Heterocyclic compounds and uses thereof

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to novel compounds that are useful as modulators of proton-activated G protein-coupled receptors. The present disclosure further relates to methods of preparing such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent, or diagnose diseases, disorders, or conditions associated with proton-activated G protein-coupled receptors. Background Art

[0002] Local acidification is a common feature of many disease processes, such as inflammation, infarction, or solid tumor growth. Acidic pH is not only a consequence of disease but also contributes to the recruitment and regulation of immune cells, alters the metabolism of parenchymal, immune, and tumor cells, regulates fibrosis, vascular permeability, oxygen utilization and consumption, tumor cell invasiveness, and influences cell survival. Therefore, cells involved in these processes require pH-sensing mechanisms. These pH sensors play an important role in both 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 become important targets. These receptors are widely expressed, upregulated in inflammation and tumors, sense changes in extracellular pH between pH 8 and 6, and are involved in regulating key 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] New therapies are needed 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 modulating (e.g., inhibiting) proton-activated G protein-coupled receptors (e.g., GPR68 (OGR1)). The identified compounds can be used to treat, prevent, and / or diagnose diseases, disorders, or conditions associated with proton-activated G protein-coupled receptors (e.g., inflammatory, fibrotic, or proliferative diseases, disorders, or conditions) and / or cancer.

[0006] Therefore, in one aspect of the present disclosure, there is provided a compound having the structure of formula (II):

[0007]

[0008] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0009] in:

[0010] X is selected from N and NR 1 ;

[0011] Y is selected from N and NR 2 ;

[0012] R 1 and R 2 Independently selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 substituted by one or more substituents selected from the following: C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0013] or R 1 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0014] Each R 9 are independently selected from H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl;

[0015] Each R 10 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and –C(O)R 9 ;

[0016] R 3 Selected from 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 and –NO2;

[0017] or R 3 and R 2Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0018] q is an integer from 0 to 3;

[0019] R 4 is selected from 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;

[0020] R 5 selected from 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 aryl, optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl;

[0021] L is a bond or selected from -C(O)N(R 9 )-, -S(O)2-, -C(O)- or -C(O)O-; or a linking group selected from optionally substituted C1-4 Alkylene, optionally substituted C 2-4 Alkenylene, –OC 1-4 Alkylene or –OC 2-4 an alkenylene linking group, each of which is optionally substituted by -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–;

[0022] R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when 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;

[0023] or R 6 and R 5Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: 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 ;

[0024] Each R 11 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, 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)2N(R 9 )2;

[0025] R 7 and R 8 Independently selected from H, C 1-6 Alkyl, C 5-10 Aryl, 5-10 membered heteroaryl and C 3-10 carbocyclyl, each of which is optionally substituted with one or more substituents 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)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 .

[0026] In some embodiments, the compounds as defined herein have the structure of Formula (III):

[0027]

[0028] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0029] In some embodiments, the compounds as defined herein have the structure of Formula (IV):

[0030]

[0031] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0032] In some embodiments, R 1 It is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 carbocyclyl, each of which is optionally substituted with one or more substituents selected from: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

[0033] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

[0034] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from methyl, ethyl, propyl or isopropyl.

[0035] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 Alkyl groups are replaced by halogen, –CN, –OR 9 ,–C(O)R 9 ,–C(O)NR 9 R 10 、C(O)SR 9 OR –C(O)OR 9 substituted, optionally wherein R 9 It's methyl.

[0036] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6The alkyl group is substituted by an optionally substituted 5-6 membered heteroaryl group or an optionally substituted 3-6 membered heterocyclyl group.

[0037] In some embodiments, R 1 It is C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a 3-6 membered heterocyclic group selected from:

[0038] as well as Each of these can be optionally substituted.

[0039] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with C 1-6 Carbocyclyl substitution.

[0040] In some embodiments, R 1 It is C 1-4 Alkyl, the C 1-4 Alkyl is C 1-6 Carbocyclyl is substituted, optionally wherein C 1-6 The carbocyclyl group is selected from optionally substituted cyclobutyl or optionally substituted cyclopropyl.

[0041] In some embodiments, R 1 yes

[0042] In some embodiments, R 3 It’s H.

[0043] In some embodiments, q is 0 or 1.

[0044] In some embodiments, the compound as defined herein has the structure of Formula (Va), (Vb), or (Vc):

[0045]

[0046] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0047] In some embodiments, R 4 is selected from 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.

[0048] In some embodiments, R 4 is selected from halogen, -CN and -NO2, optionally wherein halogen is F.

[0049] In some embodiments, the compounds as defined herein have the structure of Formula (VI):

[0050]

[0051] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0052] In some embodiments, the compounds as defined herein have the structure of Formula (VIa), (VIb), or (VIc):

[0053]

[0054] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0055] 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 Alkoxyalkyl.

[0056] In some embodiments, R 5 It’s H.

[0057] In some embodiments, R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when present, taken 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.

[0058] In some embodiments, R 6 is selected from optionally substituted C6 aryl, optionally substituted 5-membered heteroaryl and optionally substituted 6-membered heteroaryl.

[0059] In some embodiments, R 6 Selected from:

[0060] Each of these can be optionally substituted.

[0061] In some embodiments, R 6 Selected from:

[0062] Each of these can be optionally substituted.

[0063] In some embodiments, the R 6 The optional substituents are one or more substituents 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.

[0064] In some embodiments, the compound as defined herein is selected from the group consisting of:

[0065]

[0066]

[0067]

[0068] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0069] In some embodiments, the compound as defined herein is selected from the group consisting of:

[0070]

[0071]

[0072] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0073] In some embodiments, the compound as defined herein is selected from the group consisting of:

[0074] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0075] In some embodiments, R 6 is selected from optionally substituted 3-10 membered heterocyclic group and optionally substituted C 3-10 Carbocyclic group.

[0076] In some embodiments, the R 6 The optional substituents are one or more selected from halogen and -C(O)OR 11 A substituent, optionally wherein R 11 is H or optionally substituted C 1-6 alkyl.

[0077] In some embodiments, the compound as defined herein is selected from the group consisting of:

[0078]

[0079] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0080] In some embodiments, R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: 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 ;

[0081] In some embodiments, the R 6 The optional substituents are one or more selected from halogen and -C(O)OR 11 A substituent, optionally wherein R 11 is H or optionally substituted C 1-6 alkyl.

[0082] In some embodiments, the compound as defined herein has the structure:

[0083]

[0084] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0085] Also provided is a compound having the following structure:

[0086]

[0087] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is

[0089]

[0090] Also provided is a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and a pharmaceutically acceptable excipient.

[0091] Also provided is a method of 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 as defined herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein.

[0092] Also provided is the use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein, for the preparation of a medicament for treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

[0093] Also provided are compounds as defined herein, or pharmaceutically acceptable salts, solvates or stereoisomers thereof, or pharmaceutical compositions as defined herein, for use in treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

[0094] In some embodiments, the proton-activated GPCR is GPR68 (OGR1).

[0095] 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 cancer.

[0096] In some embodiments, the disease, disorder or condition is an inflammatory disease, disorder or condition. In some embodiments, the inflammatory disease, disorder or condition is selected from focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis.

[0097] In some embodiments, the inflammatory disease, disorder or condition is an autoimmune disease, disorder or condition. In some embodiments, the autoimmune disease, disorder or condition is selected from systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, multiple sclerosis and rheumatoid arthritis.

[0098] In certain embodiments, the disease, disorder or condition is a fibrotic disease, disorder or condition. In certain embodiments, the fibrotic disease, disorder or condition is selected from renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, skin fibrosis, pancreatic fibrosis and liver fibrosis. In certain 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), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

[0099] In some embodiments, the disease, disorder or condition is a proliferative disease, disorder or condition. In some embodiments, the proliferative disease, disorder or condition is selected from diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP) and proliferative vitreoretinopathy (PVR).

[0100] In some embodiments, the disease, disorder or condition is cancer. In 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.

[0101] In some embodiments, the subject is a human.

[0102] Also provided is a method of inhibiting a proton-activated GPCR in a cell, the method comprising administering to the cell an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein.

[0103] Also provided is the use of a compound as defined herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as defined herein, for the preparation of a medicament for inhibiting a proton-activated GPCR in a cell.

[0104] 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.

[0105] In some embodiments, the proton-activated GPCR is GPR68 (OGR1).

[0106] In some embodiments, the cell is a tumor cell. DETAILED DESCRIPTION

[0107] Unless specifically defined otherwise, all technical and scientific terms used herein should be understood to have the same meaning as commonly understood by one of ordinary skill in the art (eg, chemistry, biochemistry, cell culture, molecular biology, and pharmaceutics).

[0108] Unless otherwise indicated, all patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety.

[0109] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0110] Unless the context requires otherwise, 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 "subject" means "one or more subjects" unless the context clearly dictates otherwise.

[0111] As used herein, the term "about" refers to a range of + / - 5% of the specified value.

[0112] Throughout this specification, various aspects and components of the present disclosure may be presented in range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the present disclosure. Therefore, unless otherwise indicated, the description of a range should be considered to have explicitly disclosed all possible subranges and individual numerical values ​​within the range. For example, unless an integer is required or the context implies an integer, a description of a range such as from 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 stated range, for example, 1, 2, 3, 4, 5, 5.5, and 6. This applies regardless of the breadth of the disclosed range. When specific values ​​are required, these values ​​will be indicated in the specification.

[0113] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated element, integer or step or group of elements, integers or steps, but not the exclusion of any other element, integer or step or group of elements, integers or steps. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0114] The use of "or" or "and" means "and / or" unless stated otherwise.

[0115] The compounds of the present disclosure may exist in the form of 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.

[0116] The compounds disclosed herein may exist in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound and are not biologically or otherwise undesirable for use in medicine. In many cases, the compounds disclosed herein are capable of forming 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, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are 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, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, published September 11, 1987, by Johnston et al. (incorporated herein by reference in its entirety).

[0117] As used herein, “C a to C b ” or “C a-b ” (where “a” and “b” are integers) refers to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, “C1 to C4 alkyl” or “C 1-4 "Alkyl" refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0118] As used herein, the term "halogen" or "halo" means any of the radiostable atoms of column 7 of the periodic table, such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0119] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double bonds and triple bonds). An alkyl group can have 1 to 20 carbon atoms (whenever a numerical range such as "1 to 20" appears herein, it refers to each integer in 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 the occurrence of the term "alkyl" without specifying a numerical range). An alkyl group can also be a medium-sized alkyl group having 1 to 9 carbon atoms. An alkyl group can also be a low-sized alkyl group having 1 to 4 carbon atoms. An alkyl group can be designated as "C 1-4 By way of example only, "C 1-4 "Alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

[0120] As used herein, "alkoxy" refers to an alkyl radical as defined above containing at least one oxygen atom, wherein the at least one oxygen atom is located at the position where the alkoxy radical is attached to the remainder of the compound. Suitable alkoxy radicals include, for example, methoxy (-O-CH3), ethoxy (-O-CH2-CH3), propoxy (-O-CH2-CH2-CH3 (straight chain alkyl) or -O-CH-(CH3)2 (branched chain alkyl)) and -O-CH2-CH2-O-CH3. Alkoxy radicals may be substituted or unsubstituted. Alkoxy radicals may be substituted or unsubstituted. In this regard, as used herein, the term "haloalkoxy" refers to an "alkoxy radical" substituted with one or more halo radicals (i.e., one or more of F, Cl, Br, or I). An example of a "haloalkoxy radical" is -OCF3.

[0121] As used herein, "alkylthio" refers to a group of the formula -SR, wherein R is an alkyl group as defined above, such as "C 1-9 "Alkylthio" and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, isobutylmercapto, sec-butylmercapto, tert-butylmercapto and the like.

[0122] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. An alkenyl group can have from 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term "alkenyl" without specifying a numerical range. An alkenyl group can also be a medium-sized alkenyl group having from 2 to 9 carbon atoms. An alkenyl group can also be a lower alkenyl group having from 2 to 4 carbon atoms. An alkenyl group can be designated as "C2-4 By way of example only, "C 2-4 The term "alkenyl" refers to an alkenyl group having two to four carbon atoms, i.e., an alkenyl group 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, and hexenyl.

[0123] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. An alkynyl group can have from 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. An alkynyl group can also be a medium-sized alkynyl group having from 2 to 9 carbon atoms. An alkynyl group can also be a lower alkynyl group having from 2 to 4 carbon atoms. An alkynyl group can be designated as "C 2-4 By way of example only, "C 2-4 "Alkynyl" means that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0124] 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. A heteroalkyl group may have from 1 to 20 carbon atoms, but this definition also encompasses the term "heteroalkyl" where no numerical range is specified. A heteroalkyl group may also be a medium-sized heteroalkyl group having from 1 to 9 carbon atoms. A heteroalkyl group may also be a low-sized heteroalkyl group having from 1 to 4 carbon atoms. A heteroalkyl group may be designated as "C 1-4 Heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" means that there are one to four carbon atoms in the heteroalkyl chain and one or more heteroatoms additionally present in the backbone of the chain.

