C 3-10 carbocyclyl, each of which is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 5-6 Aryl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 Compounds are provided, optionally substituted with one or more substituents selected from:

[0007] In some embodiments, the compounds defined herein have the structure of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0008] In some embodiments, the compounds defined herein have the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0009] In some embodiments, R 1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 carbocyclyl, each of which is C 1-6 Alkyl, halogen, -CN, -OR 9 , and -SR 9 or C 3-6 Carbocyclyl, 5-6 membered heterocyclyl, C 5-6 one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is 1-6 Alkyl, halogen, -CN, -OR 9 , -SR9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 or -C(O)OR 9 Optionally substituted with one or more groups optionally substituted with one or more substituents selected from:

[0010] In some embodiments, R 1 is C 1-6 Alkyl, halogen, -CN, -OR 9 , and -SR 9 or C 3-6 Carbocyclyl, 5-6 membered heterocyclyl, C 5-6 one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is 1-6 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 or -C(O)OR 9 and optionally substituted with one or more substituents selected from: 1-6 It is alkyl.

[0011] In some embodiments, R 1 is optionally selected from methyl, ethyl, propyl, or isopropyl; 1-6 It is alkyl.

[0012] In some embodiments, R 1 is halogen, -CN, -OR 9 , -C(O)R 9 , -C(O)NR 9 R 10 , C(O)SR 9 , or -C(O)OR 9 C replaced with 1-6 alkyl, and optionally R 9 is methyl.

[0013] In some embodiments, R 1 is C substituted with an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 3- to 6-membered heterocyclyl 1-6 It is alkyl.

[0014] In some embodiments, R 1 teeth, [ka] C substituted with 3- to 6-membered heterocyclyl selected from 1-4 It is alkyl.

[0015] In some embodiments, R 1 is an optionally substituted C 1-6 Carbocyclyl-substituted C 1-6 It is alkyl.

[0016] In some embodiments, R 1 is C 1-6 Carbocyclyl-substituted C 1-4 alkyl, optionally C 1-6 Carbocyclyl is selected from optionally substituted cyclobutyl or optionally substituted cyclopropyl.

[0017] In some embodiments, R 1 teeth, [ka] is.

[0018] In some embodiments, R 3 is H.

[0019] In some embodiments, q is 0 or 1.

[0020] In some embodiments, the compounds defined herein have the structure of Formula (Va), (Vb), or (Vc): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0021] In some embodiments, R 4 is halogen, hydroxy, optionally substituted C 2-8 Alkoxyalkyl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 , and -NO2.

[0022] In some embodiments, R 4 is selected from halogen, —CN, and —NO 2 , and optionally halogen is F.

[0023] In some embodiments, the compounds defined herein have the structure of formula (VI): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0024] In some embodiments, the compounds defined herein have the structure of Formula (VIa), (VIb), or (VIc): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0025] In some embodiments, R 5 is H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 2-8 It is an alkoxyalkyl.

[0026] In some embodiments, R 5 is H.

[0027] In some embodiments, R 6 is C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 3-10 Carbocyclyl, C 1-10 Alkyl, C 2-10 Alkenyl, or C 2-10 alkynyl, each of which is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11)2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and two adjacent optional substituents, when present, together with the atom to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl.

[0028] In some embodiments, R 6 is selected from optionally substituted C6 aryl, optionally substituted 5-membered heteroaryl, and optionally substituted 6-membered heteroaryl.

[0029] In some embodiments, R 6 teeth, [ka] each of which may be optionally substituted.

[0030] In some embodiments, R 6 teeth, [ka] each of which may be optionally substituted.

[0031] In some embodiments, R 6 The optional substituents of are halogen, optionally substituted 5-membered heterocyclyl, optionally substituted 5-membered heteroaryl, -C(O)OR 11 , -N(R 11 )S(O)2R 11 , -C(O)N(R 11 )2, and -S(O)2N(R 11 )2 is one or more substituents selected from

[0032] In some embodiments, the compounds defined herein are [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0033] In some embodiments, the compounds defined herein are [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0034] In some embodiments, the compounds defined herein are [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0035] In some embodiments, R 6 is an optionally substituted 3- to 10-membered heterocyclyl and optionally substituted C 3-10 carbocyclyl.

[0036] In some embodiments, R 6 The optional substituents of are halogen and —C(O)OR 11and optionally one or more substituents selected from R 11 is H or optionally substituted C 1-6 It is alkyl.

[0037] In some embodiments, the compounds defined herein are [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0038] In some embodiments, R 6 and R 5 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and optionally substituted with one or more substituents optionally selected from:

[0039] In some embodiments, R 6 The optional substituents of are halogen and —C(O)OR 11and optionally one or more substituents selected from R 11 is H or optionally substituted C 1-6 It is alkyl.

[0040] In some embodiments, the compounds defined herein have the structure: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0041] The following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is [ka] is.

[0043] Also provided is a pharmaceutical composition comprising a compound defined herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0044] Also provided is a method for treating and / or preventing a disease, disorder, or condition mediated by a proton-activated GPCR in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition defined herein.

[0045] There is also provided the 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.

[0046] Also provided is 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.

[0047] In some embodiments, the proton-activated GPCR is GPR68 (OGR1).

[0048] 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.

[0049] In some embodiments, the disease, disorder, or condition is an inflammatory disease, disorder, or condition, hi some embodiments, the inflammatory disease, disorder, or condition is selected from focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.

[0050] In some embodiments, the inflammatory disease, disorder, or condition is an autoimmune disease, disorder, or condition, hi 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.

[0051] 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 hepatic fibrosis. In some embodiments, the fibrotic disease, disorder, or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial disease, cerebrovascular disease, chronic kidney disease, diabetic nephropathy, systemic sclerosis (scleroderma), hypertrophic scars, keloids, idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0052] In some embodiments, the disease, disorder, or condition is a proliferative disease, disorder, or condition, hi 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).

[0053] In some embodiments, the disease, disorder, or condition is cancer, hi some embodiments, the cancer is selected from 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.

[0054] In some embodiments, the subject is a human.

[0055] Also provided is a method of inhibiting a proton-activated GPCR in a cell, comprising administering to the cell an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition defined herein.

[0056] There is also provided the 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.

[0057] Also provided is a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition as defined herein, for use in inhibiting a proton-activated GPCR in a cell.

[0058] In some embodiments, the proton-activated GPCR is GPR68 (OGR1).

[0059] In some embodiments, the cell is a tumor cell. DETAILED DESCRIPTION OF THE INVENTION

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, cell culture, molecular biology, and pharmacology).

[0061] All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated.

[0062] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0063] 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 dictates otherwise. For example, the term "object" means "one or more objects" unless the context clearly dictates otherwise.

[0064] As used herein, the term "about" refers to a range of + / - 5% of the specified value.

[0065] Throughout this specification, various aspects and components of the present disclosure may be presented in a range format. The range format is included for convenience and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range, unless otherwise indicated. For example, recitation of a range such as 1 to 5 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., as well as individual and partial numbers within the recited range, e.g., 1, 2, 3, 4, 5, 5.5, and 6, unless an integer is required or implied by the context. This applies regardless of the breadth of the disclosed range. Where specific values ​​are required, they are provided herein.

[0066] It will be understood that throughout this specification the word "comprise" or variations such as "comprises" or "comprising" refer to the inclusion of a stated element, integer, or step, or group of elements, integers, or steps, but not to the exclusion of any other element, integer, or step, or group of elements, integers, or steps. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0067] The use of "or" or "and" means "and / or" unless stated otherwise.

[0068] The compounds of the present disclosure may exist as solvates. The term "solvate" refers to a compound formed by the interaction of a solvent with a compound described herein or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0069] The compounds of the present disclosure can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound and are not pharmaceutically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds disclosed herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups, or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic 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, and aluminum, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, and ethanolamine. Many such salts are known in the art, as described in WO87 / 05297, Johnston et al., published September 11, 1987 (incorporated herein by reference in its entirety).

[0070] As used herein, "C" refers to a group of integers where "a" and "b" are integers.a ~C b " or "C a-b " refers to the number of carbon atoms in the specified group. That is, the group may contain "a" to "b" carbon atoms inclusive. Thus, for example, "C1-C4 alkyl" or "C 1-4 An "alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0071] As used herein, the term "halogen" or "halo" means any one of the radiostable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0072] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also covers occurrences of the term "alkyl" where no numerical range is specified). An alkyl group can also be a medium-sized alkyl having 1 to 9 carbon atoms. An alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. An alkyl group can also be a "C 1-4 By way of example only, "C 1-4"Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0073] As used herein, "alkoxy" refers to the group alkyl, as defined above, containing at least one O atom, with at least one oxygen atom at the position where the alkoxy group is attached to the remainder of the compound. Non-limiting examples of suitable alkoxy groups include, for example, methoxy (-O-CH), ethoxy (-O-CH-CH), propoxy (-O-CH-CH-CH (straight chain alkyl) or -O-CH-(CH) (branched chain alkyl)), and -O-CH-CH-O-CH. An alkoxy can be substituted or unsubstituted. An alkoxy can be substituted or unsubstituted. In this regard, the term "haloalkoxy" as used herein refers to an "alkoxy" substituted with one or more halo, i.e., one or more of F, Cl, Br, or I. An example of a "haloalkoxy" is -OCF.

[0074] As used herein, "alkylthio" refers to the formula -SR, where R is a group selected from the group consisting of "C 1-9 "Alkylthio" is alkyl as defined above, including, but not limited to, methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, isobutyl mercapto, sec-butyl mercapto, tert-butyl mercapto, and the like.

[0075] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. Alkenyl groups can have from 2 to 20 carbon atoms, although this definition also covers occurrences of the term "alkenyl" where no numerical range is specified. Alkenyl groups can also be medium-sized alkenyls having from 2 to 9 carbon atoms. Alkenyl groups can also be lower alkenyls having from 2 to 4 carbon atoms. An alkenyl group is defined as "C 2-4 Alkenyl" or similar designations. By way of example only, "C 2-4 "Alkenyl" indicates that there are 2 to 4 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-1,2-dien-4-yl. Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0076] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. Alkynyl groups can have from 2 to 20 carbon atoms, although this definition also covers occurrences of the term "alkynyl" where no numerical range is specified. Alkynyl groups can also be medium-sized alkynyls having from 2 to 9 carbon atoms. Alkynyl groups can also be lower alkynyls having from 2 to 4 carbon atoms. An alkynyl group is defined as "C 2-4 By way of example only, "C 2-4"Alkynyl" indicates that there are 2 to 4 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 not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0077] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur, in the chain backbone. Heteroalkyl groups can have from 1 to 20 carbon atoms, although this definition also covers occurrences of the term "heteroalkyl" where no numerical range is specified. Heteroalkyl groups can also be medium size heteroalkyls having from 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having from 1 to 4 carbon atoms. Heteroalkyl groups are also referred to as "C 1-4 A heteroalkyl group may be designated as "heteroalkyl" or similar designation. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" indicates that the heteroalkyl chain has 1 to 4 carbon atoms and, in addition, one or more heteroatoms in the backbone of the chain.

[0078] As used herein, "alkylene" means a branched or straight-chain fully saturated diradical chemical group containing only carbon and hydrogen attached to the rest of the molecule through two points of attachment (i.e., alkanediyl). Alkylene groups can have from 1 to 20 carbon atoms, although this definition also covers occurrences of the term "alkylene" where no numerical range is specified. Alkylene groups can also be medium-sized alkylenes having from 1 to 9 carbon atoms. Alkylene groups can also be lower alkylenes having from 1 to 4 carbon atoms. An alkylene group is also referred to as a "C 1-4 By way of example only, "C 1-4"Alkylene" indicates that there are 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propane-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0079] As used herein, "alkenylene" refers to a straight or branched chain diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond attached to the rest of the molecule through two points of attachment. An alkenylene group can have from 2 to 20 carbon atoms, although this definition also covers occurrences of the term "alkenylene" where no numerical range is specified. An alkenylene group can also be a medium-sized alkenylene having from 2 to 9 carbon atoms. An alkenylene group can also be a lower alkenylene having from 2 to 4 carbon atoms. An alkenylene group can also be a "C 2-4 Alkenylene" or similar designations. By way of example only, "C 2-4 "Alkenylene" indicates that there are 2 to 4 carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, butene-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-ene- 1,1-diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-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-1,1-diyl.

[0080] 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 (e.g., pyridine) groups. 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.

[0081] 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) that contains only carbon in the ring backbone. When aryl is a ring system, all rings in the system are aromatic. Aryl groups can have from 6 to 18 carbon atoms, although this definition also covers occurrences of the term "aryl" where no numerical range is specified. In some embodiments, aryl groups have from 6 to 10 carbon atoms. An aryl group is defined as "C 6-10 aryl," "C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0082] As used herein, "aryloxy" and "arylthio" are defined as "C 6-10 aryloxy" or "C 6-10 "Arylthio" refers to RO- and RS- where R is aryl as defined above, including, but not limited to, phenyloxy.

[0083] "Aralkyl" or "arylalkyl" refers to, for example, "C 7-14 Aralkyl, etc., are aryl groups connected as substituents via alkylene groups, including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group may be a lower alkylene group (i.e., C 1-4 alkylene group).

[0084] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) containing one or more heteroatoms in the ring backbone, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, all rings in the system are aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also covers occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups can be designated as "5- to 7-membered heteroaryl," "5- to 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, isoquinrinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0085] Heteroaryl groups can be, for example, monocyclic or polycyclic (e.g., bicyclic). Polycyclic heteroaryls can, for example, contain fused rings. In bicyclic heteroaryl groups, there can be one or more heteroatoms in each ring, or there can be heteroatoms in only 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, and pyrimidinyl. Examples of bicyclic heteroaryl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.

[0086] A "heteroaralkyl" or "heteroarylalkyl" is a 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, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group may be a lower alkylene group (i.e., C 1-4 alkylene group).

[0087] As used herein, "carbocyclyl" refers to a non-aromatic ring or ring system containing only carbon atoms in the ring system backbone. When a carbocyclyl is a ring system, two or more rings can be linked together in a fused, bridged, or spiro-connected manner. A carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclyl group can have 3 to 20 carbon atoms, although this definition also covers occurrences of the term "carbocyclyl" where no numerical range is specified. A carbocyclyl group can also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group can also be a lower carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is defined as "C 3-6 Carbocyclyl may be designated as "carbocyclyl" or a similar designation. 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]nonanyl.

[0088] "(Carbocyclyl)alkyl" is, for example, "C 4-10 (carbocyclyl)alkyl" as a substituent is a carbocyclyl group connected via an alkylene group, 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.

[0089] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0090] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein the ring of the ring system is not aromatic. An example is cyclohexenyl.

