Triazole derivatives as modulators of MAS-related G protein-coupled receptor D

Abstract

The present invention provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or isotope thereof, wherein A, B, R1, R2, R3, R4, R5, R6, R7, m, n, p, and y are as defined herein, and are for use in a method of modulating MRGPRD or for use in a method of treating an MRGPRD-dependent condition. A pharmaceutical composition containing such a compound, as well as the compound itself, are also provided. JPEG2025521596000449.jpg23142

Description

Technical Field

[0001] The present invention relates to modulators of Mas-related G protein-coupled receptor D, products containing the same, and methods of using and preparing them.

Background Art

[0002] Mas-related G protein receptors (MRGPRs) are a group of orphan receptors with restricted expression in very specific tissues. Little is known about the functions of most of these receptors. There are eight related receptors in this class expressed in humans, and only four of them have orthologs (i.e., MRGPR D, E, F, and G) that are readily identifiable in other species. The other four receptors (MRGPRX1, X2, X3, X4) do not have counterparts based on homology in species other than humans and primates.

Summary of the Invention

Problems to be Solved by the Invention

[0003] This invention is based in part on the identification of MRGPRD or MRGPRD ortholog modulator compounds. MRGPRD functionally corresponds to mouse Mrgprd and rat Mrgprd. MRGPRD and its orthologs are expressed in the dorsal root ganglia and several peripheral organs. MRGPRD and its orthologs have been shown to be involved in pain signaling, physiological and pathophysiological processes of the gastrointestinal (GI) tract, cardiac Ca2 + dysregulation (cardiac output and vascular tone), and have also been shown to be expressed in the skin, immune cells, eyes, kidneys, and brain.

[0004] In one embodiment, there is provided a method of treating an MRGPRD or MRGPRD ortholog-dependent condition, the method comprising administering to a subject in need thereof a pharmaceutical composition of an effective amount of a modulator compound of the present invention.

[0005] Accordingly, in an embodiment, a method for modulating MRGPRD is provided by contacting an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, with MRGPRD, wherein A, B, R1, R2, R3, R4, R5, R6, R7, m, n, p, and y are as defined below.

Chemical formula

[0006] In other embodiments, a compound having any of the structures of (I’), (I’’), (II), (II’), (III), (IV), (V), (VA), (VB), (VC), (VD), (VI), (VIA), (VIB), (VIC), (VID), (VII), or (VIII) as defined herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0007] In some embodiments, a compound having activity as a modulator of Mas-related G protein-coupled receptor D is provided, and a compound having the following structure (IX)

Chemical formula

[0008] In some embodiments, a compound having activity as a modulator of Mas-related G protein-coupled receptor D is provided, and a compound having the following structure (X)

Chemical formula

[0009] In some embodiments, compounds are provided that are active as modulators of Mas-related G protein-coupled receptor D, and compounds having the following structure (XI) are [Chemical Formula] or R in a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof 10 , R 12 , R 17 , R 18 , and n are defined as follows.

[0010] In yet other embodiments, a pharmaceutical composition is provided that comprises a carrier or excipient and a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0011] In other embodiments, a pharmaceutical composition is provided that comprises a structure (I'), (I''), (II), (II'), (III), (IV), (V), (VA), (VB), (VC), (VD), (VI), (VIA), (VIB), (VIC), (VID), (VII), (VIII), (IX), (X), or (XI) as defined herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0012] In another embodiment, there is provided a method for treating an MRGPRD-dependent condition by administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition having structure (I), (I’), (I’’), (II), (II’), (III), (IV), (V), (VA), (VB), (VC), (VD), (VI), (VIA), (VIB), (VIC), (VID), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

Mode for Carrying Out the Invention

[0013] MRGPR The Mas-related G protein-coupled receptor (MRGPR) constitutes a subfamily of class A receptors named after its first-discovered member, Mas. MRGPR was first identified in specialized sensory neurons that encode itch (pruriceptors) and pain (nociceptors). Cell bodies of both neuron subtypes are present in the dorsal root and trigeminal ganglia (DRG and TG). Importantly, activation of Mrgprs expressed on the surface of sensory neurons has been shown to induce both histamine-independent itch, pain sensation, and mechanical / visceral hypersensitivity.