[0125] As used herein, "alkylene" means a branched or straight chain fully saturated diradical chemical group containing only carbon and hydrogen, connected to the rest of the molecule (i.e., an alkanediyl group) by two points of attachment. An alkylene group may have from 1 to 20 carbon atoms, but this definition also encompasses occurrences of the term alkylene group where no numerical range is specified. An alkylene group may also be a medium size alkylene group having from 1 to 9 carbon atoms. An alkylene group may also be a lower alkylene group having from 1 to 4 carbon atoms. An alkylene group may be designated as "C 1-4 By way of example only, "C 1-4 "Alkylene" indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propylene-1,1-diyl, propylene-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propylene-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0126] As used herein, "alkenylene" means a straight or branched chain diradical chemical group containing only carbon and hydrogen attached to the rest of the molecule by two points of attachment and containing at least one carbon-carbon double bond. An alkenylene group can have from 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term alkenylene where no numerical range is specified. An alkenylene group can also be a medium-sized alkenylene group having from 2 to 9 carbon atoms. An alkenylene group can also be a lower alkenylene group having from 2 to 4 carbon atoms. An alkenylene group can be designated as "C 2-4 By way of example only, "C 2-4 "Alkenylene" means that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of vinylene, ethylene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-vinylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, butene-1,1-diyl, but-1,3-diene-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-vinylene, 1,2-dimethyl-vinylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propenylene-1,1-diyl and 2,2-dimethyl-ethylene-1,1-diyl.

[0127] The term "aromatic" refers to a ring or ring system having a conjugated π electron system and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic groups or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0128] As used herein, "aryl" refers to an aromatic ring or ring system containing only carbon in the ring backbone (i.e., two or more fused rings sharing two adjacent carbon atoms). When an aryl group is a ring system, each ring in the system is aromatic. An aryl group may have from 6 to 18 carbon atoms, but this definition also encompasses occurrences of the term "aryl" where no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group may be designated as "C 6-10 Aryl", "C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0129] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, wherein R is an aryl group as defined above, such as "C 6-10 Aryloxy" or "C 6-10 "Arylthio" and the like, including but not limited to phenoxy.

[0130] "Aralkyl" or "arylalkyl" is an aryl group attached as a substituent through an alkylene group, such as "C 7-14 "Aralkyl" and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene).

[0131] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in the ring backbone. When a heteroaryl is a ring system, each ring in the system is aromatic. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms (including carbon atoms and heteroatoms) that make up the ring backbone), but this definition also encompasses the term "heteroaryl" in which no numerical range is specified. In some embodiments, a heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl group can be designated as a "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. Examples of heteroaryl rings include, but are not limited to, furanyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0132] Heteroaryl can be, for example, monocyclic or polycyclic (for example, bicyclic).Polycyclic heteroaryl can, for example, contain condensed rings.In bicyclic heteroaryl, one or more heteroatoms can be present in each ring, or heteroatoms can be present only in one ring in the ring.The example of monocyclic heteroaryl includes furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl.The example of bicyclic heteroaryl includes quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothienyl, benzimidazolyl, naphthyridinyl, quinolyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl [4,5-b] pyridyl, pyridopyrimidinyl, isoquinolyl and benzohydrooxazole.

[0133] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group attached as a substituent through an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene).

[0134] As used herein, "carbocyclyl" means a non-aromatic cyclic 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 joined together in a fused, bridged, or spiro manner. The carbocycle 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 can have from 3 to 20 carbon atoms, but this definition also covers the term "carbocyclyl" where no numerical range is specified. A carbocyclyl can also be a medium-sized carbocyclyl having from 3 to 10 carbon atoms. A carbocyclyl can also be a carbocyclyl having from 3 to 6 carbon atoms. A carbocyclyl can be designated as "C 3-6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0135] "(Carbocyclyl)alkyl" is a group consisting of an alkylene group (e.g., "C 4-10 (Carbocyclyl)alkyl) etc., 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.

[0136] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0137] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0138] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclyl group can be connected together in a fused, bridged or spiro manner. The heterocyclyl group can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in a non-aromatic ring or an aromatic ring in the ring system. The heterocyclyl group can have 3 to 20 ring members (i.e., the number of atoms (including carbon atoms and heteroatoms) that make up the ring backbone), but this definition also covers the term "heterocyclyl" in which no numerical range is specified. The heterocyclyl group can also be a medium-sized heterocyclyl group with 3 to 10 ring members. The heterocyclyl group can also be a heterocyclyl group with 3 to 6 ring members. The heterocyclyl group can be designated as "3-6 membered heterocyclyl" or similar names. In preferred six-membered monocyclic heterocyclyls, the heteroatoms are selected from one to three of O, N or S, and in preferred five-membered monocyclic heterocyclyls, the heteroatoms are selected from one or two heteroatoms selected from O, N or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidinedionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxinyl, 1,4-dioxinyl, 1,4-dioxinyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl, hexyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiopentyl, 1,3-dithianyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0139] Heterocyclic radical can be, for example, monocyclic or polycyclic (for example, bicyclic). Polycyclic heterocyclic radical can, for example, contain condensed rings. In bicyclic heterocyclic radicals, one or more heteroatoms can be present in each ring, or heteroatoms can be present only in one ring in the ring. Heterocyclic radicals containing suitable nitrogen atoms include corresponding N-oxides. In one example, heterocyclic radicals have three to ten atoms (i.e., 3-10 membered heterocyclic radicals). Examples of monocyclic non-aromatic heterocyclic radicals include aziridine radicals, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl. Examples of bicyclic heterocyclic radicals in which one ring is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzazepanyl.

[0140] "(Heterocyclyl)alkyl" is a heterocyclyl group attached as a substituent through an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0141] As used herein, "acyl" refers to -C(O)R, wherein R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

[0142] "O-carboxyl" refers to a "-OC(O)R" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0143] A "C-carboxyl" group refers to a "-C(O)OR" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include carboxyl (ie, -C(O)OH).

[0144] “Cyanato” refers to a “-CN” group. “Cyanate” refers to a “-OCN” group. “Isocyanate” refers to a “-NCO” group. “Thiocyanate” refers to a “-SCN” group. “Isothiocyanate” refers to a “-NCS” group.

[0145] "Sulfinyl" refers to a "-S(O)R" group, where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0146] "Sulfonyl" refers to a "-SO2R" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0147] "S-sulfonamido" refers to "-SO2NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0148] "N-sulfonamido" refers to "-N(R A )SO2R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0149] "O-carbamoyl" refers to "-OC(O)NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0150] "N-carbamoyl" refers to "-N(R A )OC(O)R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0151] "O-thiocarbamoyl" refers to "-OC(S)NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0152] "N-thiocarbamoyl" refers to "-N(R A )OC(S)R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0153] "Amino" refers to "-NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include free amino (ie, -NH2).

[0154] "Aminoalkyl" refers to an amino group attached through an alkylene group.

[0155] "Alkoxyalkyl" refers to an alkoxy group linked through an alkylene group, such as "C 2-8 Alkoxyalkyl" etc.

[0156] As used herein, a substituted group is derived from an unsubstituted parent group in which there has been an exchange 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 substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 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), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6) alkyl (i.e. , ether), aryloxy, sulfhydryl (mercapto), halo(Ci-C6)alkyl (e.g., -CF3), halo(Ci-C6)alkyl (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(Ci-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinamido, N-sulfinamido, C-carboxyl, O-carboxyl, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted," it may be substituted by the substituents described above.

[0157] It should be understood that, depending on the context, certain group naming conventions may include monoradicals or diradicals. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as an alkyl group requiring two points of attachment includes a diradical, such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions clearly indicate that the group is a diradical, such as "alkylene" or "alkenylene."

[0158] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atoms to which they are attached," this means that the collective unit of atoms and the two R groups is the ring. When used alone, the ring is not otherwise limited by the definition of each R group. For example, when the following substructure is present:

[0159]

[0160] And R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 Together with the nitrogen to which it is attached, it forms a heterocyclic group, which means that R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0161]

[0162] wherein Ring A is a heteroaryl ring containing the depicted nitrogen.

[0163] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," this means that the collective unit of atoms, the intermediate bond, and the two R groups is the ring. For example, when the following substructure is present:

[0164]

[0165] And R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 Together with the atoms to which they are attached, they form an aryl or carbocyclic group, which means that R 1 and may be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0166]

[0167] wherein A is an aryl ring or a carbocyclic group containing the depicted double bond.

[0168] When the compounds disclosed herein have at least one chiral center, they can exist as separate enantiomers and diastereomers or as mixtures of such isomers (including racemates). The separation of separate isomers or the selective synthesis of separate isomers are accomplished by applying various methods known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. In addition, the compounds disclosed herein can 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 form. In addition, some compounds in the compounds disclosed herein can 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.

[0169] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be clearly represented by other chemical structures, even when kinetically; the skilled artisan recognizes that such structures may represent only a very small fraction of a sample of such compounds. Such compounds are considered to be within the scope of the depicted structures, even though such resonance forms or tautomers are not represented herein.

[0170] Isotopes may be present in the described compounds. Each chemical element as represented in the compound structure may include any isotope of the element. For example, in the compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Any position in the compound where a hydrogen atom may be present may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, the compounds mentioned herein encompass all potential isotopic forms, unless the context clearly indicates otherwise.

[0171] 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 an activity associated with a proton-activated GPCR. In various embodiments, "modulation" can inhibit or stimulate proton-activated GPCR activity. In certain embodiments, "modulation" refers to inhibiting proton-activated GPCR activity.

[0172] A "patient" or "subject" to be treated by the methods described herein can refer to a human or 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, it is intended to encompass adult and neonatal subjects, as well as fetuses (whether male or female). In one aspect, the subject is a mammal. A patient refers to a subject having a disease, disorder, or condition. A subject, whether human or non-human, can be referred to as an individual, subject, animal, host, or recipient, as well as a patient.

[0173] The term "mammal" is used in its ordinary biological sense. Thus, the term specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0174] 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. Unless any conventional media or agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. In addition, various adjuvants commonly used in the art may also be included. Considerations for including various components in pharmaceutical compositions are described in, for example, Gilman et al. (eds.) (1990); Goodman and Oilman's: The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press.

[0175] The therapeutic effect alleviates one or more symptoms of the disease or condition to some extent and includes curing the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated; however, even after a cure is achieved, there may be certain long-term or permanent effects (such as extensive tissue damage).

[0176] As used herein, "treat," "treatment," or "treating" refers to the administration of a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease, disorder, or condition, but who is susceptible to or otherwise at risk for a particular disease, disorder, or condition, whereby the treatment reduces the likelihood that the patient will develop the disease, disorder, or condition. The term "therapeutic treatment" refers to administering a treatment to a subject who already has a disease, disorder, or condition.

[0177] 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 "at risk" for a particular condition is designed to prevent the subject from developing the disease, disorder, or condition or at least reduce the risk of developing the disease, disorder, or condition to a level no greater than that found in the general population as a whole.

[0178] As used herein, an "effective amount" is intended to mean an amount sufficient to prevent, alleviate, or eliminate a disease, disorder, or condition. In some embodiments, an effective amount can range from nanomolar to micromolar concentrations, for example, from about 1 nM to about 1,000 μM. One skilled in the art will recognize that to achieve these concentrations in vivo will depend, inter alia, on the pharmacokinetics of the exact compound selected. Thus, in some embodiments, the dosage can range from about 1 mg / kg to about 1,000 mg / kg, including all amounts therebetween, and in other embodiments from about 10 mg / kg to about 500 mg / kg, and in yet other embodiments from about 50 mg / kg to about 250 mg / kg.

[0179] As used herein, the terms "co-administration" and the like are intended to encompass 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.

[0180] Throughout this specification, references to individual steps, compositions of matter, groups of steps, or groups of compositions of matter are to be considered as encompassing both one and more (i.e., one or more) of such steps, compositions of matter, groups of steps, or groups of compositions of matter, unless expressly stated otherwise or the context requires otherwise.

[0181] Those skilled in the art will recognize that the present disclosure described herein is susceptible 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 steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of the steps or features.

[0182] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods, as described herein, are clearly within the scope of the present disclosure.

[0183] Those skilled in the art will appreciate that various changes and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure. The present embodiments are therefore considered in all respects to be illustrative and not restrictive.

[0184] Compounds of the present disclosure

[0185] The present disclosure relates, in part, to compounds that are modulators (e.g., inhibitors) of proton-activated GPCRs (e.g., GPR68 (OGR1)), which allow the compounds to be used to prevent, ameliorate, treat and / or prevent diseases, disorders or conditions associated with proton-activated GPCRs (e.g., inflammatory, fibrotic or proliferative diseases, disorders or conditions) and / or cancer.