[0091] As used herein, "heterocyclyl" refers to 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 manner. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom may be present in either the non-aromatic or aromatic ring of the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e., the number of atoms comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also covers occurrences of the term "heterocyclyl" where no numerical range is specified. Heterocyclyl groups may also be medium-sized heterocyclyls having 3 to 10 ring members. Heterocyclyl groups may also be heterocyclyls having 3 to 6 ring members. Heterocyclyl groups may be designated as "3- to 6-membered heterocyclyl" or similar designations. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from one to up to three of O, N, or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from one or two heteroatoms selected from O, N, or S.Examples of heterocyclyl rings include 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, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3-diox ...athiinyl, 1,4-oxathianyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl ,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.

[0092] Heterocyclyl groups can be, for example, monocyclic or polycyclic (e.g., bicyclic). Polycyclic heterocyclyls can, for example, contain fused rings. In bicyclic heterocyclyl groups, there can be one or more heteroatoms in each ring, or there can be a heteroatom in only one of the rings. Suitable nitrogen atom-containing heterocyclyl groups include the corresponding N-oxides. In one example, the heterocyclyl group is one of 3 to 10 atoms (i.e., a 3- to 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 benzazepanyl.

[0093] "(Heterocyclyl)alkyl" is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0094] As used herein, "acyl" refers to -C(O)R, where R is hydrogen, C, as defined herein. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0095] An "O-carboxy" group refers to an "-OC(O)R" group, where R is hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0096] A "C-carboxy" group refers to a "-C(O)OR" group, where R is hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., —C(O)OH).

[0097] A "cyano" group refers to a "-CN" group. A "cyanato" group refers to a "-OCN" group. An "isocyanato" group refers to a "-NCO" group. A "thiocyanato" group refers to a "-SCN" group. An "isothiocyanato" group refers to a "-NCS" group.

[0098] A "sulfinyl" group refers to a "-S(O)R" group, where R is hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0099] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0100] The "S-sulfonamide" group is "-SONR A R B " refers to R A and RB are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0101] An "N-sulfonamido" group is defined as "-N(R A )SO2R B " refers to R A and R B are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0102] The "O-carbamyl" group is "-OC(O)NR A R B " refers to the group R A and R B are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0103] The "N-carbamyl" group is defined as "-N(R A )OC(O)R B " refers to the group R A and R B are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0104] The "O-thiocarbamyl" group is "-OC(S)NR A R B " refers to the group R A and R B are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0105] The "N-thiocarbamyl" group is defined as "-N(R A )OC(S)R B " refers to the group R A and R B are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0106] The "amino" group is "-NR A R B " refers to the group R A and R B are each independently hydrogen, C, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, C 6-10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include free amino (i.e., -NH2).

[0107] An "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0108] The "alkoxyalkyl" group is defined as "C 2-8 "Alkoxyalkyl" refers to an alkoxy group connected via an alkylene group.

[0109] As used herein, a substituent is derived from an unsubstituted parent group with the replacement of one or more hydrogen atoms with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted," it means that the group is selected from the group consisting of C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C carbocyclyl (optionally substituted with halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy), C-C-carbocyclyl-C-C-alkyl (optionally substituted with halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy). substituted with haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C 1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), substituted with hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl,It means substituted with one or more substituents independently selected from N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," that group can be substituted with the above substituents.

[0110] It is understood that a particular radical naming convention can include either a monoradical or a diradical, depending on the context. For example, if a substituent requires two points of attachment to the rest of the molecule, the substituent is understood to be a diradical. For example, a substituent specified as alkyl, which requires two points of attachment, includes diradicals such as, for example, -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions explicitly indicate that the radical is a diradical, such as "alkylene" or "alkenylene."

[0111] When two R groups are said to form a ring "together with the atoms to which they are attached" (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), it is meant that the collective unit of atoms and the ring in which the two R groups are listed is not otherwise limited by the definition of each R group when taken individually. For example, the following substructure exists: [ka] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When they form a heterocyclyl together with the nitrogen to which they are attached, it is R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively the substructure has the structure: [ka] wherein ring A is meant to be the depicted nitrogen-containing heteroaryl ring.

[0112] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," it means that the collective unit of atoms, the intervening bond, and the two R groups is the recited ring. For example, the following substructure exists: [ka] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When they form an aryl or carbosilyl group together with the atom to which they are attached, it is R 1 may be selected from hydrogen or alkyl, or alternatively the substructure has the structure: [ka] wherein A is meant to be an aryl ring or carbosilyl containing the depicted double bond.

[0113] When the compounds disclosed herein contain at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within 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 within the scope of the compounds disclosed herein.

[0114] Those skilled in the art will recognize that some structures depicted herein may be resonance forms or tautomers of compounds that can be fairly, even kinetically, represented by other chemical structures, and that such structures may represent only a very small portion of a sample of such compounds. Although such resonance forms or tautomers are not represented herein, such compounds are considered to be within the scope of the depicted structures.

[0115] Isotopes may be present in the compounds described. Each chemical element represented in a compound structure may include any isotope of that 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 in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0116] As used herein, the terms "modulate," "modulator," and "modulation" of a proton-activated GPCR are intended to encompass antagonism, agonism, partial antagonism, and / or partial agonism of 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 the inhibition of proton-activated GPCR activity.

[0117] A "patient" or "subject" to be treated by the methods described herein can mean either a human or a non-human animal, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein 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 and fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease, disorder, or condition. Whether human or non-human, a subject may be referred to as an individual, subject, animal, host, or recipient, as well as a patient.

[0118] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0119] 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 commonly used in the art may be included. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Oilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0120] A therapeutic effect alleviates, to some extent, one or more of the symptoms of a disease or condition, including curing the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated, although certain long-term or permanent effects (such as extensive tissue damage) may exist even after a cure is achieved.

[0121] As used herein, "treat," "treatment," or "treating" refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. "Prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of the disease, disorder, or condition, but who is susceptible to or otherwise at risk for a particular disease, disorder, or condition, whereby 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 who already suffers from a disease, disorder, or condition.

[0122] As used herein, the term "at risk" refers to a higher probability of developing a disease, disorder, or condition described herein than the general population. Thus, treatment of an individual considered to be "at risk" of a particular condition is designed to prevent the subject from 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 the general population as a whole.

[0123] As used herein, "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 may range from nanomolar to micromolar concentrations, e.g., from about 1 nM to about 1,000 μM. One of ordinary skill in the art will recognize that achieving these concentrations in vivo will depend in part on the pharmacokinetics of the exact compound selected. Thus, in some embodiments, the dose may range from about 1 mg / kg to about 1,000 mg / kg, in other embodiments from about 10 mg / kg to about 500 mg / kg, and in still other embodiments from about 50 mg / kg to about 250 mg / kg, including all amounts therebetween.

[0124] As used herein, "co-administration" and like terms are meant to encompass the administration of a compound described herein and an additional therapeutic agent to a single patient, and are intended to include treatment regimens in which the compound and agent are administered by the same or different routes of administration, or at the same or different times.

[0125] Throughout this specification, unless specifically stated otherwise or unless the context otherwise requires, a reference to a single step, composition of matter, group of steps, or group of compositions of matter is intended to encompass one and more (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter.

[0126] Those skilled in the art will understand that the disclosure set forth herein may be subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The present disclosure also includes all and any and all combinations of the steps, features, compositions, and compounds referred to or shown herein, individually or collectively, or any two or more of such steps or features.

[0127] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for purposes of illustration only. Functionally equivalent products, compositions, and methods are clearly within the scope of the present disclosure as described herein.

[0128] It will be understood by those 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, and the present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0129] Compounds of the Disclosure The present disclosure is directed, in part, to compounds that are modulators, such as inhibitors, of proton-activated GPCRs, e.g., GPR68 (OGR1), enabling the compounds to be useful in the prevention, 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.

[0130] Thus, in one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, X is N and NR 1 is selected from Y is N and NR 2 is selected from R 1and R 2 However, independently, H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 or C 3-6 one or more groups selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 optionally substituted with one or more groups optionally substituted with one or more substituents selected from Alternatively, R 1 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is optionally substituted C 1-10 Alkyl, halogen, -CN, -OR 9, -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from Each R 9 are independently H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl; Each R 10 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and -C(O)R 9 is selected from R 3 is H, halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 5-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 -NO2, and -NO2; or R 3 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is C 1-10Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from q is an integer of 0 to 3, R 4 is halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 6-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 and -NO2; R 5 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-6 Carbocyclyl, optionally substituted C 5-10 selected from aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 5- to 6-membered heterocyclyl; L is a bond or -C(O)N(R 9 a linker selected from -S(O)-, -S(O)2-, -C(O)-, or -C(O)O-, or an optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, -OC 1-4 Alkylene or -OC 2-4 a linker selected from alkenylene, each of which is —O—, —S—, —NR 9 -, -NR 10 -, -C(O)N(R 9 )-, -N(R 9 )C(O)-, -S(O)2-, -N(R 9 )S(O)2-, -S(O)2N(R 9 a linker optionally interrupted by -C(O)-, -C(O)-, -C(O)O-, or -O(O)C-; R 6 But C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 3-10 Carbocyclyl, C 1-10 Alkyl, C 2-10 Alkenyl, or C 2-10 alkynyl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11, -C(O)N(R 11 )2, or -C(O)SR 11 and two adjacent optional substituents, if present, together with the atom to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl; or R 6 and R 5 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and optionally substituted with one or more substituents which may be selected from Each R 11 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkyni, optionally substituted C 5-10 Aryl, optionally substituted C 2-20 Alkoxyalkyl, C1-C6 haloalkyl, -C(O)R 9 , -OR 9, -S(O)2R 9 , and -S(O)N(R 9 )2 is selected, R 7 and R 8 However, independently, H, C 1-6 Alkyl, C 5-10 Aryl, 5- to 10-membered heteroaryl, and C 3-10 carbocyclyl, each of which is selected from C 1-6 Alkyl, C 5-6 Aryl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from The present invention provides a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is an integer from 1 to 4.

[0131] In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1 and the compound has the structure of Formula (Ia): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0132] In some embodiments, the compound has the structure of Formula (II): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0133] In some embodiments, the compound has the structure of Formula (IIa): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, In the formula, X is NR 1 and Y is N.

[0134] In other embodiments, the compound has the structure of Formula (IIb): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is N and Y is NR 2 is.

[0135] In some embodiments, R 1 and R 2 are independently H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 carbocyclyl, each of which is selected from C 1-6 Alkyl, halogen, -CN, -OR 9 , and -SR 9 or C 3-6 Carbocyclyl, 5-6 membered heterocyclyl, C 5-6 one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is 1-6 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9, =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 Optionally substituted with one or more groups optionally substituted with one or more substituents selected from:

[0136] In some embodiments, R 1 and / or R 2 is C 1-6 Alkyl, halogen, -CN, -OR 9 , and -SR 9 or C 3-6 Carbocyclyl, 5-6 membered heterocyclyl, C 5-6 one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is 1-6 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from 1-6 It is alkyl.

[0137] In some embodiments, R 1 and / or R 2 is optionally selected from methyl, ethyl, propyl, or isopropyl; 1-6 It is alkyl.

[0138] In some embodiments, R 1 and / or R 2is halogen, -CN, -OR 9 , -C(O)R 9 , -C(O)NR 9 R 10 , C(O)SR 9 , or -C(O)OR 9 C is replaced by 1-6 alkyl, and optionally R 9 is methyl.

[0139] In some embodiments, R 1 and / or R 2 is substituted with an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 3- to 6-membered heterocyclyl 1-6 It is alkyl.

[0140] In some embodiments, R 1 and / or R 2 is a C substituted with a 3- to 6-membered heterocyclyl selected from the following: 1-4 is alkyl, [ka] Each of these can be optionally substituted.

[0141] As will be apparent to one of skill in the art, optionally substituted heterocyclyl groups, if present, can have defined stereochemistry at one or more chiral centers. For example, in some embodiments, R 1 and / or R 2 is a C substituted with a 3- to 6-membered heterocyclyl selected from the following: 1-4 is alkyl, [ka] Each of these can be optionally substituted.

[0142] In some embodiments, R 1 and / or R 2 is an optionally substituted C 1-6Carbocyclyl-substituted C 1-6 In some embodiments, R 1 and R 2 are independently H and C 1-6 Carbocyclyl-substituted C 1-4 alkyl, and optionally C 1-6 Carbocyclyl is selected from optionally substituted cyclobutyl or cyclopropyl. In some embodiments, R 1 and / or R 2 teeth, [ka] is.

[0143] In various embodiments, the compound of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 But H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 or C 3-6one or more groups selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 optionally substituted with one or more groups optionally substituted with one or more substituents selected from Alternatively, R 1 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is optionally substituted C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from Each R 9 are independently H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl; Each R 10 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and -C(O)R 9is selected from R 3 is H, halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 5-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 -NO2, and -NO2; or R 3 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from q is an integer of 0 to 3, R 4 is halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 6-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 and -NO2; R 5 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-6 Carbocyclyl, optionally substituted C 5-10 selected from aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 5- to 6-membered heterocyclyl; L is a bond or -C(O)N(R 9 )-, -S(O)2-, -C(O)-, or -C(O)O-, or optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, -OC 1-4 Alkylene or -OC 2-4 alkenylene, each of which is —O—, —S—, —NR 9 -, -NR 10 -, -C(O)N(R 9 )-, -N(R 9 )C(O)-, -S(O)2-, -N(R 9 )S(O)2-, -S(O)2N(R 9 )-, -C(O)-, -C(O)O-, or -O(O)C-; R 6 But C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C3-10 Carbocyclyl, C 1-10 Alkyl, C 2-10 Alkenyl, or C 2-10 alkynyl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and two adjacent optional substituents, if present, together with the atom to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl; or R 6 and R 5 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and optionally substituted with one or more substituents which may be selected from Each R 11 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkyni, optionally substituted C 5-10 Aryl, optionally substituted C 2-20 Alkoxyalkyl, C1-C6 haloalkyl, -C(O)R 9 , -OR 9 , -S(O)2R 9 , and -S(O)N(R 9 )2 is selected, R 7 and R 8 However, independently, H, C 1-6 Alkyl, C 5-10 Aryl, 5- to 10-membered heteroaryl, and C 3-10 carbocyclyl, each of which is selected from C 1-6 Alkyl, C 5-6 Aryl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, optionally substituted with one or more substituents selected from:

[0144] In some embodiments, R 7 and R 8 independently, C 1-6 Alkyl, C 5-10 Aryl, 5- to 10-membered heteroaryl, and C 3-10 carbocyclyl, each of which is selected from C 1-6 Alkyl, C 5-6 Aryl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 is optionally substituted with one or more substituents selected from:

[0145] In some embodiments, R 7 and R 8 is H and the compound has the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0146] In some embodiments, R 1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 carbocyclyl, each of which is C 1-6 Alkyl, halogen, -CN, -OR 9 , and -SR 9or C 3-6 Carbocyclyl, 5-6 membered heterocyclyl, C 5-6 one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is 1-6 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 or -C(O)OR 9 Optionally substituted with one or more groups optionally substituted with one or more substituents selected from:

[0147] In some embodiments, R 1 is C 1-6 Alkyl, halogen, -CN, -OR 9 , and -SR 9 or C 3-6 Carbocyclyl, 5-6 membered heterocyclyl, C 5-6 one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is 1-6 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 or -C(O)OR 9 and optionally substituted with one or more substituents selected from: 1-6 It is alkyl.