[0186] Therefore, in one aspect, there is provided a compound of formula (I):

[0187]

[0188] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0189] in:

[0190] X is selected from N and NR 1 ;

[0191] Y is selected from N and NR 2 ;

[0192] R 1 and R 2 Independently selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 1-10 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 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0193] or R 1 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0194] Each R 9 are independently selected from H, optionally substituted C 1-6Alkyl and optionally substituted C 5-6 aryl;

[0195] Each R 10 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and –C(O)R 9 ;

[0196] R 3 Selected from 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 and –NO2;

[0197] or R 3 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0198] q is an integer from 0 to 3;

[0199] R 4 is selected from halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C2-6 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;

[0200] R 5 selected from 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 aryl, optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl;

[0201] L is a bond or selected from -C(O)N(R 9 )-, -S(O)2-, -C(O)- or -C(O)O-; or a linking group selected from optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, –OC 1-4 Alkylene or –OC 2-4 an alkenylene linking group, each of which is optionally substituted by -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–;

[0202] R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents, which may be selected from optionally substituted C1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when 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;

[0203] or R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from 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(R11 )2 or –C(O)SR 11 ;

[0204] Each R 11 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, 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)2N(R 9 )2;

[0205] R 7 and R 8 Independently selected from H, C 1-6 Alkyl, C 5-10 Aryl, 5-10 membered heteroaryl and C 3-10 carbocyclyl, each of which is optionally substituted with one or more substituents 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

[0206] n is an integer of 1 to 4.

[0207] 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):

[0208]

[0209] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0210] In some embodiments, the compound has the structure of Formula (II):

[0211]

[0212] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0213] In some embodiments, the compound has the structure of Formula (IIa):

[0214]

[0215] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0216] Where X is NR 1 ; and Y is N.

[0217] In other embodiments, the compound has the structure of Formula (IIb):

[0218]

[0219] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0220] wherein X is N; and Y is NR 2 .

[0221] In some embodiments, R 1 and R 2 Independently selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 carbocyclyl, each of which is optionally substituted with one or more substituents selected from: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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)SR9 OR –C(O)OR 9 .

[0222] In some embodiments, R 1 and / or R 2 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

[0223] In some embodiments, R 1 and / or R 2 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from methyl, ethyl, propyl or isopropyl.

[0224] In some embodiments, R 1 and / or R 2 It is C 1-6 Alkyl, the C 1-6 Alkyl groups are replaced by halogen, –CN, –OR 9 ,–C(O)R 9 ,–C(O)NR 9 R 10 、C(O)SR 9 OR –C(O)OR 9 substituted, optionally wherein R 9 It's methyl.

[0225] In some embodiments, R 1 and / or R 2 It is C1-6 Alkyl, the C 1-6 The alkyl group is substituted by an optionally substituted 5-6 membered heteroaryl group or an optionally substituted 3-6 membered heterocyclyl group.

[0226] In some embodiments, R 1 and / or R 2 It is C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a 3-6 membered heterocyclic group selected from:

[0227] as well as

[0228] Each of these can be optionally substituted.

[0229] As will be apparent to those skilled in the art, optionally substituted heterocyclyl groups may have defined stereochemistry at one or more chiral centers (when present). For example, in some embodiments, R 1 and / or R 2 It is C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a 3-6 membered heterocyclic group selected from:

[0230] as well as

[0231] Each of these can be optionally substituted.

[0232] In some embodiments, R 1 and / or R 2 It is C 1-6 Alkyl, the C 1-6 Alkyl is substituted with an optionally substituted C1-6 carbocyclyl. 1 and R 2 are independently selected from H and C 1-6 Carbocyclic substituted C 1-4 Alkyl, optionally wherein C 1-6 Carbocyclyl is selected from optionally substituted cyclobutyl or cyclopropyl. In some embodiments, R 1 and / or R 2 yes

[0233] In various embodiments, a compound of formula (III) is provided:

[0234]

[0235] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0236] in:

[0237] R 1 Selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 substituted by one or more groups selected from the following: C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0238] or R 1 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0239] Each R 9 are independently selected from H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl;

[0240] Each R 10 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and –C(O)R 9 ;

[0241] R 3 Selected from 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 and –NO2;

[0242] or R 3 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0243] q is an integer from 0 to 3;

[0244] R 4 is selected from 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;

[0245] R 5 selected from 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 aryl, optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl;

[0246] L is a bond or selected from -C(O)N(R 9 )-, -S(O)2-, -C(O)- or -C(O)O-; or selected from 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 optionally substituted by -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–;

[0247] R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents, which may be selected from optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when 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;

[0248] or R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from 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 ;

[0249] Each R 11 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, 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)2N(R 9 )2;

[0250] R 7 and R 8 Independently selected from H, C 1-6 Alkyl, C 5-10 Aryl, 5-10 membered heteroaryl and C 3-10 carbocyclyl, each of which is optionally substituted with one or more substituents 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 .

[0251] In some embodiments, R 7 and R 8Independently selected from C 1-6 Alkyl, C 5-10 Aryl, 5-10 membered heteroaryl and C 3-10 carbocyclyl, each of which is optionally substituted with one or more substituents 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 .

[0252] In some embodiments, R 7 and R 8 is H, and the compound has the structure of formula (IV):

[0253]

[0254] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0255] In some embodiments, R 1 It is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 carbocyclyl, each of which is optionally substituted with one or more substituents selected from: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

[0256] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

[0257] In some embodiments, R 1 It is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl or isopropyl.

[0258] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 Alkyl groups are replaced by halogen, –CN, –OR 9 ,–C(O)R 9 ,–C(O)NR 9 R 10 、C(O)SR 9 OR –C(O)OR 9 substituted, wherein in some embodiments, R 9 It's methyl.

[0259] In some embodiments, R 1 It is C1-6 Alkyl, the C 1-6 The alkyl group is substituted by an optionally substituted 5-6 membered heteroaryl group or an optionally substituted 3-6 membered heterocyclyl group. 1 Can be C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a 3-6 membered heterocyclic group selected from:

[0260] as well as Each of these can be optionally substituted.

[0261] As will be apparent to those skilled in the art, optionally substituted heterocyclyl groups may have defined stereochemistry at one or more chiral centers (when present). For example, in some embodiments, R 1 It is C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a 3-6 membered heterocyclic group selected from:

[0262] as well as Each of these can be optionally substituted.

[0263] In some embodiments, R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with C 1-6 In some embodiments, R 1 It is C 1-4 Alkyl, the C 1-4 Alkyl is C 1-6 Carbocyclyl is substituted, optionally wherein C 1-6 The carbocyclyl group is selected from optionally substituted cyclobutyl or optionally substituted cyclopropyl.

[0264] In some embodiments, R 1 yes

[0265] In other embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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)R10 ,–C(O)R 9 ,–C(O)NR 9 R 10 ,–C(O)SR 9 OR –C(O)OR 9 .

[0266] In some embodiments, R 3 is halogen, hydroxy or optionally substituted C 1-6 Alkyl, such as -CF3 or -CH2CF3. In some embodiments, R 3 It 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 Carbocyclic or optionally substituted C 5-10 In some embodiments, R 3 is –CN, –C(O)R 9 、–C(O)OR 9 、–S(O)2R 9 Or -NO2. In some embodiments, R 3 Yes – SR 9 ,–NR 9 R 10 OR 9 , such as –OMe or –OCF3.

[0267] In some embodiments, R 3 It’s H.

[0268] In some embodiments, R 3 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 .

[0269] In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, q is 0.

[0270] In some embodiments, q is 0 or 1. In some embodiments, the compound has the structure of Formula (Va), (Vb), or (Vc):

[0271]

[0272] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0273] In some embodiments, R 4 is selected from 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.

[0274] In some embodiments, R 4 is selected from halogen, -CN and -NO2. In some embodiments, R 4 In some embodiments, R 4 It's F.

[0275] In some embodiments, L is a linking group selected from: -C(O)N(R 9 )-, -S(O)2-, -C(O)- or -C(O)O-; or a linking group selected from the following: 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 optionally substituted by -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-. In certain embodiments, the linking group is selected from -S(O)2-, C(O)-, -C(O)O-. In certain embodiments, the linking group is an optionally substituted C 1-4In certain embodiments, the linking group is a C-alkylene group interrupted by -S(O)2-, -C(O)-, -C(O)O-, or -O(O)C-. 1-4 Alkylene.

[0276] In some embodiments, L is a bond, and the compound has the structure of Formula (VI):

[0277]

[0278] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0279] In some embodiments, q is 0 or 1. In some embodiments, the compound has the structure of Formula (VIa), (VIb), or (VIc):

[0280]

[0281] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0282] In some embodiments, R 4 is selected from 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.

[0283] In some embodiments, R 4 is selected from halogen, -CN, and -NO2. In some embodiments, the halogen is F.

[0284] 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 Alkoxyalkyl.

[0285] In some embodiments, R 5 It’s H.

[0286] In some embodiments, R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C2-10 Alkynyl, each of which is optionally substituted with one or more substituents, which may be selected from optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when present, taken 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.

[0287] In some embodiments, R 6 Selected from optionally substituted C 5-10 aryl and optionally substituted 5- to 10-membered heteroaryl.

[0288] In some embodiments, R 6 is an optionally substituted C 5-10 Aryl, such as phenyl, naphthyl or azulenyl, each of which may be optionally substituted. In some embodiments, R 6 is optionally substituted phenyl.

[0289] In some embodiments, R 6It is an optionally substituted 5-10 yuan heteroaryl. In some embodiments, the 5-10 yuan heteroaryl is a monocyclic heteroaryl, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl or pyrimidinyl, each of which can be optionally substituted. In some embodiments, the 5-10 yuan heteroaryl is a bicyclic heteroaryl, such as quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzophenylthio, benzimidazolyl, naphthyridinyl, quinolyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl [4,5-b] pyridyl, pyridopyrimidinyl, isoquinolyl and benzohydroxazole (benzohydroxazole), each of which can be optionally substituted.

[0290] In certain embodiments, R 6 is an optionally substituted C6 aryl group, an optionally substituted 5-membered heteroaryl group or an optionally substituted 6-membered heteroaryl group.

[0291] In certain embodiments, R 6 Selected from:

[0292]

[0293] Each of these can be optionally substituted.

[0294] In certain embodiments, R 6 Selected from:

[0295]

[0296] Each of these can be optionally substituted.

[0297] In some embodiments, selected from C 5-10 The above-mentioned R of aryl and 5-10 membered heteroaryl 6 The groups are independently substituted with one or more substituents selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when 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. In some embodiments, the one or more substituents are selected from the group consisting of halogen, an optionally substituted 5-membered heterocyclyl, an 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.

[0298] In some embodiments, R 6 is selected from optionally substituted 3-10 membered heterocyclic group and optionally substituted C 3-10 Carbocyclic group.

[0299] In some embodiments, R 6 Selected from optionally substituted 3-10 membered heterocyclyl. In some embodiments, the 3-10 membered heterocyclyl is a monocyclic heterocyclyl, such as aziridine, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or piperidonyl, each of which can be optionally substituted. In some embodiments, the 3-10 membered heterocyclyl is a bicyclic heterocyclyl, such as dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl or benzazepanyl, each of which can be optionally substituted.

[0300] In some embodiments, R 6 It is C 3-10 Carbocyclyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, norbornyl or spiro[4.4]nonanyl, each of which may be optionally substituted.

[0301] In some embodiments, the group consisting of optionally substituted 3-10 membered heterocyclyl and optionally substituted C 3-10 The above-mentioned R of the carbocyclic group 6 The groups are independently substituted with one or more substituents selected from the group consisting of: optionally substituted C 1-6Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when 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. In some embodiments, the one or more substituents are selected from the group consisting of halogen, –CN, –NO2, and –C(O)OR 11 , where R 11 It can be H or optionally substituted C 1-6 In some embodiments, the one or more substituents are halogen, -C(O)OH, or -C(O)OC 1-6 alkyl.

[0302] In some embodiments, R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from 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)R11 ,–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 .

[0303] In some embodiments, R 6 and R 5 The optionally substituted 3-10 yuan heterocyclic radical is formed together with the atom to which it is connected.The optionally substituted 3-10 yuan heterocyclic radical can be a monocyclic heterocyclic radical, such as aziridine, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or azepanyl, each of which can be optionally substituted.Alternately, the optionally substituted 3-10 yuan heterocyclic radical can be a bicyclic heterocyclic radical, such as dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl and benzazepanyl, each of which can be optionally substituted.

[0304] In some embodiments, R 6 and R 5 and the atoms 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 furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, 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 quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl[4,5-b]pyridinyl, pyridopyrimidinyl, isoquinolinyl, and benzohydrooxazole, each of which can be optionally substituted.

[0305] In some embodiments, R is selected from optionally substituted 3-10 membered heterocyclyl and optionally substituted 5-10 membered heteroaryl. 6 and R 5 The group formed together with the atoms to which it is attached is independently substituted with one or more substituents selected from the group comprising: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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, the one or more substituents are selected from the group consisting of halogen, -CN, -NO2, and -C(O)OR 11 , where R 11 It can be H or optionally substituted C 1-6 In some embodiments, the one or more substituents are halogen, -C(O)OH, or -C(O)OC 1-6 alkyl.

[0306] In some embodiments, R 6 Selected from optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl and optionally substituted C 2-10 Alkynyl.

[0307] 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 alkyl.

[0308] In some embodiments, R 6 is an optionally substituted C 2-10 In some embodiments, C 2-10 Alkenyl is a branched C 2-10 Alkenyl.

[0309] In some embodiments, R 6 is an optionally substituted C 2-10 In some embodiments, C 2-10 Alkynyl is a branched C2-10 Alkynyl.

[0310] In some embodiments, the group consisting of optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl and optionally substituted C 2-10 The above-mentioned R of the alkynyl group 6 The groups are independently substituted with one or more substituents selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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, the one or more substituents are selected from the group consisting of: -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 .

[0311] In some embodiments, the present disclosure provides a compound selected from the following structures:

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0327] In some embodiments, the compounds of the present invention are selected from any one 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 compounds of the present invention are selected from any one 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 compounds of the present invention are selected from any one of compounds 1-14 and 56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the compounds of the present invention are selected from any one of compounds 1-6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the compounds of the present invention are compound 6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the compounds of the present invention are selected from any one 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.

[0328] In some embodiments, the present disclosure provides a In certain embodiments of the compound or pharmaceutically acceptable salt thereof, the compound is

[0329] In some embodiments, the present disclosure provides a In certain embodiments of the compound or pharmaceutically acceptable salt thereof, the compound is

[0330] In some embodiments, the present disclosure provides a In certain embodiments of the compound or pharmaceutically acceptable salt thereof, the compound is

[0331] In some embodiments, the present disclosure provides a In certain embodiments of the compound or pharmaceutically acceptable salt thereof, the compound is

[0332] In some embodiments, the present disclosure provides a In certain embodiments of the compound or pharmaceutically acceptable salt thereof, the compound is

[0333] In some embodiments, the present disclosure provides a In certain embodiments of the compound or pharmaceutically acceptable salt thereof, the compound is

[0334] The compounds of the present disclosure may be provided in the form of salts, preferably pharmaceutically acceptable salts, solvates and / or stereoisomers thereof. In some embodiments, the compounds of the present disclosure may be provided in the form of pharmaceutically acceptable salts thereof.

[0335] Preparation of compounds

[0336] Compounds disclosed herein can be synthesized by the methods described below or by modifications of these methods. The method of modifying the method particularly includes temperature, solvent, reagent, etc. known to those skilled in the art. In general, during any process in the process for preparing compounds disclosed herein, it may be necessary and / or desirable to protect the sensitive or reactive groups on any molecule in the relevant molecule. This can be achieved by conventional protecting groups, such as in "Protective Groups in Organic Chemistry" (JFWMcOmie, ed., Plenum Press, 1973); and PGMGreen, TW Wutts, "Protective Groups in Organic Synthesis" (3rd edition) Wiley, New York (Wiley, New York) (1999), the protecting groups described in these two documents are hereby incorporated by reference in their entirety. Protecting groups can be removed in a convenient subsequent stage using methods known in the art. Synthetic chemical transformations that can be used to synthesize 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 hereby incorporated by reference in their entirety. The pathways shown and described herein are illustrative only and are not intended to, and should not be construed as, limiting the scope of the claims in any way. Those skilled in the art will be able to identify modifications to the disclosed syntheses and devise alternative pathways based on the disclosure herein; all such modifications and alternative pathways are within the scope of the claims.

[0337] Drugs and compositions and administration

[0338] While the compounds of the present disclosure can be administered as the raw chemical, the compounds can also be presented as pharmaceutical formulations.

[0339] Therefore, the present disclosure provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, prodrug or solvate thereof, and one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to its recipient. The appropriate formulation depends on the chosen route of administration. Any well-known techniques, carriers and excipients can be used where appropriate and understood in the art; for example, in Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present disclosure can be prepared in a manner known per se, for example by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or compression methods.

[0340] The formulation includes formulations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including skin, oral, sublingual and intraocular) administration, but the most suitable approach depends on, for example, the condition and illness of the recipient. The formulation can be conveniently present in unit dosage form and can be prepared by any method well known in the art. All methods include the step of associating a compound of the present disclosure or a pharmaceutically acceptable salt, prodrug or solvate thereof ("active ingredient") with a carrier constituting one or more auxiliary ingredients. In general, the formulation is prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0341] The formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0342] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. They can be prepared by compressing an active ingredient (such as a powder or granules) in a free-flowing form, optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be a dosage suitable for such administration. Push-fit capsules can contain an active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants 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 oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizing agent can be added. Suitable coatings are provided for dragee cores. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel (carbopol gel), polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. Dye or pigment can be added to tablet or dragee coating so that they can identify or characterize the different combinations of active compound dosage.

[0343] The compound can be formulated to be administered parenterally by injection, for example, by bolus injection or continuous infusion. The formulation for injection can be present in unit dosage form, for example, in an ampoule or in a multidose container, and be added with a preservative. The composition can take the form of a suspension, solution or emulsion such as in an oily or aqueous medium, and can contain a formulation such as a suspending agent, a stabilizer and / or a dispersant. The formulation can be present in a unit dose or multidose container, such as a sealed ampoule and a vial, and can be stored in a powder form or stored in a freeze-dried (lyophilized) condition that only requires adding a sterile liquid carrier immediately before use, such as saline or sterile pyrogen-free water. Provisional injection solutions and suspensions can be prepared by sterile powders, granules and tablets of the aforementioned kind.

[0344] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain a suitable stabilizer or agent that increases the solubility of the compound to allow the preparation of a high concentration solution.

[0345] In addition to the above formulations, the compounds of the present disclosure can also be formulated into depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin or as a slightly soluble derivative, e.g., as a slightly soluble salt.

[0346] 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 in the form of gels, suppositories, or dendrimer conjugates.

[0347] The compounds of the present disclosure may be administered topically, ie, by non-systemic administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin, such as gels, liniments, lotions, creams, ointments or pastes.

[0348] Gels for topical or transdermal administration of compounds of the present disclosure may include a mixture of a volatile solvent, a non-volatile solvent, and water. The volatile solvent component of the buffered solvent system may preferably include lower (C1-C6) alkyl alcohols, lower alkyl glycols, and lower glycol polymers. More preferably, the volatile solvent is ethanol. The volatile solvent component is believed to act as a penetration enhancer while also having a cooling effect on the skin when it evaporates. The non-volatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol is used. The non-volatile solvent slows down the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. As with the volatile solvent, the amount of the non-volatile solvent component is determined by the pharmaceutical compound or drug used. When there is too little non-volatile solvent in the system, the pharmaceutical compound may crystallize due to the evaporation of the volatile solvent, while an excess will result in a lack of bioavailability due to poor release of the drug from the solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; 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 may include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, as well as cosmetic agents.

[0349] Lotions or liniments for application to the skin may also include an agent to hasten drying and cool the skin, such as an alcohol or acetone; and / or a humectant, such as glycerol; or an oil, such as castor oil or arachis oil.

[0350] Creams, ointments, or pastes according to the present disclosure are semisolid formulations of active ingredients for external application. They can be prepared by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with an oleaginous or non-oleaginous matrix using a suitable machine. The matrix can include hydrocarbons such as hard, soft, or liquid paraffin, glycerol, beeswax, metallic soaps; mucus; oils of natural origin such as almond oil, corn oil, peanut oil, castor oil, or olive oil; lanolin or its derivatives or fatty acids such as stearic acid or oleic acid and alcohols such as propylene glycol or macrogol. The formulation can incorporate any suitable surfactant, 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 siliceous silica may also be included, as well as other ingredients such as lanolin.

[0351] How to use

[0352] Without being bound by theory, it was discovered that the compounds of the present disclosure modulate (optionally inhibit) proton-activated GPCRs, such as GPR68 (OGR1).

[0353] Thus, in one aspect, the present disclosure provides 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition as disclosed herein. The method may include identifying a subject at risk for or suffering from a disease, disorder, or condition mediated by a proton-activated GPCR, and administering to the subject an effective amount of a compound for therapeutic treatment or prophylactic treatment.

[0354] 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).

[0355] Proton-activated GPCRs, such as GPR68 (OGR1), GPR4 (GPR4), and GPR65 (TDAG8), are involved in regulating key processes in inflammation, tumor biology, and fibrosis.

[0356] Thus, in some embodiments, the disease, disorder or condition mediated by a proton-activated GPCR is an inflammatory, fibrotic or proliferative disease, disorder or condition. In certain embodiments, the disease, disorder or condition is cancer.

[0357] In some embodiments, the compounds and methods provided herein are useful for treating inflammatory diseases, disorders, or conditions.

[0358] Generally, inflammatory diseases, disorders, or conditions that may be treated with the compounds disclosed herein relate to any disease, disorder, or condition characterized by an abnormal, irregular, excessive, undesirable, or unnecessary inflammatory response.

[0359] In some embodiments, the inflammatory disease, disorder or condition is the result of tissue damage. In some embodiments, the inflammatory disease, disorder or condition is the result of an autoimmune condition, while in other embodiments, the inflammatory disease, disorder or condition is the result of a bacterial or viral infection or the presence of a toxin.

[0360] The compounds provided herein can have anti-inflammatory and / or immunomodulatory activity and can be used to treat diseases including, but not limited to, septic shock, hemodynamic shock, septic syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, transplant rejection, cancer (e.g., cutaneous T-cell lymphoma), diseases involving angiogenesis, autoimmune diseases, inflammatory diseases of the skin, inflammatory bowel disease (e.g., Crohn's disease and colitis), ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcet's disease, Sjogren's syndrome, syndrome), sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxia 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, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergies, 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 can be used to treat one or more of these diseases, disorders or conditions.

[0361] In some embodiments, the inflammatory disease, disorder or condition is at least one inflammatory disease, 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).

[0362] In some embodiments, the inflammatory disease, disorder, or condition is arthritis, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, diabetic retinopathy, retinal inflammation, retinitis, Sjögren's syndrome, macular degeneration, gout, pseudogout, pericarditis, or uveitis.

[0363] In some embodiments, the inflammatory disease, disorder, or condition is focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disorder (COPD), asthma, or cystic fibrosis.

[0364] 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 with 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.

[0365] In some embodiments, the compounds and methods provided herein are useful for treating fibrotic diseases, disorders, or conditions.

[0366] "Fibrotic condition," "fibrotic disease," and "fibrotic disorder" are used interchangeably to refer to a condition, disease, or disorder characterized by dysregulated proliferation or activity of fibroblasts 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, skin fibrosis, pancreatic fibrosis, liver fibrosis (e.g., liver fibrosis associated with chronic active hepatitis), and pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiology.

[0367] In some embodiments, the fibrotic disease, disorder, or condition is renal fibrosis, pulmonary fibrosis, cardiovascular fibrosis, ocular fibrosis, skin fibrosis, pancreatic fibrosis, or liver fibrosis.

[0368] 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 glomerulonephropathy, glomerulonephritis, and diabetic nephropathy; lung diseases, such as pulmonary fibrosis; fibrotic skin disorders, such as keloids, hypertrophic scars, and scleroderma; heart diseases, such as heart failure due to ischemic heart disease, valvular heart disease, and hypertensive heart disease, diabetic cardiomyopathy, and hypertension; and liver diseases, such as liver fibrosis.

[0369] In certain embodiments, fibrotic disease, disease or condition are nephropathy.In certain embodiments, nephropathy can include but is not limited to progressive glomerulonephropathy, include but is not limited to diabetic nephropathy (for example, due to type I or type II diabetes or systemic lupus), primary glomerulonephritis (for example, membranous nephropathy, focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis) or secondary glomerulonephritis (for example, diabetic nephropathy, ischemic nephropathy).In certain embodiments, nephropathy can include the progressive nephropathy that mainly originates from tubulointerstitial.In certain embodiments, nephropathy can include but is not limited to chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis or reflux nephropathy.

[0370] In some embodiments, fibrotic diseases, disorders, or conditions suitable for treatment by the methods provided herein include, but are not limited to, diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral 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).

[0371] In some embodiments, the compounds and methods provided herein are useful for treating a proliferative disease, disorder, or condition.

[0372] In general, proliferative diseases, disorders, or conditions that can be treated with the compounds disclosed herein relate to any disease, disorder, or condition characterized by abnormal cell proliferation. Cell proliferation can be self-propagating 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.

[0373] Proliferative diseases, disorders, or conditions that may be treated with the compounds disclosed herein include, but are not limited to, various retinopathies.

[0374] 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).

[0375] Proliferative diseases, disorders, or conditions that may be treated with the compounds disclosed herein further include, but are not limited to, various benign or malignant, metastatic or non-metastatic tumors and cancers.

[0376] Cancers that may be treated 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, squamous cell carcinoma of the lung, and adenocarcinoma, among others.

[0377] In certain embodiments, cancer is a cancer characterized by the presence of one or more tumors in the subject. Examples of cancers suitable for treatment by the compounds and methods provided herein include, but are not limited to, metastatic melanoma, metastatic prostate cancer, metastatic breast cancer, triple-negative breast cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, head and neck cancer, squamous cell lung cancer, non-small lung cell carcinoma, 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, cancer is metastatic melanoma, metastatic prostate cancer, or metastatic breast cancer. In certain embodiments, the subject has received an allogeneic tissue transplant related to cancer treatment, for example, after a hematopoietic stem cell transplant for the treatment of leukemia.