[0148] In some embodiments, R 1 is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl, or isopropyl.

[0149] In some embodiments, R 1 is halogen, -CN, -OR 9 , -C(O)R 9 , -C(O)NR 9 R 10 , C(O)SR 9 , or -C(O)OR 9 C replaced with 1-6 alkyl, and in some embodiments, R 9 is methyl.

[0150] In some embodiments, R 1 is C substituted with an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 3- to 6-membered heterocyclyl 1-6 alkyl. For example, R 1 teeth, [ka] C substituted with 3- to 6-membered heterocyclyl selected from 1-4 It can be alkyl.

[0151] As will be apparent to one of skill in the art, optionally substituted heterocyclyl groups, if present, can have defined stereochemistry at one or more chiral centers. For example, in some embodiments, R 1 teeth, [ka] C substituted with 3- to 6-membered heterocyclyl selected from1-4 It is alkyl.

[0152] In some embodiments, R 1 is an optionally substituted C 1-6 Carbocyclyl-substituted C 1-6 In some embodiments, R 1 is C 1-6 Carbocyclyl-substituted C 1-4 alkyl, optionally C 1-6 Carbocyclyl is selected from optionally substituted cyclobutyl or optionally substituted cyclopropyl.

[0153] In some embodiments, R 1 teeth, [ka] is.

[0154] In other embodiments, R 1 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is optionally substituted C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 is optionally substituted with one or more substituents selected from:

[0155] In some embodiments, R 3 is an optionally substituted C, such as halogen, hydroxy, or -CF or -CHCF.1-6 In some embodiments, R 3 is C 1-4 In some embodiments, R 3 is an optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl or optionally substituted C 5-10 In some embodiments, R 3 -CN, -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 or -NO. In some embodiments, R 3 -SR 9 , -NR 9 R 10 or -OR, such as, for example, -OMe or -OCF 9 is.

[0156] In some embodiments, R 3 is H.

[0157] In some embodiments, R 3 and R 2 together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 is optionally substituted with one or more substituents selected from:

[0158] In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, q is 0.

[0159] In some embodiments, q is 0 or 1. In some embodiments, the compound has the structure of Formula (Va), (Vb), or (Vc): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0160] In some embodiments, R 4 is halogen, hydroxy, optionally substituted C 2-8 Alkoxyalkyl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 , and -NO2.

[0161] In some embodiments, R 4 is selected from halogen, —CN, and —NO. In some embodiments, R 4 is halogen. In some embodiments, R 4 is F.

[0162] In some embodiments, L is —C(O)N(R 9 a linker selected from -S(O)-, -S(O)2-, -C(O)-, or -C(O)O-, or an optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, -OC 1-4 Alkylene or -OC 2-4 a linker selected from alkenylene, each of which is —O—, —S—, —NR 9 -, -NR10 -, -C(O)N(R 9 )-, -N(R 9 )C(O)-, -S(O)2-, -N(R 9 )S(O)2-, -S(O)2N(R 9 In certain embodiments, the linker is selected from -S(O)2-, -C(O)-, -C(O)O-. In certain embodiments, the linker is optionally interrupted by an optionally substituted C(O)-, -C(O)-, -C(O)O-, or -O(O)C-. 1-4 In certain embodiments, the linker is a C(O)-, C(O)-, C(O)O-, or C(O)C- interrupted by -S(O)-, -C(O)-, -C(O)O-, or -O(O)C-. 1-4 It is alkylene.

[0163] In some embodiments, L is a bond and the compound has the structure of formula (VI): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0164] In some embodiments, q is 0 or 1. In some embodiments, the compound has the structure of Formula (VIa), (VIb), or (VIc): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0165] In some embodiments, R 4 is halogen, hydroxy, optionally substituted C 2-8 Alkoxyalkyl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9, and -NO2.

[0166] In some embodiments, R 4 is selected from halogen, —CN, and —NO 2 . In some embodiments, halogen is F.

[0167] In some embodiments, R 5 is H, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 2-8 It is an alkoxyalkyl.

[0168] In some embodiments, R 5 is H.

[0169] In some embodiments, R 6 is C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 3-10 Carbocyclyl, C 1-10 Alkyl, C 2-10 Alkenyl, or C 2-10 alkynyl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and two adjacent optional substituents, when present, together with the atom to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl.

[0170] In some embodiments, R 6 is an optionally substituted C 5-10 It is selected from aryl and optionally substituted 5-10 membered heteroaryl.

[0171] In some embodiments, R 6 is an optionally substituted C, such as, for example, phenyl, naphthyl, or azulenyl. 5-10 aryl, each of which may be optionally substituted. In some embodiments, R 6 is an optionally substituted phenyl.

[0172] In some embodiments, R 6is an optionally substituted 5-10 membered heteroaryl. In some embodiments, the 5-10 membered heteroaryl is a monocyclic heteroaryl such as, for example, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, or pyrimidinyl, each of which can be optionally substituted. In some embodiments, the 5- to 10-membered heteroaryl is a bicyclic heteroaryl such as, for example, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole, each of which can be optionally substituted.

[0173] In certain embodiments, R 6 is an optionally substituted C6 aryl, an optionally substituted 5-membered heteroaryl, or an optionally substituted 6-membered heteroaryl.

[0174] In certain embodiments, R 6 teeth, [ka] is selected from Each of these can be optionally substituted.

[0175] In certain embodiments, R 6 teeth, [ka] is selected from Each of these can be optionally substituted.

[0176] In some embodiments, C 5-10The above R is selected from aryl, or 5- to 10-membered heteroaryl. 6 The groups are independently optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, and -C(O)SR 11 and two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl. In some embodiments, the one or more substituents are selected from the group consisting of halogen, optionally substituted 5-membered heterocyclyl, optionally substituted 5-membered heteroaryl, -C(O)OR 11 , -N(R 11 )S(O)2R 11 , -C(O)N(R 11 )2, and -S(O)2N(R 11 )2.

[0177] In some embodiments, R 6 is an optionally substituted 3- to 10-membered heterocyclyl and optionally substituted C 3-10 carbocyclyl.

[0178] In some embodiments, R 6 is selected from optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, the 3- to 10-membered heterocyclyl is a monocyclic heterocyclyl such as, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, or piperidinonyl, each of which can be optionally substituted. In some embodiments, the 3- to 10-membered heterocyclyl is a bicyclic heterocyclyl such as dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, or benzazepanyl, each of which can be optionally substituted.

[0179] In some embodiments, R 6 is, for example, a C cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bicycle[2.2.2]octanyl, adamantyl, norbornyl, or spiro[4.4]nonanyl. 3-10 carbocyclyl, each of which may be optionally substituted.

[0180] In some embodiments, optionally substituted 3- to 10-membered heterocyclyl and optionally substituted C 3-10 The above R is selected from carbocyclyl 6 The groups are independently optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, and -C(O)SR 11 and two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl. In some embodiments, the one or more substituents are halogen, —CN, —NO, and —C(O)OR. 11 wherein R 11 is H or optionally substituted C 1-6 In some embodiments, one or more of the substituents may be a halogen, —C(O)OH, or —C(O)OC. 1-6 It is alkyl.

[0181] In some embodiments, R 6 and R 5 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and optionally substituted with one or more substituents which may be selected from:

[0182] In some embodiments, R 6 and R 5 together with the atoms to which they are attached form an optionally substituted 3- to 10-membered heterocyclyl. The optionally substituted 3- to 10-membered heterocyclyl can be, for example, a monocyclic heterocyclyl such as aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, or azepanyl, each of which can be optionally substituted. Alternatively, the optionally substituted 3- to 10-membered heterocyclyl can be, for example, a bicyclic heterocyclyl such as dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzazepanyl, each of which can be optionally substituted.

[0183] In some embodiments, R 6 and R 5together with the atom to which they are attached form an optionally substituted 5-10 membered heteroaryl. In some embodiments, the optionally substituted 5-10 membered heteroaryl is a monocyclic heteroaryl such as, for example, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl, each of which can be optionally substituted. In some embodiments, the optionally substituted 5-10 membered heteroaryl is a bicyclic heteroaryl such as, for example, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole, each of which can be optionally substituted.

[0184] In some embodiments, R, together with the atoms to which they are attached, are selected from optionally substituted 3- to 10-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl. 6 and R 5 The group formed by 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, and -C(O)SR 11 In some embodiments, the one or more substituents are selected from the group including halogen, —CN, —NO, and —C(O)OR. 11 wherein R 11 is H or optionally substituted C 1-6 In some embodiments, one or more of the substituents may be a halogen, —C(O)OH, or —C(O)OC. 1-6 It is alkyl.

[0185] In some embodiments, R 6 is an optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 alkynyl.

[0186] In some embodiments, R 6 is an optionally substituted C 1-10 In some embodiments, C 1-10 Alkyl is a branched C 1-10 It is alkyl.

[0187] In some embodiments, R 6 is an optionally substituted C 2-10 In some embodiments, C is alkenyl. 2-10 Alkenyl is a branched C 2-10 It is alkenyl.

[0188] In some embodiments, R 6 is an optionally substituted C 2-10 In some embodiments, C is alkynyl. 2-10 Alkynyl is a branched C 2-10 It is alkynyl.

[0189] In some embodiments, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, and optionally substituted C 2-10 The above R is selected from alkynyl 6 The groups are independently optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, and -C(O)SR 11 In some embodiments, one or more of the substituents is substituted with one or more substituents selected from the group comprising: -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, and -C(O)SR 11 is selected from the group consisting of:

[0190] In some embodiments, the disclosure provides a compound selected from the following structures: [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15

[0191] In some embodiments, the compound of the present disclosure is selected from any of compounds 1-19, 23, 25, 36, 38, 54, 56, 62, and 68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound of the present disclosure is selected from any of compounds 1-14, 16-18, 23, 25, 36, 54, 56, and 62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound of the present disclosure is selected from any of compounds 1-14 and 56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound of the present disclosure is selected from any of compounds 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound of the present disclosure is compound 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound of the present disclosure is selected from any of compounds 19, 38, and 68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound of the present disclosure is compound 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0192] In some embodiments, the present disclosure provides a structure [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound or pharmaceutically acceptable salt, the compound has the formula: [ka] is.

[0193] In some embodiments, the present disclosure provides a structure [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound or pharmaceutically acceptable salt, the compound has the formula: [ka] is.

[0194] In some embodiments, the present disclosure provides a structure [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound or pharmaceutically acceptable salt, the compound has the formula: [ka] is.

[0195] In some embodiments, the present disclosure provides a structure [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound or pharmaceutically acceptable salt, the compound has the formula: [ka] is.

[0196] In some embodiments, the present disclosure provides a structure [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound or pharmaceutically acceptable salt, the compound has the formula: [ka] is.

[0197] In some embodiments, the present disclosure provides a structure [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound or pharmaceutically acceptable salt, the compound has the formula: [ka] is.

[0198] The compounds of the present disclosure may be provided in the form of their salts, preferably pharmaceutically acceptable salts, solvates, and / or stereoisomers. In some embodiments, the compounds of the present disclosure may be provided in the form of their pharmaceutically acceptable salts.

[0199] Preparation of compounds The compounds disclosed herein can be synthesized by the methods described below or by modifications of these methods. Modifications to the methodology include, among other things, temperatures, solvents, reagents, and the like, known to those skilled in the art. Generally, during any of the processes for the preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved using 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. Hutts, Protecting Groups in Organic Synthesis (3rd ed.), Wiley, New York (1999), both of which are incorporated herein by reference in their entirety. Protecting groups can be removed at a convenient later stage using methods known in the art. Synthetic chemical transformations useful for synthesizing applicable compounds are known in the art and include, for example, 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, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended to, and should not be construed to, limit the scope of the claims in any way. Those of skill in the art will recognize modifications of the disclosed compounds and will be able to devise alternative routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims.

[0200] Pharmaceuticals and Compositions and Administration While the compounds of the present disclosure can be administered as the raw chemical, it is also possible to present them as pharmaceutical formulations.

[0201] Thus, the present disclosure provides pharmaceutical compositions 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 must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Appropriate formulations depend on the chosen route of administration. Any of the well-known techniques, carriers, and excipients are suitable and can be used as understood in the art, for example, in Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present disclosure can be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0202] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and ocular) administration, although the most suitable route will depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may 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 (the "active ingredient"), with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0203] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0204] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and 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 a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can be formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. The sugar-coated core is provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or sugar-coated tablets for identification or to characterize different combinations of active compound doses.

[0205] The compounds can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. Injectable formulations can be presented in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating 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 be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0206] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0207] In addition to the above-mentioned formulations, the compound of the present disclosure can also be formulated as depot preparation.Such long-acting formulations can be administered by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection.Therefore, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0208] The compounds may 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 may also be formulated in vaginal compositions as gels, suppositories, or dendrimer conjugates.

[0209] The compounds of the present disclosure can be administered topically, i.e., non-systemically. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration into the skin, such as gels, liniments, lotions, creams, ointments, or pastes.

[0210] Gels for topical or transdermal administration of compounds of the present disclosure may contain a mixture of a volatile solvent, a non-volatile solvent, and water. The volatile solvent component of the buffer solvent system may preferably include a lower (Cl-C6) alkyl alcohol, a lower alkyl glycol, and a lower glycol polymer. More preferably, the volatile solvent is ethanol. The volatile solvent component is believed to act as a penetration enhancer while also providing a cooling effect on the skin as it evaporates. The non-volatile solvent portion of the buffer solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol is used. The non-volatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffer solvent system. The amount of this non-volatile solvent component, as well as the volatile solvent, is determined by the pharmaceutical compound or drug used. If there is too little non-volatile solvent in the system, the pharmaceutical compound may crystallize due to evaporation of the volatile solvent, while an excess will result in a lack of bioavailability due to insufficient release of the drug from the solvent mixture. The buffer component of the buffer solvent system may be selected from any buffer commonly used in the art, and preferably, water is used. There are several optional ingredients that can be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents can include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, as well as cosmetic agents.