[0378] In some embodiments, the cancer suitable for treatment by the compounds and methods provided herein is breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer, or kidney cancer.

[0379] In some embodiments, the subject is a human.

[0380] As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to cure the identified disease or condition, ameliorate the identified disease or condition, slow the progression of the identified disease or condition, prevent the identified disease or condition, or reduce the likelihood of the onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by assays such as those disclosed in the Examples below. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically and prophylactically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0381] For any compound, a therapeutically or prophylactically effective amount can be initially estimated in a cell culture assay, for example, of tumor cells, or in an animal model (typically 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.

[0382] Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is 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 it can be expressed as the ratio ED 50 / LD 50 Pharmaceutical compositions that exhibit a large therapeutic index are preferred. However, pharmaceutical compositions that exhibit a narrow therapeutic index are also within the scope of the present invention. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for human use. The dosage contained in such compositions preferably lies within a range of circulating concentrations that include the ED with little or no toxicity. 50 The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0383] The exact dosage will be determined by the practitioner based on factors relevant to the subject in need of treatment. Dosage and administration are adjusted to provide sufficient levels of active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, time and frequency of administration, drug combination, reaction sensitivity and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, weekly or biweekly, depending on the half-life and clearance rate of the particular formulation.

[0384] An effective amount of a compound of the present disclosure for modulating (e.g., inhibiting) a proton-activated GPCR, such as GPR68 (OGR1), includes an amount that can establish a concentration of between about 1 nm and about 1,000 μM in one embodiment, between about 1 nM and about 250 μM in another embodiment, between about 1 nM and about 100 μM in another embodiment, and between about 1 nM and about 50 μM in yet another embodiment. 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 that can establish a concentration of between about 1 μM and 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 (e.g., GPR68 (OGR1)) is an amount that can establish a concentration of about 100 μM, about 90 μM, about 80 μM, about 70 μM, about 60 μM, about 50 μM, about 40 μM, about 30 μM, about 20 μM, about 10 μM, or about 1 μM. In certain embodiments, an effective amount of a compound of the present disclosure for modulating (e.g., inhibiting) a proton-activated GPCR (e.g., GPR68 (OGR1)) is an amount that can establish 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 clear to those skilled in the art, the exact amount of the 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 based on the pharmacokinetics / metabolism of the compound and, when the disease, condition, or disorder is already established, may also vary based on the stage or severity of the disease, condition, or disorder. Dosing and amount are also affected by the mode of administration, such as oral versus intravenous administration.

[0385] In some embodiments, treating a disease, disorder, or condition described herein increases the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average 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 aspect, the increase in the average survival time of a population can be measured, for example, by calculating the average survival length of a population after starting treatment with an active compound. In another preferred aspect, the increase in the average survival time of a population can also be measured, for example, by calculating the average survival length of a population after completing a first round of treatment with an active compound.

[0386] In some embodiments, treating a disease, disorder, or condition described herein results in a reduction in mortality among the treated population of subjects compared to a population of subjects receiving vehicle alone. In another aspect, treating a condition described herein results in a reduction in mortality among the treated population of subjects compared to an untreated population. In another aspect, treating a condition described herein results in a reduction in mortality among the treated population of subjects compared to a population receiving monotherapy with a drug that is not a compound of these Examples, or a pharmaceutically acceptable salt, metabolite, analog, or derivative thereof. Preferably, the reduction in mortality is greater than about 2%; more preferably, greater than about 5%; more preferably, greater than about 10%; and most preferably, greater than about 25%. In one preferred aspect, the reduction in mortality among the treated population of subjects can be measured by any reproducible means. In another preferred aspect, the reduction in mortality among the treated population of subjects can be measured, for example, by calculating the average number of disease-related deaths per unit time after the start of treatment with the active compound. In another preferred aspect, the reduction in mortality among the treated population of subjects can also be measured, for example, by calculating the average number of disease-related deaths per unit time after the completion of the first round of treatment with the active compound.

[0387] In certain embodiments, treatment of a disease, disorder, or condition described herein results in a decrease in the rate of cell proliferation. Preferably, following treatment, the rate of cell proliferation is decreased 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 aspect, the rate of cell proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0388] In another aspect, treating a disease, disorder, or condition described herein results in a decrease 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 measurement means. 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.

[0389] 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% relative to its 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.

[0390] The methods described herein may include identifying a subject in need of treatment. In a preferred embodiment, the methods include identifying a mammal in need of treatment. In a highly preferred embodiment, the methods include identifying a human in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject that may benefit from treatment. For example, identifying a subject in need of treatment may be accomplished by clinical diagnosis, laboratory testing, or any other means known to those skilled in the art, including any combination of means for identification.

[0391] As described elsewhere herein, if desired, the compounds described herein can be formulated into pharmaceutical compositions and can be administered by any route that allows the treatment of a disease or condition. The preferred route of administration is oral administration. Administration can take the form of a single dose administration, or the compounds of these embodiments can be administered over a period of time in divided doses or with a continuous release formulation or administration method (e.g., a pump). However, when the compounds of these embodiments are administered to a subject, the amount of the compound administered and the selected route of administration should be selected to allow for effective treatment of the disease condition.

[0392] Additional embodiments include administering a combination of compounds to a subject in need thereof. A combination may include a compound, composition, pharmaceutical composition described herein and an additional drug for treating and / or preventing a disease, disorder, or condition mediated by a proton-activated GPCR.

[0393] Some embodiments include co-administration of a compound, composition, and / or pharmaceutical composition described herein and an additional drug. "Co-administration" means that two or more agents can be present in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In some embodiments, the agents are administered simultaneously. In some such embodiments, combined 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 by the same route (e.g., oral). In some other embodiments, the agents are administered by different routes, such as one route is administered orally and the other route is administered intravenously. Thus, for example, the combination of active ingredients can be: (1) co-formulated and administered or delivered simultaneously in the form of a combined formulation; (2) delivered alternately or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods described herein can include, for example, sequentially administering or delivering the active ingredients in the form of separate solutions, emulsions, suspensions, tablets, pills, or capsules, or by separate injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially (ie, serially), whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy can also be employed.

[0394] For example, the compounds and / or pharmaceutical compositions described herein can be co-administered with another drug or therapy for treating and / or preventing a disease, disorder, or condition mediated by a proton-activated GPCR. In some embodiments, the compounds and / or pharmaceutical compositions described herein can be co-administered with a drug or therapy for treating and / or preventing an inflammatory, fibrotic, or proliferative disease, disorder, or condition. In certain embodiments, the compounds and / or pharmaceutical compositions described herein can be co-administered with a drug or therapy for treating and / or preventing cancer.

[0395] Another embodiment of the present disclosure provides a method for inhibiting a proton-activated GPCR in a cell, the method comprising administering to the cell an effective amount of a compound of the present disclosure. The cell may be in cell culture. The cell may be present in a tissue or otherwise contain tissue. The tissue may be human tissue.

[0396] In some embodiments, the proton-activated GPCR is GPR68 (OGR1).

[0397] In certain embodiments, the cell is a tumor cell. The tumor cell can be a pancreatic tumor cell, a head and neck tumor cell, a lung tumor cell, a kidney tumor cell, a breast tumor cell, a colon tumor cell, an ovarian tumor cell, a lymph node tumor cell, a stomach tumor cell, an esophageal tumor cell, a skin tumor cell, a brain tumor cell, an oral tumor cell, a pharyngeal tumor cell, a thyroid tumor cell, an adrenal tumor, a leukemia cell, a sarcoma cell, a testicular tumor cell, a bladder tumor cell, or a prostate tumor cell. The tumor cell can be in cell culture. The cell can be present in tumor tissue or otherwise comprise tumor tissue.

[0398] The present disclosure is further described by the following examples, which are not intended to limit the scope of the claims.

[0399] Example 1. Experimental preparation and analysis conditions

[0400] Abbreviations

[0401] 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); H2O (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 (milliliter), mmol (millimolar); 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 (trimethylsilylpolyphosphate); DCE (1,2-dichloroethane); HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); (COCl)2 (oxalyl chloride) ; Cs2CO3 (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 hydride); Aq (aqueous solution); HPLC: high performance liquid chromatography; M: molar, molecular ion; UV: ultraviolet; UPLC: ultra-performance liquid chromatography.

[0402] General experiments

[0403] All starting materials and solvents were obtained from commercial sources or prepared according to literature references.Unless otherwise indicated, the reaction mixtures were stirred magnetically and the reactions were carried out at room temperature (about 20°C).

[0404] Unless otherwise indicated, column chromatography was performed on an automated flash chromatography system (such as the Biotage Isolera Rf system) using pre-packed silica (40 μm) cartridges.

[0405] Recorded using a Bruker AVANCE 400 MHz spectrometer 1 H NMR spectroscopy. 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 the central peak of the residual protic solvent or the internal standard of tetramethylsilane as reference. Spectra were recorded at 298 K unless otherwise indicated.

[0406] A Waters ACQUITY HPLC system equipped with an ACQUITY PDA detector and an ACQUITY QDa mass detector was used. Analytical UPLC-MS experiments were performed on an H-Class system, running one of the analytical methods described below, to determine retention times and associated mass ions.

[0407] LC-MS analytical experiments 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 to determine retention times and associated mass ions.

[0408] Preparative HPLC general method:

[0409] HPLC instrument: Shimadzu 20AP UV detector: SPD-20A. UV wavelength: 214 nm and 254 nm.

[0410] Condition 1: Mobile phase A: water; Mobile phase B: acetonitrile.

[0411] Condition 2: Mobile phase A: water containing 0.1% trifluoroacetic acid; Mobile phase B: acetonitrile.

[0412] Condition 3: Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile.

[0413] Condition 4: Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile.

[0414] Column: Agilent 10 Prep-C18 250x21.2mm. Column temperature: ambient

[0415] LC gradient: 20% to 85% in 20 minutes; then 85% to 100% in 0.01 minutes; then held at 100% for 5 minutes; then 100% to 20% in 0.01 minutes; held at 20% for 5 minutes.

[0416] LC flow rate: 20 ml / min binary pump.

[0417] Use from The 'structure to name' conversion of Professional 17 (PerkinElmer) generated the structural nomenclature.

[0418] Analytical methods

[0419] Method 1 - Acid method (Shimadzu 3 minutes)

[0420] Column: Shimadzu LC-20AD series, binary pump, diode array detector. Agilent Poroshell 120EC-C18, 2.7 μm, 4.6 × 50 mm column.

[0421] Detection: 2020, quadrupole LC / MS, ion source: API-ESI, TIC: 100-900 m / z, drying gas flow: 15 L / min, nebulizer pressure: 1.5 L / min, drying gas temperature: 250°C, Vcap: 4500 V. Samples were dissolved in methanol at a concentration of 1-10 μg / mL and filtered through a 0.22 μm filter. Injection volume: 1-10 μL. Detection: 214 nm, 254 nm. Detection wavelengths: 214 nm, 254 nm.

[0422] Solvents: A: water containing 0.05% v / v formic acid, B: MeCN containing 0.05% v / v formic acid.

[0423] gradient:

[0424] T (minutes) A(％) B(％) Flow rate (ml / min) 0.00 80 15 1.5 0.28 80 15 1.5 2.38 10 90 1.5 2.39 0 100 1.5 2.69 0 100 1.5 2.70 85 15 1.5 3.00 85 15 1.5

[0425] Method 2 – Acidic 5-minute method (Shimadzu 5-minute)

[0426] Column: Shimadzu LC-20AD series, binary pump, diode array detector. Agilent Poroshell 120EC-C18, 2.7 μm, 4.6 × 50 mm column.

[0427] Detection: 2020, quadrupole LC / MS, ion source: API-ESI, TIC: 100-900 m / z, drying gas flow: 15 L / min, nebulizer pressure: 1.5 L / min, drying gas temperature: 250°C, Vcap: 4500 V. Samples were dissolved in methanol at a concentration of 1-10 μg / mL and filtered through a 0.22 μm filter. Injection volume: 1-10 μL. Detection wavelengths: 214 nm, 254 nm.

[0428] Solvents: A: water containing 0.05% formic acid (v / v), B: MeCN containing 0.05% formic acid (v / v).

[0429] gradient:

[0430] T (minutes) A(％) B(％) Flow rate (ml / min) 0.00 80 15 1.0 0.50 80 15 1.0 4.00 15 85 1.0 4.01 0 100 1.0 4.50 0 100 1.0 4.51 85 15 1.0 5.00 85 15 1.0

[0431] Method 3 – Acidic Method (Waters QDa 3 minutes)

[0432] Column: Waters QDa, binary pump, diode array detector. Waters CORTECS UPLC, C18, 1.6 μm, 2.1×50 mm column.

[0433] Detection: QDa, quadrupole LC / MS, ion source: API-ES, TIC: 70–900 m / z, fragmentor voltage: 70, drying gas flow: 12 L / min, nebulizer pressure: 36 psi, drying gas temperature: 350°C, Vcap: 3000 V. Samples were dissolved in methanol at a concentration of 1–10 μg / mL and filtered through a 0.22 μm filter. Injection volume: 1–10 μL. Detection: 214 nm, 254 nm.