[0211] Lotions or liniments for application to the skin may also contain agents that promote drying and cooling of the skin, such as alcohol or acetone, and / or moisturizers, such as glycerol, or oils, such as castor oil or peanut oil.

[0212] Creams, ointments, or pastes according to the present disclosure are semi-solid formulations of the active ingredient for external application. They can be prepared by mixing the active ingredient in finely divided or powdered form with an oily or non-oily base using a suitable machine, either alone or in solution or suspension in an aqueous or non-aqueous fluid. The base can include hydrocarbons such as hard, soft, or liquid paraffin, glycerol, beeswax, and metal soaps; mucilage; natural oils such as almond, corn, peanut, castor, or olive oil; steric acids or fatty acids such as oleic acid, together with alcohols such as wool fat or its derivatives, or propylene glycol, or macrogels. The formulation can incorporate any suitable surface active agent, such as anionic, cationic, or nonionic surfactants, such as sorbitan esters or their polyoxyethylene derivatives. Suspending agents such as natural gums, cellulose derivatives, or inorganic materials such as silica, and other ingredients such as lanolin, can also be included.

[0213] How to use Without being bound by theory, compounds of the present disclosure have been found to modulate, and optionally inhibit, proton-activated GPCRs such as GPR68 (OGR1).

[0214] Accordingly, in one aspect, the present disclosure provides methods for 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 disclosed herein. The method may include identifying a subject at risk for or having a disease, disorder, or condition mediated by a proton-activated GPCR, and administering to the subject an effective amount of the compound for therapeutic or prophylactic treatment.

[0215] 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).

[0216] Proton-activated GPCRs such as GPR68 (OGR1), GPR4 (GPR4), and GPR65 (TDAG8) are involved in regulating key processes in inflammation, tumor biology, and fibrosis.

[0217] Thus, in some embodiments, the proton-activated GPCR-mediated disease, disorder, or condition is an inflammatory, fibrotic, or proliferative disease, disorder, or condition, hi certain embodiments, the disease, disorder, or condition is cancer.

[0218] In some embodiments, the compounds and methods provided herein are useful for treating an inflammatory disease, disorder, or condition.

[0219] Generally, the inflammatory disease, disorder, or condition treatable with the compounds disclosed herein relates to any disease, disorder, or condition characterized by an abnormal, irregular, excessive, incorrect, or inappropriate inflammatory response.

[0220] In some embodiments, the inflammatory disease, disorder, or condition is the result of damage to tissue, hi some embodiments, the inflammatory disease, disorder, or condition is the result of an autoimmune condition, while in further embodiments, the inflammatory disease, disorder, or condition is the result of a bacterial or viral infection or the presence of a toxin.

[0221] The compounds provided herein may have anti-inflammatory and / or immunomodulatory activity and may be used to treat a variety of conditions, including septic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infections, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, transplant rejection, cancer such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Beche's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, and the like. The compounds and methods provided herein may be useful in treating diseases, disorders, or conditions, including, but not limited to, sciatica, complex regional pain syndrome, radiation injury, hyperoxic alveolar damage, 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, stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, idiopathic fibrosing alveolitis, 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.

[0222] 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 non-alcoholic steatohepatitis (NASH).

[0223] 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.

[0224] In some embodiments, the inflammatory disease, disorder, or condition is focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis.

[0225] 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.

[0226] In some embodiments, the compounds and methods provided herein are useful for treating a fibrotic disease, disorder, or condition.

[0227] "Fibrotic condition," "fibrotic disease," and "fibrotic disorder" are used interchangeably to refer to conditions, diseases, or disorders characterized by dysregulated fibroblast proliferation or activity, and / or abnormal accumulation of fibronectin, and / or pathological or excessive accumulation of collagenous tissue. Fibrotic disorders include, but are not limited to, renal fibrosis, dermal fibrosis, pancreatic fibrosis, hepatic fibrosis (e.g., hepatic fibrosis associated with chronic active hepatitis), and pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiology.

[0228] In some embodiments, the fibrotic disease, disorder, or condition is renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, dermal fibrosis, pancreatic fibrosis, or hepatic fibrosis.

[0229] In some embodiments, fibrotic diseases, disorders, or conditions suitable for treatment by the methods provided herein include, but are not limited to, kidney diseases such as progressive glomerular kidney disease, glomerulonephritis, and diabetic nephropathy; lung diseases such as pulmonary fibrosis; fibrotic skin disorders such as keloids, hypertrophic scars, and scleroderma; heart diseases such as ischemic heart disease, valvular heart disease, and hypertensive heart disease, diabetic cardiomyopathy, and heart failure due to hypertension; and liver diseases such as hepatic fibrosis.

[0230] In certain embodiments, the fibrotic disease, disorder, or condition is kidney disease. In some embodiments, kidney disease can include, but is not limited to, progressive glomerular kidney disease, including, but not limited to, diabetic nephropathy (e.g., as a result of type 1 or type 11 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 nephritis). In some embodiments, kidney disease can include progressive kidney disease primarily of tubulointerstitial origin. In some embodiments, kidney disease can include, for example, chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0231] In some embodiments, fibrotic diseases, disorders, or conditions suitable for treatment with the methods provided herein include, but are not limited to, diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial 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 sclerosing cholangitis (PSC).

[0232] In some embodiments, the compounds and methods provided herein are useful for treating a proliferative disease, disorder, or condition.

[0233] Generally, proliferative diseases, disorders, or conditions treatable with the compounds disclosed herein relate to any disease, disorder, or condition characterized by abnormal cell proliferation. Cell proliferation can be autogenic and include inappropriate or excessive wound healing responses. Cell proliferation can increase the influx of inflammatory cytokines and inflammatory cells, and is therefore associated with inflammation and / or degeneration.

[0234] Proliferative diseases, disorders, or conditions treatable with the compounds disclosed herein include, but are not limited to, various retinopathies.

[0235] In some embodiments, 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).

[0236] Proliferative diseases, disorders, or conditions treatable with the compounds disclosed herein further include, but are not limited to, various tumors and cancers, benign or malignant, metastatic or non-metastatic.

[0237] Cancers treatable with the compounds disclosed herein include a variety of cancers, including breast cancer, skin cancer, ovarian cancer, renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, lung squamous cell carcinoma, and adenocarcinoma, among others.

[0238] In some embodiments, the cancer is characterized by the presence of one or more tumors in a subject. Examples of cancers suitable for treatment with 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 cell lung cancer, Merkel cell carcinoma, sarcoma, hepatocellular carcinoma, multiple myeloma, pancreatic cancer, colorectal cancer, cervical cancer, gastric cancer, kidney cancer, metastatic renal cell carcinoma, leukemia, ovarian cancer, and malignant glioma. In certain embodiments, the cancer is metastatic melanoma, metastatic prostate cancer, or metastatic breast cancer. In some embodiments, the subject has received an allogeneic tissue transplant associated with cancer treatment, for example, after a hematopoietic stem cell transplant used to treat leukemia.

[0239] In some embodiments, cancers suitable for treatment with the compounds and methods provided herein are 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.

[0240] In some embodiments, the subject is a human.

[0241] As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to cure, ameliorate, slow the progression of, prevent, or reduce the likelihood of onset of a specified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. This effect may be detected, for example, by the assays disclosed in the Examples below. The precise effective amount for a subject will depend upon the subject's 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.

[0242] For any compound, the therapeutically and prophylactically effective amount can be estimated initially either in cell culture assays, for example, of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0243] Therapeutic / prophylactic efficacy and toxicity are determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and the ratio, ED 50 / LD 50 Pharmaceutical compositions exhibiting large therapeutic indices are preferred. However, pharmaceutical compositions exhibiting narrow therapeutic indices are also within the scope of the present invention. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for human use. The doses contained in such compositions are preferably within the ED50 range with little or no toxicity. 50 The dosage may vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0244] The exact dosage will be determined by a physician in light of factors related to the subject requiring treatment. Dosage and administration will be adjusted to provide a sufficient level of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's overall health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0245] An effective amount of a compound of the present disclosure for modulating, e.g., inhibiting, a proton-activated GPCR such as GPR68 (OGR1) includes, in one embodiment, an amount capable of establishing a concentration of about 1 nM to about 1,000 μM, in another embodiment, about 1 nM to about 250 μM, in another embodiment, about 1 nM to about 100 μM, and in yet another embodiment, about 1 nM to about 50 μM. In some embodiments, an effective amount of a compound of the present disclosure for modulating, e.g., inhibiting, a proton-activated GPCR such as GPR68 (OGR1) is an amount capable of establishing a concentration of 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 a compound of the present disclosure for modulating, e.g., inhibiting, a proton-activated GPCR such as GPR68 (OGR1) is an amount capable of establishing 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 a compound of the present disclosure for modulating, e.g., inhibiting, a proton-activated GPCR such as GPR68 (OGR1) is an amount capable of establishing a concentration of 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 apparent to one of skill in the art, the exact amount of compound can depend on various factors, including body weight, age, and sex. An effective amount of a compound of the present disclosure may include a dosing regimen that follows the pharmacokinetics / metabolism of the compound and may also vary depending on the stage or severity of the disease, condition, or disorder if the disease, condition, or disorder is already established. Dosage and amount are also affected by the mode of administration, such as oral versus intravenous administration.

[0246] In some embodiments, treating a disease, disorder, or condition described herein results in an increase in the mean survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the mean survival time is increased by more than about 30 days, more preferably more than about 60 days, more preferably more than about 90 days, and even more preferably more than about 120 days. The increase in the survival time of a population can be measured by any reproducible means. In a preferred embodiment, the increase in the mean survival time of a population can be measured, for example, by calculating the mean survival time for the population after initiation of treatment with an active compound. In another preferred embodiment, the increase in the mean survival time of a population can also be measured, for example, by calculating the mean survival time for the population after completion of a first round of treatment with an active compound.

[0247] In some embodiments, treating a disease, disorder, or condition described herein results in a reduction in mortality in a population of treated subjects compared to a population of subjects receiving carrier alone. In another aspect, treating a condition described herein results in a reduction in mortality in a population of treated subjects compared to an untreated population. In a further aspect, treating a condition described herein results in a reduction in mortality in a population of treated subjects compared to a population receiving monotherapy with a drug other than a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog, or derivative thereof. Preferably, the mortality rate is reduced 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 preferred aspects, the reduction in mortality in a population of treated subjects can be measured by any reproducible means. In another preferred aspect, the reduction in mortality in a population can be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after initiation of treatment with the active compound. In another preferred aspect, the reduction in mortality in a population can be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after completion of a first round of treatment with the active compound.

[0248] In certain embodiments, treating a disease, disorder, or condition described herein results in a reduction in the rate of cell proliferation. Preferably, after treatment, the rate of cell proliferation is reduced by at least about 5%, more preferably at least about 10%, more preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and most preferably at least about 75%. The rate of cell proliferation can be measured by any reproducible means of measurement. In a preferred embodiment, the rate of cell proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0249] 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 at least about 10%, more preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and most preferably at least about 75%. The proportion of proliferating cells can 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 non-dividing cells in a tissue sample. In another preferred aspect, the proportion of proliferating cells is equivalent to the mitotic index.

[0250] In another aspect, treating a disease, disorder, or condition described herein results in a decrease in the size of the area or zone of cellular proliferation. Preferably, after treatment, the size of the area or zone of cellular proliferation is reduced by at least 5% compared to the size before treatment, 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 size of the area or zone of cellular proliferation can be measured by any reproducible means of measurement. In a preferred aspect, the size of the area or zone of cellular proliferation can be measured as the diameter or width of the area or zone of cellular proliferation.

[0251] The methods described herein can include identifying a subject in need of treatment. In a preferred embodiment, the method includes identifying a mammal in need of treatment. In a highly preferred embodiment, the method includes identifying a human in need of treatment. Identifying a subject in need of treatment can be achieved by any means that indicates a subject that could benefit from treatment. For example, identifying a subject in need of treatment can occur by clinical diagnosis, clinical testing, or any other means known to those skilled in the art, including any combination of means for identification.

[0252] As described elsewhere herein, the compounds described herein may be formulated into pharmaceutical compositions, if desired, and administered by any route that allows for the treatment of a disease or condition. A preferred route of administration is oral administration. Administration may take the form of a single dose, or the compounds of the embodiments may be administered over a period of time, either in divided doses or in continuous release formulations or administration methods (e.g., pumps). However, however the compounds of the embodiments are administered to a subject, the amount of compound administered and the route of administration selected must be selected to allow for effective treatment of the disease state.

[0253] Further embodiments include administering to a subject in need thereof a combination of compounds, which may include a compound, composition, or pharmaceutical composition described herein with an additional pharmaceutical agent for treating and / or preventing a disease, disorder, or condition mediated by a proton-activated GPCR.

[0254] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein with an additional pharmaceutical agent. "Co-administration" means that two or more agents may be found in a 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, co-administration is achieved by combining the agents in a single dosage form. In some embodiments, the agents are administered sequentially. In some embodiments, the agents are administered via the same route, such as orally. In some other embodiments, the agents are administered via different routes, such as one administered orally and another administered intravenously. Thus, for example, a combination of active ingredients may be (1) co-formulated and administered or delivered in a combined formulation, (2) delivered in parallel as alternating or separate formulations, or (3) delivered via any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods described herein can comprise sequentially administering or delivering active ingredients, for example, in separate solutions, emulsions, suspensions, tablets, pills or capsules, or by different injections in separate syringes.Generally, during alternation therapy, the effective dosage of each active ingredient is administered sequentially, i.e., consecutively, while in simultaneous therapy, the effective dosage of two or more active ingredients is administered together.Various sequences of intermittent combination therapy can also be used.

[0255] For example, the compounds and / or pharmaceutical compositions described herein may be co-administered with additional pharmaceutical agents or therapies for the treatment and / or prevention of diseases, disorders, or conditions mediated by proton-activated GPCRs. In some embodiments, the compounds and / or pharmaceutical compositions described herein may be co-administered with pharmaceutical agents or therapies for the treatment and / or prevention of inflammatory, fibrotic, or proliferative diseases, disorders, or conditions. In certain embodiments, the compounds and / or pharmaceutical compositions described herein may be co-administered with pharmaceutical agents or therapies for the treatment and / or prevention of cancer.

[0256] A further embodiment of the present disclosure provides a method for inhibiting proton-activated GPCR in a cell, comprising administering to the cell an effective amount of a compound of the present disclosure. The cell may be in a cell culture. The cell may be in a tissue or may otherwise comprise a tissue. The tissue may be a human tissue.

[0257] In some embodiments, the proton-activated GPCR is GPR68 (OGR1).

[0258] In some embodiments, the cells are tumor cells. The tumor cells can be pancreatic tumor cells, head and neck tumor cells, lung tumor cells, kidney tumor cells, breast tumor cells, colon tumor cells, ovarian tumor cells, lymph node tumor cells, stomach tumor cells, esophageal tumor cells, skin tumor cells, brain tumor cells, oral tumor cells, pharyngeal tumor cells, thyroid tumor cells, adrenal tumor cells, leukemia cells, sarcoma cells, testicular tumor cells, bladder tumor cells, or prostate tumor cells. The tumor cells can be in cell culture. The cells can be present in or otherwise comprise tumor tissue.

[0259] The present disclosure is further illustrated by the following examples, which are not intended to limit the scope of the claims.

[0260] Example 1. Experimental preparation and analysis conditions Abbreviation Chloroform-d (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), 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), HO (water), MeCN (acetonitrile), EtOAc (ethyl acetate), g (gram), h (hour), nm (nanometer), 1 H NMR (proton nuclear magnetic resonance), Hz (hertz), LC-MS (liquid chromatography-mass spectrometry), MS (mass spectrometry), mg (milligram), MHz (megahertz), min (minute), mL (millitoliter), mmol (millimol), ppm (parts per million), R t (retention time), RT (room temperature), TLC (thin layer chromatography), v / v (volume / volume), m / z (mass-to-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), (COCl)2 (oxalyl chloride), Cs 2CO3 (cesium carbonate), NH4Cl (ammonium chloride), SOCl2 (thionyl chloride), DIPEA (N,N-diisopropylethylamine), MW (microwave), NH4Cl (ammonium chloride), DMAP (4-dimethylaminopyridine), LiOH (lithium hydroxide), NaH (sodium hydrogen carbonate), Aq (aqueous solution), HPLC: high performance liquid chromatography, M: molar concentration, molecular ion concentration, UV: ultraviolet, UPLC: ultra high performance liquid chromatography.

[0261] General Experiment All starting materials and solvents were either obtained from commercial sources or prepared according to literature references. Unless otherwise indicated, reaction mixtures were magnetically stirred and carried out at room temperature (approximately 20° C.).

[0262] Column chromatography was carried out on an automated flash chromatography system such as a Biotage Isolera Rf system using pre-packed silica (40 μm) cartridges unless otherwise indicated.

[0263] 1 1 H NMR spectra were recorded using a Bruker AVANCE 400 MHz spectrometer. 1 H data 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 peak of the residual protic solvent or an internal standard of tetramethylsilane as reference. Spectra were recorded at 298 K unless otherwise indicated.

[0264] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA Detector and an ACQUITY QDa Mass Detector, implementing one of the analytical methods described below.

[0265] 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.

[0266] General method for preparative HPLC: HPLC equipment: Shimadzu 20AP UV detector: SPD-20A. UV wavelength: 214nm and 254nm.

[0267] Condition 1: Mobile phase A: water, mobile phase B: acetonitrile.

[0268] Condition 2: Mobile phase A: water containing 0.1% trifluoroacetic acid, mobile phase B: acetonitrile.

[0269] Condition 3: Mobile phase A: water containing 0.1% formic acid, mobile phase B: acetonitrile.

[0270] Condition 4: Mobile phase A: water containing 0.1% ammonium hydroxide, Mobile phase B: acetonitrile.

[0271] Column: Agilent 10 Prep-C18 250 x 21.2 mm. Column temperature: ambient temperature.

[0272] LC gradient: 20% to 85% in 20 min, then 85% to 100% in 0.01 min, then hold at 100% for 5 min, then 100% to 20% in 0.01 min, hold at 20% for 5 min.

[0273] LC flow rate: 20 mL / min binary pump.

[0274] Structural nomenclature was generated using the "Structure to Name" conversion from ChemDraw® Professional 17 (PerkinElmer).

[0275] Analysis method Method 1 - Acid method (Shimadzu 3 minutes) Column: Shimadzu LC-20AD series, binary pump, diode array detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm column.

[0276] Detection: 2020, quadrupole LC / MS, ion source: API-ESI, TIC: 100-900 m / z, drying gas flow rate: 15 L / min, nebulizer pressure: 1.5 L / min, drying gas temperature: 250 °C, Vcap: 4500 V. Samples were dissolved in methanol at 1-10 μg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL. Detector: 214 nm, 254 nm. Detection wavelength: 214 nm, 254 nm.

[0277] Solvents: A: 0.05% v / v formic acid in water, B: 0.05% v / v formic acid in MeCN.

[0278] gradient: [Table 2]

[0279] Method 2 - Acidic 5 minutes method (Shimadzu 5 minutes) Column: Shimadzu LC-20AD series, binary pump, diode array detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm column.

[0280] Detection: 2020, quadrupole LC / MS, ion source: API-ESI, TIC: 100-900 m / z, drying gas flow rate: 15 L / min, nebulizer pressure: 1.5 L / min, drying gas temperature: 250 °C, Vcap: 4500 V. Samples were dissolved in methanol at 1-10 μg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL. Detection wavelengths: 214 nm, 254 nm.

[0281] Solvents: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v).

[0282] gradient: [Table 3]

[0283] Method 3 - Acid method (Waters QDa 3 minutes) Column: Waters QDa, binary pump, diode array detector. Waters CORTECS UPLC, C18, 1.6 μm, 2.1 x 50 mm column.

[0284] Detection: QDa, quadrupole LC / MS, ion source: API-ES, TIC: 70-900 m / z, fragmentor: 70, drying gas flow rate: 12 L / min, nebulizer pressure: 36 psi, drying gas temperature: 350 °C, Vcap: 3000 V. Samples were dissolved in methanol at 1-10 μg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL. Detectors: 214 nm, 254 nm.

[0285] Solvents: A: 0.05% formate in water (v / v), B: 0.05% formate in MeCN (v / v).

[0286] gradient: [Table 4]

[0287] Method 4 - Acid method (Agilent 3 minutes) Column: Agilent Technologies 1290 Series, binary pump, diode array detector. Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 × 50 mm.

[0288] Detection: G6120A, quadrupole LC / MS, ion source: API-ES, TIC: 70-1000 m / z, fragmentor: 70, drying gas flow rate: 12 L / min, nebulizer pressure: 36 psi, drying gas temperature: 350 °C, Vcap: 3000 V. Samples were dissolved in methanol at 1-10 μg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL. Detectors: 214 nm, 254 nm.

[0289] Solvents: A: 0.05% formate in water (v / v), B: 0.05% formate in MeCN (v / v).

[0290] gradient: [Table 5]

[0291] Example 2. Synthesis of intermediates The compounds of the present disclosure may be prepared by methods known to those skilled in the art and / or as described in the synthetic experimental procedures provided below.

[0292] Intermediate 1. (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid [ka]

[0293] Step 1: 5-Bromo-1-(cyclopropylmethyl)-1H-indazole To a solution of 5-bromo-1H-indazole (200.00 g, 1.02 mol) in THF (1200 mL) was added t-BuOK (136.68 g, 1.22 mol) and (bromomethyl)cyclopropane (164.44 g, 1.22 mol) at 0 °C. The reaction mixture was stirred at 50 °C overnight. The reaction mixture was treated with water, extracted with EtOAc (1000 mL * 2), washed with brine (1000 mL), and dried over Na SO . The organic phase was concentrated in vacuo and purified by silica gel column chromatography (PE / EtOAc = 30 / 1 to 10 / 1) to give the title compound (125 g, 0.49 mol, 49.0% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6)δ 8.01(dd, J=20.2, 1.4Hz, 2H), 7.74-7.66(m, 1H), 7.47(dd, J=8.9, 1.8Hz, 1H), 4 .29(d, J=7.0Hz, 2H), 1.32-1.12(m, 1H), 0.51-0.40(m, 2H), 0.43-0.30(m, 2H).

[0294] Step 2: tert-butyl (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylate To a solution of 5-bromo-1-(cyclopropylmethyl)-1H-indazole (125.00 g, 0.49 mol) in DMF (500 mL), Pd(OAc) (11.17 g, 0.05 mol), DPPP (41.06 g, 0.10 mol), TEA (100.73 g, 1.00 mol), and tert-butyl acrylate (318.99 g, 2.49 mol) were added under N atmosphere and stirred overnight at 110 °C. The mixture was concentrated in vacuo, extracted with EtOAc (1000 mL*3), washed with brine (1000 mL*2), and dried over Na2SO4. The organic phase was concentrated in vacuo and purified by silica gel column chromatography (PE / EtOAc=40 / 1 to DCM / EtOAc=100 / 1) to give the title compound (110.0 g, 0.37 mol, 74.1% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.10(d, J=0.9Hz, 1H), 8.04(d, J=1.5Hz, 1H), 7.78(dd, J=8.9, 1.5Hz, 1H), 7.76-7.63(m, 2H), 6.50(d, J=1 5.9Hz, 1H), 4.31(d, J=7.0Hz, 2H), 1.49(s, 9H), 1.44-1.20(m, 1H), 0.53-0.42(m, 2H), 0.46-0.35(m, 2H).

[0295] Step 3: (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid To a solution of tert-butyl (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylate (110.0 g, 0.37 mol) in DCM (350 mL) was added TFA (840.7 g, 7.37 mol) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, washed with MeOH, and the filter cake was concentrated in vacuo to give the title compound (76.0 g, 0.31 mol, 85.1% yield) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 12.28(s, 1H), 8.13(d, J=0.7Hz, 1H), 8.06(d, J=1.4Hz, 1H), 7.83-7.69(m, 3H), 6.53(d, J=1 5.9Hz, 1H), 4.34(d, J=7.0Hz, 2H), 1.35-1.23(m, 1H), 0.55-0.44(m, 2H), 0.48-0.37(m, 2H).

[0296] Intermediate 2. (E)-3-(1-methyl-1H-indazol-5-yl)acrylic acid [ka]

[0297] Step 1: tert-butyl (E)-3-(1-methyl-1H-indazol-5-yl)acrylate Starting with 5-bromo-1-methyl-1H-indazole (10.0 g, 47.62 mmol) using the procedure outlined in Step 2 of Intermediate 1. The title compound (7.0 g, 27.13 mmol, 57% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.08(s, 1H), 8.03(s, 1H), 7.80(s, 1H), 7.66(s, 2H), 6.47(s, 1H), 4.02(s, 3H), 1.49(s, 9H).

[0298] Step 2: (E)-3-(1-methyl-1H-indazol-5-yl)acrylic acid Starting with tert-butyl (E)-3-(1-methyl-1H-indazol-5-yl)acrylate (7.0 g, 27.13 mmol), using the procedure outlined in Step 3 of Intermediate 1, the title compound (5.0 g, 24.75 mmol, 91% yield) was obtained as a white solid. 1H NMR (400MHz, DMSO-d6)δ 12.15(s, 1H), 8.10(s, 1H), 8.04(s, 1H), 7.79(d, J=8.9Hz, 1H), 7.71(d, J =16.0Hz, 1H), 7.66(d, J=8.8Hz, 1H), 6.51(d, J=15.9Hz, 1H), 4.05(s, 3H).

[0299] Intermediate 3. 3-(2-aminophenyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0300] Step 1: tert-butyl (2-cyanophenyl)carbamate To a solution of 2-aminobenzonitrile (1.0 g, 8.46 mmol) in DCM (30 mL) was added di-tert-butyl dicarbonate (2.2 g, 10.15 mmol), TEA (1.28 g, 12.69 mmol), and DMAP (100 mg, 0.85 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 hours. The solvent was removed, treated with water, extracted with EtOAc (100 mL*3), washed with brine (100 mL*2), and dried over Na2SO4. The organic phase was concentrated in vacuo and purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give the title compound (700.0 mg, 3.2 mmol, 38% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 8.23 ​​(d, J = 8.5 Hz, 1H), 7.59-7.50 (m, 2H), 7.13-6.96 (m, 2H), 1.54 (d, J = 1.5 Hz, 9H).

[0301] Step 2: tert-butyl (E)-(2-(N'-hydroxycarbamimidoyl)phenyl)carbamate To a solution of tert-butyl (2-cyanophenyl)carbamate (700.0 mg, 3.2 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (449 mg, 6.4 mmol) and MeONa (346 mg, 6.4 mmol) at room temperature. The resulting solution was refluxed for 16 h. The solvent was removed, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to give the title compound (350.0 mg, 1.4 mmol, 44% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6)δ 10.41(s, 1H), 9.98(s, 1H), 8.15(dd, J=8.4, 1.2Hz, 1H), 7.58(dd, J=7.9, 1.6Hz, 1H), 7. 32(ddd, J=8.6, 7.4, 1.6Hz, 1H), 7.04(td, J=7.6, 1.3Hz, 1H), 6.12(s, 2H), 1.47(s, 9H).

[0302] Step 3: tert-butyl (2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)carbamate To a solution of tert-butyl (E)-(2-(N'-hydroxycarbamimidoyl)phenyl)carbamate (350.0 mg, 1.4 mmol) in DCM (10 mL) was added ethyl carbonochloridate (228 mg, 2.09 mmol) and TEA (282 mg, 2.78 mmol) at room temperature. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed, treated with water, extracted with EtOAc (100 mL*3), washed with brine (100 mL*3), and dried over Na2SO4. The organic phase was concentrated in vacuo, and the crude product was dissolved in EtOAc (10 mL), and K2CO3 (959 mg, 6.95 mmol) was added. The mixture was refluxed for 16 hours. The solvent was removed and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1) to give the title compound (280.0 mg, 1.0 mmol, 71% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 12.84(s, 1H), 9.21(s, 1H), 7.94(d, J=8.3Hz, 1H), 7.61(d, J=1.3Hz, 2H), 7.29-7.17(m, 1H), 1.46(s, 9H).

[0303] Step 4: 3-(2-aminophenyl)-1,2,4-oxadiazol-5(4H)-one Using the procedure outlined in Step 3 of Intermediate 1, starting with tert-butyl (2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)carbamate (280.0 mg, 1.0 mmol), the title compound (177.0 mg, 1.0 mmol, 100% yield) was obtained as a white solid and used directly in the next step without further purification. UPLC-MS (Method 3) m / z 178.0 at 1.126 min, (M+H) + .

[0304] Intermediate 4. 3-(2-aminophenyl)-1,2,4-oxadiazol-5(4H)-one [ka]

[0305] Step 1: 5-(2-nitrophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazol-2(3H)-one To a solution of 5-(2-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (600.0 mg, 2.9 mmol) in DMF (10 mL) was added NaH (66.6 mg, 2.9 mmol) at 0 °C. The solution was stirred at the same temperature for 1 hour, and then SEMCl (579.4 mg, 3.47 mmol) was added. The resulting solution was stirred at room temperature for 16 hours. The solvent was treated with water, extracted with EtOAc (100 mL * 3), washed with brine (100 mL * 3), and dried over Na2SO4. The organic phase was concentrated in vacuo and purified by preparative TLC (PE / EtOAc = 5 / 1) to give the title compound (700.0 mg, 2.07 mmol, 71% yield) as a yellow solid.1 H NMR (400MHz, DMSO-d6) δ 8.16(s, 1H), 7.90(s, 3H), 5.14(s, 2H), 3.70-3.63(m, 2H), 0.93-0.88(m, 2H), -0.00(s, 9H).