[0434] Solvents: A: 0.05% formate in water (v / v), B: 0.05% formate in MeCN (v / v).

[0435] gradient:

[0436] T (minutes) A(％) B(％) Flow rate (ml / min) 0.00 80 20 0.6 1.80 20 80 0.6 2.65 20 80 0.6 2.80 80 20 0.6 3.00 80 20 0.6

[0437] Method 4 - Acidic Method (Agilent 3 minutes)

[0438] Column: Agilent Technologies 1290 Series, binary pump, diode array detector. Agilent Eclipse Plus RRH DC18, 1.8 μm, 3.0 × 50 mm.

[0439] Detection: G6120A, quadrupole LC / MS, ion source: API-ES, TIC: 70–1000 m / z, fragmentor voltage: 70, drying gas flow: 12 L / min, nebulizer pressure: 36 psi, drying gas temperature: 350°C, Vcap: 3000 V. Samples were dissolved in methanol at a concentration of 1–10 μg / mL and filtered through a 0.22 μm filter. Injection volume: 1–10 μL. Detection: 214 nm, 254 nm.

[0440] Solvents: A: 0.05% formate in water (v / v), B: 0.05% formate in MeCN (v / v).

[0441] gradient:

[0442]

[0443]

[0444] Example 2. Synthesis of intermediates

[0445] The compounds of the present disclosure can be prepared by methods well known to those skilled in the art and / or as described in the synthetic experimental procedures shown below.

[0446] Intermediate 1. (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid

[0447]

[0448] Step 1: 5-Bromo-1-(cyclopropylmethyl)-1H-indazole

[0449] At 0 ° C, t-BuOK (136.68 g, 1.22 mol) and (bromomethyl) cyclopropane (164.44 g, 1.22 mol) were added to a solution of 5-bromo-1H-indazole (200.00 g, 1.02 mol) in THF (1200 mL). The reaction mixture was stirred at 50 ° C overnight. The reaction mixture was treated with water and extracted with EtOAc (1000 mL * 2), washed with brine (1000 mL) and dried over Na2SO4. 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. 1H NMR(400MHz, DMSO-d6)δ8.01(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).

[0450] Step 2: (E)-tert-Butyl 3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylate

[0451] Under N2 atmosphere, to a solution of 5-bromo-1-(cyclopropylmethyl)-1H-indazole (125.00 g, 0.49 mol) in DMF (500 mL) was added Pd(OAc)2 (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), and stirred at 110°C overnight. The mixture was concentrated in vacuo and 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) δ8.10(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=15.9Hz,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).

[0452] Step 3: (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid

[0453] 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 reaction was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and washed with MeOH, and the filter cake was concentrated under vacuum to give the title compound (76.0 g, 0.31 mol, 85.1% yield) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ12.28(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=15.9Hz,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).

[0454] Intermediate 2. (E)-3-(1-methyl-1H-indazol-5-yl)acrylic acid

[0455]

[0456] Step 1: (E)-tert-Butyl 3-(1-methyl-1H-indazol-5-yl)acrylate

[0457] Using the procedure outlined in Step 2 of Intermediate 1, starting from 5-bromo-1-methyl-1H-indazole (10.0 g, 47.62 mmol), the title compound was obtained as a white solid (7.0 g, 27.13 mmol, 57% yield). 1 H NMR (400MHz, DMSO-d6) δ8.08(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).

[0458] Step 2: (E)-3-(1-methyl-1H-indazol-5-yl)acrylic acid

[0459] Using the procedure outlined in Step 3 of Intermediate 1, starting from tert-butyl (E)-3-(1-methyl-1H-indazol-5-yl)acrylate (7.0 g, 27.13 mmol), the title compound was obtained as a white solid (5.0 g, 24.75 mmol, 91% yield). 1H NMR (400MHz, DMSO-d6) δ12.15(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).

[0460] Intermediate 3. 3-(2-aminophenyl)-1,2,4-oxadiazol-5(4H)-one

[0461]

[0462] Step 1: tert-Butyl (2-cyanophenyl)carbamate

[0463] At room temperature, 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), DMAP (100 mg, 0.85 mmol). The resulting solution was stirred at room temperature for 16 hours. The solvent was removed and 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).

[0464] Step 2: tert-Butyl (E)-(2-(N'-hydroxycarbamimidoyl)phenyl)carbamate

[0465] 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 hours. 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. 1H NMR (400MHz, DMSO-d6) δ10.41(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).

[0466] Step 3: tert-Butyl (2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)carbamate

[0467] 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 chloroformate (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 and 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 to give a crude product, which was dissolved in EtOAc (10 mL) and K2CO3 (959 mg, 6.95 mmol) was added. The mixture solution was refluxed for 16 hours. The solvent was removed and 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. 1 H NMR (400MHz, DMSO-d6) δ12.84(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).

[0468] Step 4: 3-(2-aminophenyl)-1,2,4-oxadiazol-5(4H)-one

[0469] Using the procedure outlined in Step 3 of Intermediate 1, starting from 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 was obtained as a white solid (177.0 mg, 1.0 mmol, 100% yield) and was then used directly in the next step without further purification. UPLC-MS (Method 3) m / z 178.0, (M+H) + At 1.126 minutes.

[0470] Intermediate 4.3-(2-aminophenyl)-1,2,4-oxadiazol-5(4H)-one

[0471]

[0472] Step 1: 5-(2-nitrophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazol-2(3H)-one

[0473] 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) δ8.16(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).

[0474] Step 2: 5-(2-aminophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazol-2(3H)-one

[0475] A mixture solution 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 hours. 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. 1H NMR(400MHz,DMSO-d6)δ7.48(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).

[0476] Example 3. Synthesis of Compound 6

[0477]

[0478] Step 1: Methyl (E)-2-(3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamido)benzoate

[0479] At 0 ° C, to a mixture of (E) -3- (1- (cyclopropylmethyl) -1H- indazole -5- bases) acrylic acid (intermediate 1, 76.0g, 0.31mol) in DCM (500mL) was added (COCl) 2 (59.65g, 0.47mol) and catalyst DMF. The reaction solution was stirred at room temperature for 1 hour. The mixture reaction solution was concentrated and dissolved in DCM (500mL), followed by addition of methyl 2-aminobenzoate (47.42g, 0.31mol) and DIPEA (120.19g, 0.93mol). The resulting solution was stirred at room temperature for 3 hours. The mixture reaction solution was concentrated in a vacuum and purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to DCM / EtOAc = 30 / 1) to obtain 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) δ10.86(s,1H),8.48(dd,J=8.5,1.1Hz,1H),8.13(d,J=16.2Hz,2 H),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),7.6 7(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=6.9 Hz,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).

[0480] Step 2: (E)-2-(3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamido)benzoic acid

[0481] A mixture of (E)-methyl 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 hours. The solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 3 with 2M HCl. The mixture was extracted with EtOAc, dried over Na2SO4 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, (MH) - At 2.185 minutes. 1 H NMR (400MHz, DMSO-d6) δ13.60 (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 =6.9Hz, 2H), 1.29 (t, J = 9.8Hz, 1H), 0.49 (d, J = 7.6Hz, 2H), 0.41 (t, J = 4.4Hz, 2H).

[0482] Example 4. Synthesis of Compound 9

[0483]

[0484] Step 1: (E)-3-(1-methyl-1H-indazol-5-yl)-N-(pyridin-2-yl)acrylamide

[0485] To a mixture of (E)-3-(1-methyl-1H-indazole-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 catalyst DMF at 0 ° C. The reaction solution was stirred at room temperature for 1 hour. The mixture reaction solution 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 reaction solution 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 minutes. 1 H NMR (400MHz, DMSO-d6) δ10.68(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).

[0486] Example 5. Synthesis of Compound 12

[0487]

[0488] Step 1: (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)-N-(2-nitrophenyl)acrylamide

[0489] Using the procedure outlined in Step 1 of Example 1, starting from (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylic acid (500.0 mg, 2.06 mmol), the title compound was obtained as a yellow solid (500.0 mg, 1.38 mmol, 67% yield). 1 H NMR(400MHz,DMSO-d6)δ10.47(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).

[0490] Step 2: (E)-N-(2-aminophenyl)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)acrylamide

[0491] Using the procedure outlined in Step 2 of Intermediate 4, starting from (E)-3-(1-(cyclopropylmethyl)-1H-indazol-5-yl)-N-(2-nitrophenyl)acrylamide (500.0 mg, 1.38 mmol), the title compound was obtained as a yellow solid (400.0 mg, 1.2 mmol, 87% yield). 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.13(s,1H),7.99(s,1H),7.78(d,J=8.8 Hz,1H),7.72–7.62(m,2H),7.35(d,J=7.9Hz,1H),6.96–6.83(m,2H),6.76(dd ,J=8.0,1.4Hz,1H),6.58(td,J=7.6,1.4Hz,1H),4.95(s,2H),4.32(d,J=7.0H z, 2H), 1.28 (d, J = 2.9Hz, 1H), 0.49 (dt, J = 7.8, 2.9Hz, 2H), 0.43–0.37 (m, 2H).

[0492] Step 3: (E)-3-(1-(Cyclopropylmethyl)-1H-indazol-5-yl)-N-(2-((2,2,2-trifluoroethyl)sulfonamido)phenyl)acrylamide

[0493] To a mixture of (E)-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 solution was stirred at room temperature for 1 hour. 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 and purified by preparative HPLC (eluted with 10% to 90% MeCN / H2O, 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, (MH) - At 2.300 minutes. 1H NMR(400MHz, DMSO-d6)δ9.73(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,1H),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).

[0494] Example 6. Analytical data such as synthesized compounds

[0495] The following exemplary compounds were prepared by the methods described above in Examples 3 to 5; or by methods analogous to the methods described above, substituting appropriate starting materials and intermediates as necessary.

[0496]

[0497]

[0498]

[0499]

[0500] Example 7. Biological testing

[0501] GPR68 cAMP GloSensor Assay Protocol

[0502] The assay was developed to provide a rapid screening assay to determine the potency and EC50 / IC50 of compounds at the GPR68 receptor in transiently transfected cells.

[0503] Assay design principles

[0504] GPR68 senses extracellular pH. It was found that in cells expressing GPR68, the levels of cyclic adenosine monophosphate (cAMP), a secondary messenger associated with GPCR activation in cAMP-dependent pathways, were elevated at neutral to acidic extracellular pH (pH 7.0-6.5). The pH sensing ability of GPR68 was further tested and confirmed because cAMP levels were found to increase when GPR68 was stimulated by pH values ​​less than pH 7.2.

[0505] In order to determine the 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 of a GPR68 expression vector and a cAMP sensing reporter vector (GloSensor, Promega). The transfected cells as a pool are evenly re-plated in an assay plate to minimize variations in the experiment. GPR68 receptor signaling will be measured by the increase in Gs to cAMP, as indicated by Luc activation in the basal (pH 8.4 or pH 7.4) or activated (pH 6.5 or pH 6.0) state.

[0506] Reagent List

[0507] GloSensor TM cAMP reagent (Promega, catalog number E1291)

[0508] Human GPR68 NM_001177676.2_pcDNA3.1(+) (Genscript)

[0509] GloSensor TM -22F cAMP reporter gene vector (Promega, catalog number E2301)

[0510] DMEM (Gibco, catalog number 11995065)

[0511] FBS, qualified, New Zealand origin (Gibco, catalog number 10091148)

[0512] Penicillin-streptomycin (Gibco, catalog number 15140122)

[0513] 0.25% Trypsin-EDTA (Gibco, catalog number 25200056)

[0514] PBS (Gibco, catalog number 10010049)

[0515] 1x HBSS (Gibco, catalog number 14175079)

[0516] HEPES (Gibco, catalog number 15630080)

[0517] MES (Sigma, catalog number M2933-25G)

[0518] TAPS (Sigma, catalog number T5316-25G)

[0519] NaOH (Sigma, catalog number 221465)

[0520] BSA (Sigma, catalog number B2064-50G)

[0521] Opti-MEM (Gibco, catalog number 31985070)

[0522] DMSO (Sigma, catalog number D5879-1L)

[0523] FuGene HD transfection reagent (Promega, catalog number E2311)

[0524] Consumables / Supplies List

[0525] 96-well plate (Corning, catalog number 3610)

[0526] 6-well plate (Corning, catalog number 3516)

[0527] 96-well V-bottom plate (Greiner Bio-one, catalog number 651201)

[0528] 100 mm cell culture dish (Corning, catalog number CLS430167)

[0529] Equipment and Settings

[0530] Liquid handler: Echo (LABCYTE Echo550), BRAVO (Agilent)

[0531] Incubator (Grant Bio-Constant Incubator Shaker PHMP)

[0532] Plate centrifuge (Eppendorf 5910R)

[0533] Plate reader: Envision (PE).