[0306] Step 2: 5-(2-aminophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazol-2(3H)-one A mixture of 5-(2-nitrophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazol-2(3H)-one (700 mg, 2.07 mmol), Fe powder (579.0 mg, 10.37 mmol), and NHCl (555.0 mg, 10.37 mmol) in EtOH / HO (16 mL, v / v = 3:1) was stirred at 80 °C for 3 h. The solvent was treated with water, extracted with EtOAc (100 mL * 3), washed with brine (100 mL * 2), and dried over NaSO. The organic phase was concentrated in vacuo to give the title compound (380.0 mg, 1.23 mmol, 59% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 7.48(s, 1H), 7.25(s, 1H), 6.87(s, 1H), 6.67(s, 1H), 6.38(s, 2H), 5.12(s, 2H), 3.70(s, 2H), 0.93-0.88(m, 2H), -0.02(s, 9H).

[0307] Example 3. Synthetic Route to Compound 6 [ka] Step 1: Methyl (E)-2-(3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamido)benzoate To a mixture of (£)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid (Intermediate 1, 76.0 g, 0.31 mol) in DCM (500 mL) was added (COCl) (59.65 g, 0.47 mol) and cat. DMF at 0 °C. The reaction was stirred at room temperature for 1 h. The mixture was concentrated and dissolved in DCM (500 mL), followed by the addition of methyl 2-aminobenzoate (47.42 g, 0.31 mol) and DIPEA (120.19 g, 0.93 mol). The resulting solution was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to DCM / EtOAc = 30 / 1) to give a residue, which was washed with MeOH and filtered. The filter cake was concentrated in vacuo to give the title compound (80 g, 67.9%) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 10.86(s, 1H), 8.48(dd, J=8.5, 1.1Hz, 1H), 8.13(d, J=16.2Hz, 2H), 7.98(dd, J=8. 0, 1.6Hz, 1H), 7.86(dd, J=8.8, 1.5Hz, 1H), 7.78(d, J=15.9Hz, 2H), 7.67(ddd, J=8. 6, 7.3, 1.7Hz, 1H), 7.28-7.19(m, 1H), 6.93(d, J=15.6Hz, 1H), 4.35(d, J=6.9Hz, 2H) ), 3.92(s, 3H), 1.37-1.22(m, 1H), 0.51(dt, J=8.0, 2.8Hz, 2H), 0.49-0.38(m, 2H).

[0308] Step 2: (E)-2-(3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamido)benzoic acid A mixture of methyl (E)-2-(3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamido)benzoate (100.0 g, 0.26 mol) and LiOH (33.48 g, 0.8 mmol) in THF (400 mL) and water (80 mL) was stirred at 40° C. for 2 h. The solvent was removed under reduced pressure, and the pH of the aqueous solution was adjusted to 3 with 2 M HCl. The mixture was extracted with EtOAc, dried over NaSO, and concentrated under pressure to give the crude product. The crude product was washed with MeOH, and the filter cake was dried under vacuum to give the crude title compound (55.3 g, 0.15 mmol, 59% yield) as a white solid. UPLC-MS (Method 4) m / z 360.2 at 2.185 min, (M−H) - . 1 H NMR (400 MHz, DMSO-d) δ 13.60(s, 1H), 11.33(s, 1H), 8.64(d, J=8.4Hz, 1H), 8.11(d, J=12.9Hz, 2H) , 8.02(d, J=7.8Hz, 1H), 7.84(d, J=8.9Hz, 1H), 7.82-7.71(m, 2H), 7.63(t, J =7.8Hz, 1H), 7.17(t, J=7.6Hz, 1H), 6.87(d, J=15.6Hz, 1H), 4.32(d, J=6.9H) z, 2H), 1.29(t, J=9.8Hz, 1H), 0.49(d, J=7.6Hz, 2H), 0.41(t, J=4.4Hz, 2H).

[0309] Example 4. Synthetic Route to Compound 9 [ka] Step 1: (E)-3-(1-methyl-1H-indazol-5-yl)-N-(pyridin-2-yl)acrylamide To a mixture of (£)-3-(1-methyl-1H-indazol-5-yl)acrylic acid (Intermediate 2, 100.0 mg, 0.49 mol) in DCM (5 mL) was added (COCl) (62.0 g, 0.49 mol) and cat. DMF at 0°C. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated and dissolved in pyridine (1 mL), and then a solution of methyl 2-aminobenzoate (184.0 mg, 1.96 mol) in DCM (5 mL) and DMAP (6 mg, 0.05 mmol) was added. The resulting solution was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo and purified by preparative TLC to give the title compound (47.0 mg, 0.17 mmol, 35%) as a white solid. UPLC-MS (Method 2) m / z 279.15 (M+H) at 3.017 min. + . 1 H NMR (400MHz, DMSO-d6)δ 10.68(s, 1H), 8.37-8.33(m, 1H), 8.23(d, J=8.4Hz, 1H), 8.13(s, 1H), 8.01(s, 1H), 7.83(t, J =8.0Hz, 1H), 7.79-7.66(m, 3H), 7.13(t, J=6.2Hz, 1H), 7.03(d, J=15.7Hz, 1H), 4.07(s, 3H).

[0310] Example 5. Synthetic Route to Compound 12 [ka] Step 1: (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)-N-(2-nitrophenyl)acrylamide Using the procedure outlined in Step 1 of Example 1, starting with (£)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid (500.0 mg, 2.06 mmol), the title compound (500.0 mg, 1.38 mmol, 67% yield) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6)δ 10.47(s, 1H), 8.14(d, J=0.9Hz, 1H), 8.05(s, 1H), 7.98(s, 1H), 7.85-7.78(m, 2H), 7.77-7.71(m , 3H), 7.40(s, 1H), 6.88(s, 1H), 4.32(s, 2H), 1.29-1.25(m, 1H), 0.53-0.47(m, 2H), 0.40(s, 2H).

[0311] Step 2: (E)-N-(2-aminophenyl)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamide Using the procedure outlined in Step 2 of Intermediate 4, starting with (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)-N-(2-nitrophenyl)acrylamide (500.0 mg, 1.38 mmol), the title compound (400.0 mg, 1.2 mmol, 87% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d) δ 9.34(s, 1H), 8.13(s, 1H), 7.99(s, 1H), 7.78(d, J=8.8Hz, 1H), 7.72-7.6 2(m, 2H), 7.35(d, J=7.9Hz, 1H), 6.96-6.83(m, 2H), 6.76(dd, J=8.0, 1.4 Hz, 1H), 6.58(td, J=7.6, 1.4Hz, 1H), 4.95(s, 2H), 4.32(d, J=7.0Hz, 2H), 1.28(d, J=2.9Hz, 1H), 0.49(dt, J=7.8, 2.9Hz, 2H), 0.43-0.37(m, 2H).

[0312] Step 3: (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)-N-(2-((2,2,2-trifluoroethyl)sulfonamido)phenyl)acrylamide To a mixture of (£)-N-(2-aminophenyl)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamide (150.0 mg, 0.45 mol) in DCM (500 mL) was added pyridine (71.0 mg, 0.90 mol) and 2,2,2-trifluoroethane-1-sulfonyl chloride (91.0 mg, 0.50) at 0 °C. The reaction was stirred at room temperature for 1 h. The solvent was treated with water, extracted with EtOAc (50 mL*3), washed with brine (50 mL*2), and dried over Na2SO4. The organic phase was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (eluted with 10%-90% MeCN / HO containing 0.1% HCOOH) to give the title compound (80.0 mg, 0.17 mmol, 38% yield) as a yellow solid. UPLC-MS (Method 1) m / z 477.1 at 2.300 min (M-H) - . 1 H NMR (400MHz, DMSO-d6)δ 9.73(s, 1H), 9.66(s, 1H), 8.14(s, 1H), 8.05(s, 1H), 7.82-7.70(m, 4H), 7.51-7.44(m, 1H), 7.35-7.19(m, 2H), 6.94(d, J=15.6Hz, 1 H), 4.55(q, J=9.8Hz, 2H), 4.33(d, J=6.9Hz, 2H), 1.29(ddt, J=12.5, 7.7, 3.9Hz, 1H), 0.53-0.45(m, 2H), 0.41(h, J=5.5, 5.0Hz, 2H).

[0313] Example 6. Analytical data of the compounds synthesized in the examples The compounds of the following examples were prepared by the methods described above in Examples 3-5, or by methods analogous to those described above, substituting the appropriate starting materials and intermediates as necessary. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0314] Example 7. Biological testing GPR68 cAMP GloSensor Assay Protocol The assay was developed to provide a quick screening assay for determining the potency and EC50 / IC50 of compounds against the GPR68 receptor using transiently transfected cells.

[0315] Assay design principles GPR68 senses extracellular pH. Levels of cyclic adenosine monophosphate (cAMP), a second messenger associated with GPCR activation in the cAMP-dependent pathway, were found to increase at neutral to acidic extracellular pH (pH 7.0-6.5) in cells expressing GPR68. Because cAMP levels were found to increase when GPR68 was stimulated by pH values ​​below pH 7.2, the pH-sensing ability of GPR68 was further tested and confirmed.

[0316] To determine compound activity in GPR68 inhibition, a GPR68-dependent cAMP assay was developed and validated. The principle of this method is to express GPR68 in HEK293T cells by transient transfection with a GPR68 expression vector and a cAMP-sensing reporter vector (GloSensor, Promega). The transfected cells are uniformly replated in assay plates to minimize experimental variability. GPR68 receptor signaling is measured via a cAMP increase from Gs, as indicated by Luc activation under basal (pH 8.4 or pH 7.4) or activated (pH 6.5 or pH 6.0) conditions. Reagent List GloSensor™ cAMP Reagent (Promega, Catalog No. E1291) Human GPR68 NM_001177676.2_pcDNA3.1(+)(Genscript) GloSensor™-22 FcAMP Reporter Vector (Promega, Catalog No. E2301) DMEM (Gibco, catalog number 11995065) FBS, qualified, New Zealand origin (Gibco, catalog number 10091148) Penicillin-streptomycin (Gibco, catalog number 15140122) 0.25% Trypsin-EDTA (Gibco, catalog number 25200056) PBS (Gibco, catalog number 10010049) 1x HBSS (Gibco, catalog number 14175079) HEPES (Gibco, catalog number 15630080) MES (Sigma, catalog number M2933-25G) TAPS (Sigma, catalog number T5316-25G) NaOH (Sigma, catalog number 221465) BSA (Sigma, catalog number B2064-50G) Opti-MEM (Gibco, catalog number 31985070) DMSO (Sigma, catalog number D5879-1L) FuGeneHD Transfection Reagent (Promega, Catalog No. E2311) Consumables / Supplies List 96-well plate (Corning, Cat. No. 3610) 6-well plate (Corning, Cat. No. 3516) 96-well V-bottom plate (Greiner Bio-one, Cat. No. 651201) 100mm cell culture dish (Corning, Catalog No. CLS430167) Equipment and Settings Liquid handler: Echo (LABCYTE Echo550), BRAVO (Agilent) Incubator (Grant-bio Thermo-shaker PHMP) Plate centrifuge (Eppendorf 5910R) Plate reader: Envision (PE).

[0317] Experimental procedure Cell culture procedures 1. Thawing Cells 1) Frozen cells were rapidly thawed in a 37°C water bath with gentle continuous agitation.

[0318] 2) The cells were gently added dropwise to a 15 ml centrifuge tube containing 10 ml of fresh pre-warmed complete medium, and then centrifuged at 1000 rpm for 5 minutes.

[0319] 3) The supernatant medium was discarded, and the cell pellet was resuspended in 10 ml of fresh, prewarmed complete medium. The cells were transferred to a 10 cm dish and incubated at 37°C with 5% CO2 until the cells reached >90% confluence. The recovery rate of frozen cells was typically >80%.

[0320] 2. Subculture This cell line was usually split twice every 1–2 days at a dilution ratio of 1:3 to 1:5. Fresh cells typically required 1–2 days to grow to 85% confluence.

[0321] 1) All medium was carefully aspirated, and the cell monolayer was gently washed with 5 mL of pre-warmed PBS per 10 cm dish. The cell layer was rinsed with an appropriate amount (1 mL gently for a 10 cm dish) of 0.2% trypsin-EDTA, which was then removed by aspiration.

[0322] 2) Five times the volume of trypsin medium was added to stop the trypsin, and the cells were harvested by centrifugation at 1000 rpm for 5 minutes at room temperature.

[0323] 3) Resuspend the cells using an appropriate amount of complete medium and split the cells as needed.

[0324] 3. Changing the Medium 1) The medium was gently aspirated off.

[0325] 2) Fresh warmed complete medium (37°C) was transferred to a 10 cm dish.

[0326] 4. Freezing the Cells 1) Repeat steps 1 to 3 of subculture.

[0327] 2) The cells were centrifuged at 1000 rpm for 5 minutes.

[0328] 3) Aspirate the supernatant and collect 1-2 x 10 6 Cells were resuspended in fresh freezing medium at a density of 100 cells / ml. 1 ml of cells was added per cryovial.

[0329] 4) Place the cryovial of cells into a cryogenic freezer, then transfer the container to -80°C and leave overnight.

[0330] 5) The cryogenic vial was transferred to liquid nitrogen (-196°C).

[0331] Assay procedure Step 1: Cells were seeded in 6-well plates. 1) When the cell confluence was about 80%, the cells were detached with 0.25% trypsin.

[0332] 2) The detached cells were resuspended in 3 ml of fresh cell culture medium, the number of cells was counted, and the cells were diluted to an appropriate density.

[0333] 3) 1.5 x 10^6 cells were seeded into a 6-well plate (Cat. No. 3516) in 2 ml per well containing the necessary media for transfection so that the cells were 80-85% confluent at the time of transfection.

[0334] 4) The cells were incubated in a CO2 incubator at 37°C for 6 hours.

[0335] Step 2: Transfected in 6-well plates 5) The DMEM medium was gently aspirated off, and serum-free Opti-MEM™ medium was then added to the 6-well plate.

[0336] 6) 2.5 μg of GPR68 and 2.5 μg of GloSensor-22F in a 1:1 ratio, and 12 μl of FuGeneHD were added to 120 μl of serum-free Opti-MEM® medium. The mixture was gently mixed and incubated at room temperature for 15 minutes.

[0337] 7) After 15 minutes of incubation, 137 μl of DNA transfection reagent complex was added to each well containing cells and medium. The plate was gently mixed by rocking back and forth.

[0338] 8) Cells were incubated at 37°C in a CO2 incubator for 19 hours until ready to assay transgene expression.

[0339] Step 3: Cells were replated in 96-well plates 40,000 cells / well, 100 μl / well were seeded into a 96-well plate (Cat. No. 3610) with complete DMEM medium and incubated overnight.

[0340] Step 4: Test Compounds 1. Different pH buffer solutions were prepared. [Table 7]

[0341] 2. Prepared Compounds 1) Compounds were solubilized in 100% DMSO to a concentration of 50 mM.

[0342] 2) Compound DMSO solutions prepared in a 384LDV Echo Plate: The highest concentration was 10 mM, 3x, 10 dose response, so intermediate concentrations were created by serial dilution (1:2) starting from 10,000 μM. 5 μL of test intermediate compound + 10 μL of DMSO solution was transferred to the 384LDV Echo Plate. The Echo Plate was centrifuged at 1000 rpm for 30 seconds before echo processing. Compounds were transferred in 180 nL volumes to a 96-assay plate (Corning, Cat. No. 3599) using an Echo 550, with 10 compound concentration points in duplicate (final highest concentration of 10 μM, 3x, 10 dose response in duplicate). The final DMSO concentration was 0.1%.

[0343] 3) For low and high control wells, 180 nL of DMSO was transferred by ECHO.

[0344] 4) 180nL / well of compound in 100% DMSO in assay plates. The layout of the low control wells and 180nL / well of DMSO in high control wells was as shown below. Compounds were prepared in assay plates at 100x working concentrations in 100% DMSO, the assay volume was 150 μL and the final DMSO concentration was 0.1%. [Table 8]

[0345] 3. Luciferin Road 1) The medium was removed, and 100 μL / well of GloSensor (50×) was added to the cells, followed by incubation at room temperature for 2 hours. [Table 9]

[0346] 2) After 2 hours of incubation, luminescence was pre-read at -5 minutes for background.

[0347] 4. Compound Addition and Lum Signal Collection 1) Compounds were diluted to 10 μM maximum in assay buffer as follows: • ECHO - 180 nL of compound / DMSO was transferred to a 96-well plate (corning, cat no. 651201). 150 μL of different pH buffer solutions were added to the compound plate and mixed well.

[0348] 2) 80 μL of GloSensor was removed from the cell plate, and 100 μL / well of pH buffer with or without compound was added to the cell plate.

[0349] 3) The cell plate was immediately transferred to a plate reader.

[0350] 4) The luminescence signal from 0 to 30 minutes was read and collected using Envision.

[0351] Compound plates and pH activation maps [Table 10]

[0352] Data analysis The percent (%) inhibition at each concentration of compound was calculated based on and relative to the signal in high and low control wells included in each assay plate, with high control wells designated as 0% inhibition (pH 6.0) and low control wells designated as 100% inhibition (pH 8.4).

[0353] The inhibition rate of the compound was calculated according to the following formula: Inhibition %=[CTL pH6.0-CPD pH6.0] / [CTL pH6.0-CTL pH8.4]*100

[0354] The concentration of the test compound and the % inhibition value were plotted, and the concentration of the compound required for 50% inhibition (IC 50 ) was determined using a four-parameter logistic dose-response equation.

[0355] Reference peptide / compound endpoint values ​​(IC 50 ) was assessed for each experiment as a quality control measure. Experiments were considered acceptable if the endpoint values ​​were within 3-fold of the expected values.

[0356] result The results of the GPR68 cAMP GloSensor assay described above were compared with the IC 50 The values ​​obtained represent the concentration of test compound required for 50% inhibition. The results of this assay for sample compounds of the present disclosure are provided in Table 1 below. [Table 11]

[0357] The present disclosure is further described with reference to the following numbered embodiments:

[0358] Itemized Listing of Embodiments Embodiment 1. Structure of Formula (I): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, X is N and NR 1 is selected from Y is N and NR 2 is selected from R 1 and R 2 However, independently, H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 or C 3-6 one or more groups selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 optionally substituted with one or more groups optionally substituted with one or more substituents selected from Alternatively, R 1 and R 2 together with the atoms to which they are attached, optionally substituted C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9forming a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl optionally substituted with one or more substituents selected from Each R 9 are independently H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl; Each R 10 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and -C(O)R 9 is selected from R 3 is H, halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 5-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 -NO2, and -NO2; or R 3 and R 2 together with the atoms to which they are bonded, C 1-10 Alkyl, halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9, or -C(O)OR 9 forming a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl optionally substituted with one or more substituents selected from q is an integer of 0 to 3, R 4 is halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkylthio, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 6-10 Aryl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 and -NO2; R 5 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-6 Carbocyclyl, optionally substituted C 5-10 selected from aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 5- to 6-membered heterocyclyl; L is a bond or -C(O)N(R 9 a linker selected from -S(O)-, -S(O)2-, -C(O)-, or -C(O)O-, or an optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, -OC 1-4 Alkylene or -OC 2-4a linker selected from alkenylene, each of which is —O—, —S—, —NR 9 -, -NR 10 -, -C(O)N(R 9 )-, -N(R 9 )C(O)-, -S(O)2-, -N(R 9 )S(O)2-, -S(O)2N(R 9 a linker optionally interrupted by -C(O)-, -C(O)-, -C(O)O-, or -O(O)C-; R 6 But C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 3-10 Carbocyclyl, C 1-10 Alkyl, C 2-10 Alkenyl, or C 2-10 alkynyl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 and two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl; or R 6 and R5 together with the atoms to which they are attached, optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 forming a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl optionally substituted with one or more substituents optionally selected from Each R 11 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkyni, optionally substituted C 5-10 Aryl, optionally substituted C 2-20 Alkoxyalkyl, C1-C6 haloalkyl, -C(O)R 9 , -OR 9 , -S(O)2R 9 , and -S(O)N(R 9 )2 is selected, R 7 and R 8 However, independently, H, C 1-6 Alkyl, C 5-10 Aryl, 5- to 10-membered heteroaryl, and C 3-10 carbocyclyl, each of which is selected from C 1-6 Alkyl, C 5-6 Aryl, halogen, -CN, -OR 9, -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 and optionally substituted with one or more substituents selected from A compound wherein n is an integer of 1 to 4.

[0359] Embodiment 2. Structure of Formula (Ia): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0360] Embodiment 3. Structure of Formula (II): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0361] Embodiment 4. Structure of Formula (IIa): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0362] Embodiment 5. Structure of Formula (III): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0363] Embodiment 6.R 1 But C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-6 carbocyclyl, or heterocyclyl, each of which is selected from halogen, —CN, —OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 or C 1-6 one or more groups selected from carbocyclyl, heterocyclyl, and heteroaryl, each of which is selected from halogen, —CN, —OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 The compound of any one of embodiments 1-5, optionally substituted with one or more groups optionally substituted with one or more substituents selected from:

[0364] Embodiment 7.R 1 But halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 or C 1-6 one or more groups selected from carbocyclyl, heterocyclyl, and heteroaryl, each of which is selected from halogen, —CN, —OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 C optionally substituted with one or more groups optionally substituted with one or more substituents selected from 1-6 The compound of any one of embodiments 1-6, wherein is alkyl.

[0365] Embodiment 8.R 1 But C 1-6 The compound of any one of embodiments 1-7, wherein is alkyl.

[0366] Embodiment 9.R 1 The compound of any one of embodiments 1-8, wherein is methyl, ethyl, propyl, or isopropyl.

[0367] Embodiment 10.R 1 The compound of any one of embodiments 1-9, wherein is methyl.

[0368] Embodiment 11.R 1 But, -OR 9 , -C(O)R 9 , -C(O)NR9 R 10 , C(O)SR 9 , or -C(O)OR 9 C replaced with 1-6 The compound of any one of embodiments 1-8, wherein is alkyl.

[0369] Embodiment 12.R 9 is methyl.

[0370] Embodiment 13.R 1 is substituted with halogen or -CN 1-6 The compound of any one of embodiments 1 to 8, wherein alkyl and optionally halogen is F.

[0371] Embodiment 14.R 1 But halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 C substituted with heteroaryl optionally substituted with one or more substituents selected from 1-6 The compound of any one of embodiments 1-8, wherein is alkyl.

[0372] Embodiment 15.R 1 is an optionally substituted 5-membered heteroaryl, and the 5-membered heteroaryl is selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, and thiadiazolyl, each of which can be optionally substituted.

[0373] Embodiment 16.R 1C substituted with heterocyclyl 1-6 alkyl and heterocyclyl is halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9 , or -C(O)OR 9 The compound of any one of embodiments 1-8, optionally substituted with one or more substituents selected from:

[0374] Embodiment 17. A compound according to embodiment 16, wherein the heterocyclyl is an optionally substituted 3- to 6-membered heterocyclyl.

[0375] Embodiment 18. A compound of embodiment 16 or embodiment 17, wherein heterocyclyl is an optionally substituted oxygen heterocycle.

[0376] Embodiment 19. The oxygen heterocycle is [ka] and n is 0 or 1, each of which may be optionally substituted.

[0377] Embodiment 20.R 1 But halogen, -CN, -OR 9 , -SR 9 , -S(O)2R 9 , -NR 9 R 10 , -NO2, =(O), =(S), =(N)R 9 , =(N)R 10 , -C(O)R 9 , -C(O)NR 9 R 10 , -C(O)SR 9, or -C(O)OR 9 C optionally substituted with one or more substituents selected from 1-6 Carbocyclyl-substituted C 1-6 The compound of any one of embodiments 1-8, wherein is alkyl.

[0378] Embodiment 21.C 1-6 Compounds according to embodiment 20, wherein carbocyclyl is optionally substituted cyclopropyl.

[0379] Embodiment 22.R 1 but, [ka] 22. The compound of embodiment 20 or 21, wherein

[0380] Embodiment 23.R 7 and R 8 is H and the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0381] Embodiment 24.R 3 The compound of any one of embodiments 1-23, wherein is H.

[0382] Embodiment 25. A compound according to any one of embodiments 1 to 24, wherein q is 0, 1, or 2.

[0383] Embodiment 26. A structure of formula (Va), (Vb), or (Vc): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0384] Embodiment 27.R 4 is halogen, hydroxy, optionally substituted C 2-8 Alkoxyalkyl, -CN, -OR 9 , -SR 9 , -NR 9 R 10 , -C(O)R 9 , -C(O)OR 9 , -S(O)2R 9 27. The compound of any one of embodiments 1-26, wherein the compound is selected from —NO 2 , and —NO 2 .

[0385] Embodiment 28.R 4 The compound of any one of embodiments 1-27, wherein is selected from halogen, —CN, and —NO 2 .

[0386] Embodiment 29.R 4 The compound of any one of embodiments 1-28, wherein is halogen, preferably F.

[0387] Embodiment 30. L is -S(O)2-, optionally substituted C 1-4 Alkylene, or C 2-4 The compound of any one of embodiments 1-29, wherein the linker is selected from alkenylene.

[0388] Embodiment 31. A compound in which L is a bond and the structure of formula (VI): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0389] Embodiment 32. Structure of Formula (VIa), (VIb), or (VIc): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0390] Embodiment 33.R 5 But H, C 1-6 Alkyl, or C 2-8 The compound of any one of embodiments 1-32, which is alkoxyalkyl.

[0391] Embodiment 34.R 5 The compound of any one of embodiments 1-33, wherein is H.

[0392] Embodiment 35.R 6 But C 6-10 aryl, or 5- to 6-membered heteroaryl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11and wherein two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5-6 membered heteroaryl or an optionally substituted fused 5-6 membered heterocyclyl.

[0393] Embodiment 36.R 6 wherein the optional substituents are halogen, optionally substituted 5-membered heterocyclyl, optionally substituted 5-membered heteroaryl, —C(O)OR 11 , -N(R 11 )S(O)2R 11 , -C(O)N(R 11 )2, and -S(O)2N(R 11 36. The compound of any one of embodiments 1-35, wherein one or more substituents are selected from:

[0394] Embodiment 37.R 6 The compound of any one of embodiments 1-36, wherein is selected from a C6 aryl, a 5-membered heteroaryl, or a 6-membered heteroaryl, each of which can be optionally substituted.

[0395] Embodiment 38.R 6 but, [ka] is selected from The compound of any one of embodiments 1 to 37, each of which can be optionally substituted.

[0396] Embodiment 39. [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0397] Embodiment 40. [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0398] Embodiment 41. [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0399] Embodiment 42.R 6 3-10 membered heterocyclyl and C 3-10 carbocyclyl, each of which is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11)2, -NO2, =(O), =(S), =(N)R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 The compound of any one of embodiments 1-34, optionally substituted with one or more substituents optionally selected from:

[0400] Embodiment 43.R 6 The optional substituents of -C(O)OR are halogen and -C(O)OR 11 and R is one or more substituents selected from 11 is H or optionally substituted C 1-6 The compound of embodiment 42, wherein the aryl is alkyl.

[0401] Embodiment 44. [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0402] Embodiment 45.R 6 and R 5 together with the atoms to which they are attached, optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, halogen, -CN, -OR 11 , -SR 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -S(O)(NR 10 )R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -N(R 11 )S(O)2R 11 , -N(R 11 )2, -NO2, =(O), =(S), =(N)R11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 )2, or -C(O)SR 11 The compound of any one of embodiments 1 to 34, wherein the compound forms a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, optionally substituted with one or more substituents optionally selected from:

[0403] Embodiment 46.R 6 The optional substituents of are -C(O)OR 11 and R is a selected halogen of one or more substituents from 11 is H or optionally substituted C 1-6 The compound of embodiment 45, wherein the aryl is alkyl.

[0404] Embodiment 47. Structure: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0405] Embodiment 48. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0406] Embodiment 49. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0407] Embodiment 50. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0408] Embodiment 51. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0409] Embodiment 52. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0410] Embodiment 53. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0411] Embodiment 54. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0412] Embodiment 55. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0413] Embodiment 56. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0414] Embodiment 57. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0415] Embodiment 58. Structure: [ka] or a pharmaceutically acceptable salt thereof.

[0416] Embodiment 59. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0417] Embodiment 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0418] Embodiment 61. A method for 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 of any one of embodiments 1 to 59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of embodiment 60.

[0419] Embodiment 62. The method of embodiment 61, wherein the proton-activated GPCR is GPR68 (OGR1).

[0420] Embodiment 63. The method of embodiment 61 or embodiment 62, 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 cancer.

[0421] Embodiment 64. The method of embodiment 63, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition.

[0422] Embodiment 65. The method of embodiment 64, wherein the inflammatory disease, disorder, or condition is selected from focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.

[0423] Embodiment 66. The method of embodiment 64, wherein the inflammatory disease, disorder, or condition is an autoimmune disease, disorder, or condition.