[0534] Experimental procedures

[0535] Cell culture procedures

[0536] 1. Thawing Cells

[0537] 1) Thaw frozen cells quickly in a 37°C water bath with gentle continuous stirring.

[0538] 2) Gently add the cells dropwise to a 15 ml centrifuge tube containing 10 ml of fresh pre-warmed complete medium. Then centrifuge the cells at 1000 rpm for 5 minutes.

[0539] 3) Discard the supernatant culture medium and resuspend the cell pellet in 10 ml of fresh, pre-warmed complete culture medium. Transfer the cells to a 10 cm dish and incubate at 37°C with 5% CO2 until the cells reach >90% confluence. The recovery rate of frozen cells is typically 80% or higher.

[0540] 2. Subculture

[0541] This cell line is typically split twice every 1-2 days at a dilution ratio of 1:3 to 1:5. Fresh cells typically require 1-2 days to grow to 85% confluency.

[0542] 1) Carefully aspirate all the culture medium, gently wash the cell monolayer with 5 mL of pre-warmed PBS for a 10 cm dish, rinse the cell layer with an appropriate amount (gently, 1 mL for a 10 cm dish) of 0.2% trypsin-EDTA, and then aspirate it.

[0543] 2) Add 5 times the volume of trypsin medium to stop trypsinization, and harvest the cells by centrifugation at 1000 rpm for 5 minutes at room temperature.

[0544] 3) Resuspend the cells in an appropriate amount of complete culture medium and split the cells as needed.

[0545] 3. Replacement of culture medium

[0546] 1) Gently aspirate the culture medium.

[0547] 2) Transfer fresh warm complete medium (37°C) to a 10 cm culture dish.

[0548] 4. Freezing Cells

[0549] 1) Repeat subculture steps 1-3.

[0550] 2) Centrifuge the cells at 1000 rpm for 5 minutes.

[0551] 3) Draw off the supernatant and add 1-2x10 6 Resuspend the cells in fresh freezing medium at a density of 10 cells / ml. Add 1 ml of cells to each cryogenic vial.

[0552] 4) Place the cryogenic vial of cells into a cryogenic freezing container, which is then transferred to -80°C overnight.

[0553] 5) Transfer the cryogenic vial into liquid nitrogen (-196°C).

[0554] Determination procedure

[0555] Step 1: Seed cells into 6-well plates

[0556] 1) When the cell confluence reached about 80%, the cells were detached using 0.25% trypsin.

[0557] 2) Resuspend the isolated cells in 3 ml of fresh cell culture medium, count the cells, and dilute the cells to an appropriate density.

[0558] 3) 1.5 x 10^6 cells were seeded into 6-well plates (Catalog No. 3516) at 2 ml / well, including the required transfection wells, so that the cell confluency was 80%-85% at the time of transfection.

[0559] 4) Incubate the cells at 37°C in a CO2 incubator for 6 hours.

[0560] Step 2: Transfection in 6-well plates

[0561] 5) Gently draw out the DMEM medium. Then add serum-free Culture medium was added to 6-well plates.

[0562] 6) Add 2.5 μg GPR68 and 2.5 μg GloSensor-22F at a 1:1 ratio and 12 μl FuGeneHD to 120 μl serum-free Mix gently and incubate at room temperature for 15 minutes.

[0563] 7) After the 15-minute incubation, add 137 μl of DNA transfection reagent complex to each well containing cells and culture medium. Gently mix by rocking the plate back and forth.

[0564] 8) Incubate the cells at 37°C CO2 The cells were incubated in an incubator for 19 h until they were ready for determination of transgene expression.

[0565] Step 3: Reseeding cells in 96-well plates

[0566] 40,000 cells were seeded in 100 μl / well in a 96-well plate (Cat. No. 3610) containing complete DMEM medium; incubated overnight.

[0567] Step 4: Test Compounds

[0568] 1. Preparation of buffer solutions at different pH values

[0569]

[0570] 2. Preparation of Compounds

[0571] 1) The compound was dissolved in 100% DMSO to a concentration of 50 mM.

[0572] 2) Prepare compound DMSO solution in 384LDV echo plate: the highest concentration is 10mM, 3-fold, 10 dose-response, so intermediate concentrations are generated by serial dilution (1:2) starting from 10000μM. Transfer 5μL of the intermediate compound tested + 10μl DMSO solution to the 384LDV echo plate. Centrifuge the echo plate at 1000rpm for 30 seconds and then perform the echo program. Transfer 180nL volume of compound to a 96 assay plate (Corning, catalog number 3599) by Echo550 to make duplicate compound 10 concentration points (the final highest concentration is 10μM, 3-fold, 10 dose-response, in duplicate). The final DMSO concentration is 0.1%.

[0573] 3) For the low and high control wells, transfer 180 nL of DMSO by ECHO.

[0574] 4) The layout of the assay plate with 180 nL / well of 100% DMSO containing compound, low control wells, and high control wells is shown below.

[0575] Compounds were prepared in 100% DMSO at 100X working concentration in assay plates, the assay volume was 150 μL, and the final DMSO concentration was 0.1%.

[0576]

[0577] 3. Fluorescein Loading

[0578] 1) Remove the culture medium and add 100 μL / well GloSensor (50X) to the cells, followed by incubation at room temperature for 2 hours.

[0579]

[0580] 2) After 2 hours of incubation, pre-read the background luminescence at -5 minutes.

[0581] 4. Compound Addition and Lum Signal Collection

[0582] 1) Dilute compounds to a maximum of 10 μM in assay buffer as follows:

[0583] • Transfer 180 nL of compound / DMSO ECHO- to a 96-well plate (Corning, Cat. No. 651201).

[0584] ● Add 150 μL of buffer of different pH values ​​to the compound plate and mix thoroughly.

[0585] 2) Remove 80 μL of GloSensor from the cell plate and add 100 μL / well of pH buffer with or without compound to the cell plate.

[0586] 3) Immediately transfer the cell plate to a plate reader.

[0587] 4) Read and collect the luminescence signal from 0 to 30 minutes on Envision.

[0588] Compound plates and pH-activated profiles

[0589]

[0590] High control: pH 6.0 + 0.1% DMSO

[0591] Low control: pH 8.4 + 0.1% DMSO

[0592] Compound: pH 6.0 buffer + compound

[0593] Data Analysis

[0594] The percent inhibition (%) at each compound concentration was calculated based on and relative to the signal in the high and low control wells contained within each assay plate. The high control wells were 0% inhibition (pH 6.0) and the low control wells were 100% inhibition (pH 8.4).

[0595] The inhibition rate of the compound was calculated according to the following formula:

[0596] Inhibition % = [CTL pH 6.0 - CPD pH 6.0] / [CTL pH 6.0 - CTL pH 8.4] * 100

[0597] The concentrations of test compounds and % inhibition values ​​were plotted, and the compound concentration required for 50% inhibition (IC 50 ).

[0598] The endpoint value (IC 50 ) was used as a quality control measure. The experiment was considered acceptable if the endpoint value was within 3 times of the expected value.

[0599] result

[0600] IC 50 The results of the described GPR68 cAMP GloSensor assay given by the values ​​indicate 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.

[0601] Table 1. GPR68 cAMP Glosensor assay results

[0602]

[0603]

[0604] The present disclosure is further described by reference to the following numbered examples.

[0605] Itemized List of Embodiments

[0606] Example 1. A compound having the structure of formula (I):

[0607]

[0608] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0609] in:

[0610] X is selected from N and NR 1 ;

[0611] Y is selected from N and NR 2 ;

[0612] R 1 and R 2 Independently selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 substituted by one or more groups selected from the following: C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 1-10 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 ;

[0613] or R 1 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0614] Each R 9 are independently selected from H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl;

[0615] Each R 10 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and –C(O)R 9 ;

[0616] R 3 Selected from 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 3-10Carbocyclyl, 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 and –NO2;

[0617] or R 3 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, wherein the fused 5-6 membered heteroaryl or the fused 5-6 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: 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 ;

[0618] q is an integer from 0 to 3;

[0619] R 4 is selected from 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;

[0620] R 5 selected from H, optionally substituted C 1-6Alkyl, 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 aryl, optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl;

[0621] L is a bond or selected from -C(O)N(R 9 )-, -S(O)2-, -C(O)- or -C(O)O-; or a linking group selected from optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, –OC 1-4 Alkylene or –OC 2-4 an alkenylene linking group, each of which is optionally substituted by -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–;

[0622] R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 alkynyl, each optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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)R11 、–C(O)OR 11 、–C(O)N(R 11 )2 or –C(O)SR 11 wherein two adjacent optional substituents, when 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;

[0623] or R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, said 3-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally substituted with one or more substituents optionally selected from the group consisting of: 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 ;

[0624] Each R 11 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, 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)2N(R 9 )2;

[0625] R 7 and R 8 Independently selected from H, C 1-6 Alkyl, C5-10 Aryl, 5-10 membered heteroaryl and C 3-10 carbocyclyl, each optionally substituted by one or more substituents selected from the group consisting of: 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 ;

[0626] n is an integer of 1 to 4.

[0627] Example 2. The compound according to Example 1, which has the structure of Formula (Ia):

[0628]

[0629] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0630] Example 3. The compound according to Example 1 or Example 2, which has the structure of Formula (II):

[0631]

[0632] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0633] Embodiment 4. The compound according to any one of embodiments 1 to 3, which has the structure of formula (IIa):

[0634]

[0635] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0636] Embodiment 5. The compound according to any one of embodiments 1 to 4, which has the structure of formula (III):

[0637]

[0638] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0639] Embodiment 6. A compound according to any one of embodiments 1 to 5, wherein R 1 It is C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-6 Carbocyclyl or heterocyclyl, each of which is optionally substituted with one or more substituents 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 substituted by one or more groups selected from the following: C 1-6 Carbocyclyl, heterocyclyl and heteroaryl, each of which is optionally substituted with one or more substituents 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 .

[0640] Embodiment 7. A compound according to any one of embodiments 1 to 6, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of 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 substituted by one or more groups selected from the following: C 1-6 Carbocyclyl, heterocyclyl and heteroaryl, each of which is optionally substituted with one or more substituents 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 .

[0641] Embodiment 8. A compound according to any one of embodiments 1 to 7, wherein R 1 It is C 1-6 alkyl.

[0642] Embodiment 9. A compound according to any one of embodiments 1 to 8, wherein R 1 is methyl, ethyl, propyl or isopropyl.

[0643] Embodiment 10. A compound according to any one of embodiments 1 to 9, wherein R 1 It's methyl.

[0644] Embodiment 11. A compound according to any one of embodiments 1 to 8, wherein R 1 It is C 1-6 Alkyl, the C 1-6 Alkyl is replaced by –OR 9 ,–C(O)R 9 ,–C(O)NR 9 R 10 、C(O)SR 9 OR –C(O)OR 9 replace.

[0645] Embodiment 12. The compound according to embodiment 11, wherein R 9 It's methyl.

[0646] Embodiment 13. A compound according to any one of embodiments 1 to 8, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with halogen or -CN, optionally wherein the halogen is F.

[0647] Embodiment 14. A compound according to any one of embodiments 1 to 8, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a heteroaryl group, which is optionally substituted with one or more substituents selected from the group consisting of 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 .

[0648] Embodiment 15. The compound according to embodiment 14, wherein R 1 is an optionally substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl and thiadiazolyl, each of which may be optionally substituted.

[0649] Embodiment 16. A compound according to any one of embodiments 1 to 8, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of 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 .

[0650] Embodiment 17. The compound of embodiment 16, wherein the heterocyclyl is an optionally substituted 3- to 6-membered heterocyclyl.

[0651] Embodiment 18. The compound of embodiment 16 or embodiment 17, wherein the heterocyclyl is an optionally substituted oxacyclyl.

[0652] Embodiment 19. The compound of embodiment 18, wherein the oxygen heterocycle is selected from: as well as Each of these can be optionally substituted.

[0653] Embodiment 20. A compound according to any one of embodiments 1 to 8, wherein R 1 It is C 1-6 Alkyl, the C 1-6 Alkyl is C 1-6 Carbocyclic substitution, the C 1-6 The carbocyclyl group is optionally substituted with one or more substituents selected from the group consisting of 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 .

[0654] Embodiment 21. The compound according to embodiment 20, wherein said C 1-6 Carbocyclyl is optionally substituted cyclopropyl.

[0655] Embodiment 22. The compound according to embodiment 20 or 21, wherein R 1 yes

[0656]

[0657] Embodiment 23. A compound according to any one of embodiments 1 to 22, wherein R 7 and R 8 is H, and the compound has the structure of formula (IV):

[0658]

[0659] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0660] Embodiment 24. A compound according to any one of embodiments 1 to 23, wherein R 3It’s H.

[0661] Embodiment 25. The compound of any one of embodiments 1 to 24, wherein q is 0, 1 or 2.

[0662] Embodiment 26. The compound of any one of Embodiments 1 to 25 having the structure of Formula (Va), (Vb) or (Vc):

[0663]

[0664] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0665] Embodiment 27. A compound according to any one of embodiments 1 to 26, wherein R 4 is selected from 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.