[0424] Embodiment 67. The method of embodiment 66, 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.

[0425] Embodiment 68. The method of embodiment 63, wherein the disease, disorder, or condition is a fibrotic disease, disorder, or condition.

[0426] Embodiment 69. The method of embodiment 68, wherein the fibrotic disease, disorder, or condition is selected from renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, dermal fibrosis, pancreatic fibrosis, and hepatic fibrosis.

[0427] Embodiment 70. The method of embodiment 68, wherein the fibrotic disease, disorder, or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial 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 sclerosing cholangitis (PSC).

[0428] Embodiment 71. The method of embodiment 63, wherein the disease, disorder, or condition is a proliferative disease, disorder, or condition.

[0429] Embodiment 72. The method of embodiment 71, wherein the proliferative disease, disorder, or condition is selected from diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0430] Embodiment 73. The method of embodiment 63, wherein the disease, disorder, or condition is cancer.

[0431] Embodiment 74. The method of embodiment 73, wherein the cancer is selected from 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.

[0432] Embodiment 75. The method of any one of embodiments 61 to 74, wherein the subject is a human.

[0433] Embodiment 76. A method of inhibiting a proton-activated GPCR in a cell population, comprising administering to the cell population an effective amount of a compound of any one of embodiments 1 to 59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of embodiment 60.

[0434] Embodiment 77. The method of embodiment 76, wherein the proton-activated GPCR is GPR68 (OGR1).

[0435] Embodiment 78. The method of embodiment 76 or embodiment 77, wherein the cell is a tumor cell.

[0436] Embodiment 79. The steps, features, integers, compositions, and / or compounds disclosed herein or indicated individually or collectively in the specification of this application, and any and all combinations of two or more of said steps or features.

Claims

1. Structure of Formula (II): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, X is N and NR １ is selected from Y is N and NR ２ is selected from R １ and R ２ However, independently, H, C １－１０ Alkyl, C １－１０ Heteroalkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－６ selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is １－１０ Alkyl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ or C ３－６ one or more substituents selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which is C １－１０ Alkyl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ optionally substituted with one or more substituents selected from Or, R １ and R ２ together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is optionally substituted C １－１０ Alkyl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ and optionally substituted with one or more substituents selected from Each R ９ are independently H, optionally substituted C １－６ Alkyl, and optionally substituted C ５－６ aryl; Each R １０ are independently H, optionally substituted C １－６ Alkyl, optionally substituted C ５－６ Aryl, and —C(O)R ９ is selected from R ３ is H, halogen, hydroxy, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ alkylthio, optionally substituted C ２－８ Alkoxyalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ５－１０ Aryl, —CN, —OR ９ , -SR ９ , -NR ９ R １０ , -C(O)R ９ , -C(O)OR ９ , -S(O) ２ R ９ , and -NO ２ Selected from or or R ３ and R ２ together with the atom to which they are attached form a fused 5- to 6-membered heteroaryl or a fused 5- to 6-membered heterocyclyl, each of which is C １－１０ Alkyl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ and optionally substituted with one or more substituents selected from q is an integer from 0 to 3, R ４ is halogen, hydroxy, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ alkylthio, optionally substituted C ２－８ Alkoxyalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ６－１０ Aryl, —CN, —OR ９ , -SR ９ , -NR ９ R １０ , -C(O)R ９ , -C(O)OR ９ , -S(O) ２ R ９ , and -NO ２ is selected from R ５ is H, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ２－８ Alkoxyalkyl, optionally substituted C ３－６ Carbocyclyl, optionally substituted C ５－１０ selected from aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 5- to 6-membered heterocyclyl; L is a bond or —C(O)N(R ９ ) -, -S(O) ２ a linker selected from -, -C(O)-, or -C(O)O-, or an optionally substituted C １－４ Alkylene, optionally substituted C ２－４ Alkenylene, —OC １－４ Alkylene, or —OC ２－４ a linker selected from alkenylene, each of which is —O—, —S—, —NR ９ -, -NR １０ -, -C(O)N(R ９ ) -, -N(R ９ )C(O)-,-S(O) ２ -, -N(R ９ ) S (O) ２ -, -S(O) ２ N (R ９ a linker optionally interrupted by —C(O)—, —C(O)O—, or —O(O)C—; R ６ But C ５－１０ aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, C ３－１０ Carbocyclyl, C １－１０ Alkyl, C ２－１０ Alkenyl, or C ２－１０ alkynyl, each of which is optionally substituted C １－６ Alkyl, optionally substituted C ５－６ Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, —CN, —OR １１ , -SR １１ , -S(O) ２ R １１ , -S(O) ２ N (R １１ ) ２ , -S(O)(NR １０ ) R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , -N(R １１ ) ２ , -NO ２ , =(O), =(S), =(N)R １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)N(R １１ ) ２ , or -C(O)SR １１ and two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl; or R ６ and R ５ together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C １－１０ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, halogen, —CN, —OR １１ , -SR １１ , -S(O) ２ R １１ , -S(O) ２ N (R １１ ) ２ , -S(O)(NR １０ ) R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , -N(R １１ ) ２ , -NO ２ , =(O), =(S), =(N)R １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)N(R １１ ) ２ , or -C(O)SR １１ and optionally substituted with one or more substituents optionally selected from Each R １１ are independently H, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkyny, optionally substituted C ５－１０ Aryl, optionally substituted C ２－２０ Alkoxyalkyl, C １ -C ６ Haloalkyl, —C(O)R ９ , -OR ９ , -S(O) ２ R ９ , and -S(O) ２ N (R ９ ) ２ is selected from R ７ and R ８ However, independently, H, C １－６ Alkyl, C ５－１０ Aryl, 5- to 10-membered heteroaryl, and C ３－１０ carbocyclyl, each of which is selected from C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ５－６ Aryl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ A compound optionally substituted with one or more substituents selected from:

2. Structure of formula (III): 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. Structure of formula (IV): 【Transformation 3】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

4. R １ But C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, or C ３－６ carbocyclyl, each of which is C １－６ Alkyl, halogen, —CN, —OR ９ , and -SR ９ or C ３－６ Carbocyclyl, 5- to 6-membered heterocyclyl, C ５－６ one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is １－６ Alkyl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ 4. The compound of any one of claims 1 to 3, optionally substituted with one or more groups optionally substituted with one or more substituents selected from:

5. R １ But C １－６ Alkyl, halogen, —CN, —OR ９ , and -SR ９ or C ３－６ Carbocyclyl, 5- to 6-membered heterocyclyl, C ５－６ one or more groups selected from aryl, and 5- to 6-membered heteroaryl, each of which is １－６ Alkyl, halogen, —CN, —OR ９ , -SR ９ , -S(O) ２ R ９ , -NR ９ R １０ , -NO ２ , =(O), =(S), =(N)R ９ , = (N)R １０ , -C(O)R ９ , —C(O)NR ９ R １０ , -C(O)SR ９ , or —C(O)OR ９ C optionally substituted with one or more groups optionally substituted with one or more substituents selected from １－６ The compound of any one of claims 1 to 4, which is alkyl.

6. R １ is optionally selected from methyl, ethyl, propyl, or isopropyl; １－６ The compound of any one of claims 1 to 5, which is alkyl.

7. R １ is halogen, -CN, -OR ９ , -C(O)R ９ , —C(O)NR ９ R １０ , C(O)SR ９ , or —C(O)OR ９ C substituted with １－６ alkyl, and optionally R ９ The compound according to any one of claims 1 to 5, wherein is methyl.

8. R １ is substituted with an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 3- to 6-membered heterocyclyl １－６ The compound of any one of claims 1 to 5, which is alkyl.

9. R １ but, 【Chemistry 4】 C substituted with 3- to 6-membered heterocyclyl selected from １－４ The compound of claim 8, wherein the compound is alkyl.

10. R １ is optionally substituted C １－６ Carbocyclyl-substituted C １－６ The compound of any one of claims 1 to 5, which is alkyl.

11. R １ But C １－６ Carbocyclyl-substituted C １－４ alkyl, and optionally C １－６ 11. The compound of claim 10, wherein carbocyclyl is selected from optionally substituted cyclobutyl or optionally substituted cyclopropyl.

12. R １ but, 【Transformation 5】 11. The compound according to claim 9 or 10, wherein

13. R ３ The compound of any one of claims 1 to 12, wherein is H.

14. The compound according to any one of claims 1 to 13, wherein q is 0 or 1.

15. Structure of Formula (Va), (Vb), or (Vc): 【Transformation 6】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. R ４ is halogen, hydroxy, optionally substituted C ２－８ Alkoxyalkyl, —CN, —OR ９ , -SR ９ , -NR ９ R １０ , -C(O)R ９ , -C(O)OR ９ , -S(O) ２ R ９ , and -NO ２ The compound according to any one of claims 1 to 15, selected from:

17. R ４ is halogen, -CN, and -NO ２ 17. The compound of claim 1, wherein the halogen is selected from the group consisting of:

18. Structure of formula (VI): 【Transformation 7】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

19. Structure of formula (VIa), (VIb), or (VIc): 【Transformation 8】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

20. R ５ is H, optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, or optionally substituted C ２－８ The compound of any one of claims 1 to 19, which is an alkoxyalkyl.

21. R ５ The compound of any one of claims 1 to 20, wherein is H.

22. R ６ But C ５－１０ aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, C ３－１０ Carbocyclyl, C １－１０ Alkyl, C ２－１０ Alkenyl, or C ２－１０ alkynyl, each of which is optionally substituted C １－６ Alkyl, optionally substituted C ５－６ Aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, halogen, —CN, —OR １１ , -SR １１ , -S(O) ２ R １１ , -S(O) ２ N (R １１ ) ２ , -S(O)(NR １０ ) R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , -N(R １１ ) ２ , -NO ２ , =(O), =(S), =(N)R １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)N(R １１ ) ２ , or -C(O)SR １１ wherein two adjacent optional substituents, if present, together with the atoms to which they are attached, may form an optionally substituted fused 5- to 6-membered heteroaryl or an optionally substituted fused 5- to 6-membered heterocyclyl.

23. R ６ is optionally substituted C ６ The compound of any one of claims 1 to 22, wherein the compound is selected from aryl, optionally substituted 5-membered heteroaryl, and optionally substituted 6-membered heteroaryl.

24. R ６ but, 【Chemistry 9】 24. The compound of any one of claims 1 to 23, selected from:

25. R ６ but, 【Chemistry 10】 is selected from The compound of any one of claims 1 to 24, each of which may be optionally substituted.

26. R ６ wherein said optional substituents are halogen, optionally substituted 5-membered heterocyclyl, optionally substituted 5-membered heteroaryl, —C(O)OR １１ , -N(R １１ ) S (O) ２ R １１ , -C(O)N(R １１ ) ２ , and -S(O) ２ N (R １１ ) ２ 26. The compound of any one of claims 1 to 25, wherein one or more substituents are selected from: 【Request Item 27】 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 27. The compound of any one of claims 1 to 26, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Request Item 28】 【Chemistry 12-1】 【Chemistry 12-2】 28. The compound of any one of claims 1 to 27, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Request Item 29】 【Chemistry 13】 29. The compound of any one of claims 1 to 28, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

30. R ６ optionally substituted 3- to 10-membered heterocyclyl and optionally substituted C ３－１０ 23. The compound of any one of claims 1 to 22, selected from carbocyclyl.

31. R ６ wherein said optional substituents are halogen and —C(O)OR １１ and optionally one or more substituents selected from R １１ is H or optionally substituted C １－６ 31. The compound of claim 30, which is alkyl. 【Request Item 32】 【Chemistry 14】 32. The compound of claim 30 or 31, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

33. R ６ and R ５ together with the atom to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted C １－１０ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, halogen, —CN, —OR １１ , -SR １１ , -S(O) ２ R １１ , -S(O) ２ N (R １１ ) ２ , -S(O)(NR １０ ) R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , -N(R １１ ) ２ , -NO ２ , =(O), =(S), =(N)R １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)N(R １１ ) ２ , or -C(O)SR １１ 23. The compound of any one of claims 1 to 22, optionally substituted with one or more substituents optionally selected from:

34. R ６ wherein said optional substituents are halogen and —C(O)OR １１ and optionally one or more substituents selected from R １１ is H or optionally substituted C １－６ 34. The compound of claim 33, which is alkyl.

35. structure: 【Chemistry 15】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

36. structure: 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

37. The compound is 【Chemistry 17】 37. The compound of claim 36, wherein:

38. 38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

39. 39. A method of treating and / or preventing a disease, disorder, or condition mediated by proton-activated GPCRs in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 38.

40. 40. Use of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 38, 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.

41. 39. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 38, for use in the treatment and / or prevention of a disease, disorder, or condition mediated by proton-activated GPCRs in a subject in need thereof.

42. 42. A compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition for the method of claim 39, the use of claim 40, or the use of claim 41, wherein the proton-activated GPCR is GPR68 (OGR1).

43. 43. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition according to any one of claims 39 to 42, 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 cancer.

44. 44. The method, use, or compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 43, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition.

45. 45. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 44, wherein the inflammatory disease, disorder, or condition is selected from focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.

46. 45. The method, use, or compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 44, wherein the inflammatory disease, disorder, or condition is an autoimmune disease, disorder, or condition.

47. 47. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 46, 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.

48. 44. The method, use, or compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 43, wherein the disease, disorder, or condition is a fibrotic disease, disorder, or condition.

49. 49. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 48, wherein the fibrotic disease, disorder, or condition is selected from renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, dermal fibrosis, pancreatic fibrosis, and hepatic fibrosis.

50. 49. The method, use, or compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 48, wherein the fibrotic disease, disorder, or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial 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 sclerosing cholangitis (PSC).

51. 44. The method, use, or compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 43, wherein the disease, disorder, or condition is a proliferative disease, disorder, or condition.

52. 52. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 51, wherein the proliferative disease, disorder, or condition is selected from diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

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

54. 54. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition of claim 53, wherein the cancer is selected from 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.

55. 55. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition according to any one of claims 49 to 54, wherein the subject is a human.

56. 39. A method of inhibiting a proton-activated GPCR in a cell, comprising administering to the cell an effective amount of a compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 38.

57. 40. Use of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 38, in the manufacture of a medicament for the inhibition of proton-activated GPCR in a cell.

58. 39. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 38, for use in inhibiting a proton-activated GPCR in a cell.

59. 59. A compound or a pharmaceutically acceptable salt, solvate, or stereoisomer, or pharmaceutical composition for the method of claim 56, the use of claim 57, or the use of claim 58, wherein the proton-activated GPCR is GPR68 (OGR1).

60. 60. The method, use, or compound for use, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical composition according to any one of claims 56 to 59, wherein the cell is a tumor cell.

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