[0666] Embodiment 28. A compound according to any one of embodiments 1 to 27, wherein R 4 Selected from halogen, –CN and –NO2.

[0667] Embodiment 29. A compound according to any one of embodiments 1 to 28, wherein R 4 is halogen, preferably F.

[0668] Embodiment 30. A compound according to any one of embodiments 1 to 29, wherein L is a linking group selected from: -S(O)2-, optionally substituted C 1-4 Alkylene or C 2-4 Alkenylene.

[0669] Embodiment 31. A compound according to any one of embodiments 1 to 30, wherein L is a bond and the compound has the structure of Formula (VI):

[0670]

[0671] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0672] Embodiment 32. The compound according to embodiment 31, which has the structure of formula (VIa), (VIb) or (VIc):

[0673]

[0674] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0675] Embodiment 33. A compound according to any one of embodiments 1 to 32, wherein R 5 It is H, C 1-6 Alkyl or C 2-8 Alkoxyalkyl.

[0676] Embodiment 34. A compound according to any one of embodiments 1 to 33, wherein R 5 It’s H.

[0677] Embodiment 35. A compound according to any one of embodiments 1 to 34, wherein R 6 Selected from C 6-10 aryl or 5-6 membered heteroaryl, each optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when present, taken 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.

[0678] Embodiment 36. A compound according to any one of embodiments 1 to 35, wherein R 6 The optional substituents are one or more substituents selected from the group consisting of halogen, optionally substituted 5-membered heterocyclyl, optionally substituted 5-membered heteroaryl, -C(O)OR 11 ,–N(R11 )S(O)2R 11 、–C(O)N(R 11 )2 and –S(O)2N(R 11 )2.

[0679] Embodiment 37. A compound according to any one of embodiments 1 to 36, wherein R 6 is selected from C6 aryl, 5-membered heteroaryl or 6-membered heteroaryl, each of which may be optionally substituted.

[0680] Embodiment 38. A compound according to any one of embodiments 1 to 37, wherein R 6 Selected from:

[0681]

[0682] Each of these can be optionally substituted.

[0683] Embodiment 39. A compound according to any one of embodiments 35 to 38, selected from the group consisting of:

[0684]

[0685]

[0686]

[0687] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0688] Embodiment 40. A compound according to any one of embodiments 35 to 39, selected from the group consisting of:

[0689]

[0690]

[0691] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0692] Embodiment 41. A compound according to any one of embodiments 35 to 40, selected from the group consisting of:

[0693] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0694] Embodiment 42. A compound according to any one of embodiments 1 to 34, wherein R 6 is selected from 3-10 membered heterocyclic group and C 3-10carbocyclyl, each optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 .

[0695] Embodiment 43. The compound according to embodiment 42, wherein R 6 The optional substituents are one or more selected from halogen and -C(O)OR 11 A substituent, wherein R 11 is H or optionally substituted C 1-6 alkyl.

[0696] Embodiment 44. The compound of embodiment 42 or embodiment 43, which is selected from the group consisting of:

[0697]

[0698]

[0699] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0700] Embodiment 45. A compound according to any one of embodiments 1 to 34, wherein R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, said 3-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-10 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C2-6 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 .

[0701] Embodiment 46. The compound according to embodiment 45, wherein R 6 The optional substituents are one or more selected from halogen and -C(O)OR 11 A substituent, wherein R 11 is H or optionally substituted C 1-6 alkyl.

[0702] Embodiment 47. The compound of embodiment 45 or embodiment 46, which has the following structure:

[0703]

[0704] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0705] Example 48. A compound having the following structure:

[0706]

[0707] or a pharmaceutically acceptable salt thereof.

[0708] Embodiment 49. The compound of embodiment 48 or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0709]

[0710] Example 50. A compound having the following structure:

[0711]

[0712] or a pharmaceutically acceptable salt thereof.

[0713] Embodiment 51. The compound of embodiment 50 or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0714]

[0715] Example 52. A compound having the following structure:

[0716]

[0717] or a pharmaceutically acceptable salt thereof.

[0718] Embodiment 53. The compound of embodiment 52 or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0719]

[0720] Example 54. A compound having the following structure:

[0721]

[0722] or a pharmaceutically acceptable salt thereof.

[0723] Embodiment 55. The compound of embodiment 54 or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0724]

[0725] Example 56. A compound having the following structure:

[0726]

[0727] or a pharmaceutically acceptable salt thereof.

[0728] Embodiment 57. The compound of embodiment 56 or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0729]

[0730] Example 58. A compound having the following structure:

[0731]

[0732] or a pharmaceutically acceptable salt thereof.

[0733] Embodiment 59. The compound of embodiment 58 or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0734]

[0735] 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.

[0736] Embodiment 61. A method of treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to Embodiment 60.

[0737] Embodiment 62. The method of embodiment 61, wherein the proton-activated GPCR is GPR68 (OGR1).

[0738] 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.

[0739] Embodiment 64. The method of embodiment 63, wherein the disease, disorder or condition is an inflammatory disease, disorder or condition.

[0740] 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 disorder (COPD), asthma and cystic fibrosis.

[0741] Embodiment 66. The method of embodiment 64, wherein the inflammatory disease, disorder or condition is an autoimmune disease, disorder or condition.

[0742] 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.

[0743] Embodiment 68. The method of embodiment 63, wherein the disease, disorder or condition is a fibrotic disease, disorder or condition.

[0744] 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, skin fibrosis, pancreatic fibrosis and liver fibrosis.

[0745] Example 70. The method of Example 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).

[0746] Embodiment 71. The method of embodiment 63, wherein the disease, disorder or condition is a proliferative disease, disorder or condition.

[0747] 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).

[0748] Embodiment 73. The method of embodiment 63, wherein the disease, disorder or condition is cancer.

[0749] 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.

[0750] Embodiment 75. The method of any one of embodiments 61 to 74, wherein the subject is human.

[0751] Embodiment 76. A method of inhibiting a proton-activated GPCR in a cell population, the method comprising administering to the cell population an effective amount of a compound according to any one of embodiments 1 to 59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to embodiment 60.

[0752] Embodiment 77. The method of embodiment 76, wherein the proton-activated GPCR is GPR68 (OGR1).

[0753] Example 78. The method of Example 76 or Example 77, wherein the cell is a tumor cell.

[0754] Example 79. The steps, features, integers, compositions and / or compounds disclosed herein, individually or collectively, or indicated in the specification of this application, individually or collectively, and any and all combinations of two or more of said steps or features.

Claims

1. A compound having a structure of formula (II): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in: X is selected from N and NR 1 ; Y is selected from N and NR 2 ; R 1 and R 2 Independently selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 substituted by one or more substituents selected from the following: C 3-6 Carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 R 1 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ; Each R 9 are independently selected from H, optionally substituted C 1-6 Alkyl and optionally substituted C 5-6 aryl; Each R 10 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl and –C(O)R 9 ; R 3 Selected from 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 and –NO2; or R 3 and R 2 Together with the atoms to which they are attached, they form a fused 5-6 membered heteroaryl or a fused 5-6 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: 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 ; q is an integer from 0 to 3; R 4 is selected from 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 selected from 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 aryl, optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl; L is a bond or is selected from -C(O)N(R 9 )-, -S(O)2-, -C(O)- or -C(O)O-; or a linking group selected from optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, –OC 1-4 Alkylene or –OC 2-4 an alkenylene linking group, each of which is optionally substituted by -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 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when present, together with the atoms to which they are attached, are capable of forming an optionally substituted fused 5-6 membered heteroaryl or an optionally substituted fused 5-6 membered heterocyclyl; or R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: 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 ; Each R 11 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, 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)2N(R 9 )2; R 7 and R 8 Independently selected from H, C 1-6 Alkyl, C 5-10 Aryl, 5-10 membered heteroaryl and C 3-10 carbocyclyl, each of which is optionally substituted with one or more substituents 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)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 .

2. The compound according to claim 1, which has the structure of formula (III): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. The compound according to claim 1 or claim 2, which has the structure of formula (IV): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

4. The compound according to any one of claims 1 to 3, wherein R 1 It is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 carbocyclyl, each of which is optionally substituted with one or more substituents selected from: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

5. The compound according to any one of claims 1 to 4, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, halogen, –CN, –OR 9 and –SR 9 ; or substituted by one or more groups selected from the following: C 3-6 Carbocyclic group, 5-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: C 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 .

6. The compound according to any one of claims 1 to 5, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from methyl, ethyl, propyl or isopropyl.

7. A compound according to any one of claims 1 to 5, wherein R 1 It is C 1-6 Alkyl, the C 1-6 Alkyl groups are replaced by halogen, –CN, –OR 9 ,–C(O)R 9 ,–C(O)NR 9 R 10 、C(O)SR 9 OR –C(O)OR 9 substituted, optionally wherein R 9 It's methyl.

8. A compound according to any one of claims 1 to 5, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is substituted by an optionally substituted 5-6 membered heteroaryl group or an optionally substituted 3-6 membered heterocyclyl group.

9. The compound according to claim 8, wherein R 1 It is C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a 3-6 membered heterocyclic group selected from: as well as Each of these can be optionally substituted.

10. The compound according to any one of claims 1 to 5, wherein R 1 It is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with C 1-6 Carbocyclyl substitution.

11. The compound according to claim 10, wherein R 1 It is C 1-4 Alkyl, the C 1-4 Alkyl is C 1-6 Carbocyclyl is substituted, optionally wherein C 1-6 The carbocyclyl group is selected from optionally substituted cyclobutyl or optionally substituted cyclopropyl.

12. The compound according to claim 9 or claim 10, wherein R 1 yes 13. A compound according to any one of claims 1 to 12, wherein R 3 It’s H.

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

15. The compound according to any one of claims 1 to 14, which has the structure of formula (Va), (Vb) or (Vc): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

16. A compound according to any one of claims 1 to 15, wherein R 4 is selected from 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.

17. A compound according to any one of claims 1 to 16, wherein R 4 is selected from halogen, -CN and -NO2, optionally wherein halogen is F.

18. The compound according to any one of claims 1 to 17, which has the structure of formula (VI): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

19. The compound according to any one of claims 1 to 18, which has the structure of Formula (VIa), (VIb) or (VIc): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

20. A compound according to any one of claims 1 to 19, wherein 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 Alkoxyalkyl.

21. A compound according to any one of claims 1 to 20, wherein R 5 It’s H.

22. A compound according to any one of claims 1 to 21, wherein R 6 Selected from C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-10 Carbocyclic group, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 5-6 Aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5-6 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 wherein two adjacent optional substituents, when present, together with the atoms to which they are attached, are capable of forming an optionally substituted fused 5-6 membered heteroaryl or an optionally substituted fused 5-6 membered heterocyclyl.

23. A compound according to any one of claims 1 to 22, wherein R 6 is selected from optionally substituted C6 aryl, optionally substituted 5-membered heteroaryl and optionally substituted 6-membered heteroaryl.

24. A compound according to any one of claims 1 to 23, wherein R 6 Selected from: Each of these can be optionally substituted.

25. A compound according to any one of claims 1 to 24, wherein R 6 Selected from: Each of these can be optionally substituted.

26. A compound according to any one of claims 1 to 25, wherein R 6 The optional substituents are one or more substituents 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.

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

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

29. A compound according to any one of claims 1 to 28, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

30. A compound according to any one of claims 1 to 22, wherein R 6 is selected from optionally substituted 3-10 membered heterocyclic group and optionally substituted C 3-10 Carbocyclic group.

31. The compound according to claim 30, wherein R 6 The optional substituents are one or more selected from halogen and -C(O)OR 11 A substituent, optionally wherein R 11 is H or optionally substituted C 1-6 alkyl.

32. A compound according to claim 30 or claim 31 selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

33. A compound according to any one of claims 1 to 22, wherein R 6 and R 5 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents optionally selected from the group consisting of: 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 .

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

35. A compound according to claim 33 or claim 34 having the structure: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

36. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

37. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein the compound is:

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. A method of 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 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.

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, for the preparation of a medicament for treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

41. 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 treating and / or preventing a disease, disorder or condition mediated by a proton-activated GPCR in a subject in need thereof.

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

43. The method, use, or compound for use according to any one of claims 39 to 42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, 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. The method, use, or compound for use according to claim 43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition.

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

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

47. The method, use, or compound for use according to claim 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, 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. The method, use, or compound for use according to claim 43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, wherein the disease, disorder, or condition is a fibrotic disease, disorder, or condition.

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

50. The method, use, or compound for use of claim 48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, 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. The method, use, or compound for use according to claim 43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, wherein the disease, disorder, or condition is a proliferative disease, disorder, or condition.

52. The method, use, or compound for use according to claim 51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, 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. The method, use, or compound for use according to claim 43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, wherein the disease, disorder, or condition is cancer.

54. The method, use, or compound for use according to claim 53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, 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. The method, use, or compound for use according to any one of claims 49 to 54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, wherein the subject is a human.

56. A method of inhibiting a proton-activated GPCR in a cell, the method comprising administering to the cell an effective amount 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.

57. 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, for the preparation of a medicament for inhibiting a proton-activated GPCR in a cell.

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

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

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