[0014] Eight human MRGPRs are composed of MRGPRX1-4 and MRGPRD-G. MrgprX1-4 are expressed only in humans and non-human primates, while MRGPRD-G appear to be expressed in all mammals, and orthologs of MRGPRD are readily identified despite low sequence homology. Notably, MRGPRD is encoded by a single-copy MRGPRD gene with orthologs defined in rodents and humans, thus constituting an attractive therapeutic target for pain and other indications.

[0015] Despite the sensory nature of these receptors, the function of these MRGPRs will prove elusive. Triangulation of agonist profiles, receptor expression in tissues, and loss / gain of function in animal (disease) models will prove critical in realizing the therapeutic potential of these receptors.

[0016] MRGPRD agonists The first ligand described for the MRGPRD in humans, rats, mice, and monkeys was β-alanine. This amino acid analog is produced in the liver from uracil or from dietary carnosine by the enzyme carnosinase. It is involved in the upregulation of Gq proteins, phospholipase C, and inositol-3-phosphate-induced Ca2+ + Binding to calcium-activated chloride channels via release is described.

[0017] Alamandin, Ala1-Ang-(1-7), a peptide of the renin-angiotensin system (RAS), is also reported as a potent agonist of the MRGPRD. The peptide appears to interact differently with the receptor than β-alanine, as β-alanine does not inhibit the vasodilatory action of alamandin. However, D-Pro7-Ang-(1-7) was shown to be an inhibitor of alamandin binding to the MRGPRD.

[0018] 5-oxoETE, a lipid elevated in the gut of IBS patients, has been shown to induce calcium signaling in sensory neurons that is dependent on the presence of the MRGPRD, suggesting that 5-oxoETE may signal to neurons via the MRGPRD.

[0019] MRGPRD expression In addition to DRGs, MRGPRD transcript expression is identified in several peripheral organs, including arteries, heart, bladder, gastrointestinal tract, eye, brain, and kidney, suggesting that MRGPRD may be involved in several peripheral indications.

[0020] MRGPRD in neurons of the dorsal root ganglion MRGPRD is labeled by isolectin-B4 and is expressed at very high levels in most unmyelinated nociceptive neurons that are expressed in DRG. Similar to other members of the MRGPR family, MRGPRD is suggested to be highly associated with the sensations of pain and itching.

[0021] Activation of MRGPRD is shown to mediate pain signaling characterized by hypersensitivity to multiple stimuli leading to sensations associated with pain integrated in the brain. Indeed, increased expression of MRGPRD is seen in models of neuropathic pain.

[0022] MRGPRD in the intestine The expression of MRGPRD is demonstrated in sensory neurons innervating the colon. It has also been reported that 41% of TRPV1-positive neurons in sensory neurons projecting to the colon express MRGPRD. Activation of MRGPRD signaling in the colon is shown to be involved in the development of pain sensation in the context of irritable bowel syndrome (IBS).

[0023] The expression of MRGPRD in enteric neurons indicates that MRGPRD is strongly associated with physiological and pathophysiological processes of the gastrointestinal tract such as intestinal motility / motor disorders and intestinal inflammation.

[0024] Recent studies have shown an increase in the arachidonic acid metabolite 5-oxoETE in biopsies of clinically established IBS patients compared to healthy subjects. 5-oxoETE is shown to induce calcium signaling in sensory neurons. In the absence of MRGPRD, activation of sensory neurons by 5-oxoETE is significantly reduced, suggesting that 5-oxoETE may signal to neurons via MRGPRD.

[0025] MRGPRD in vascular tissue In the aorta / heart, MRGPRD is activated by alamandine, a receptor agonist, and causes endothelium-dependent vasodilation in the aortic rings of rats and mice. In hypertensive rats, alamandine treatment restores systolic function and prevents Ca 2+ dysregulation via activation of MrgprD in cardiomyocytes.

[0026] Alamandine via MRGPRD induces AMPK / NO signaling to counterregulate ANGII-induced hypertrophy, highlighting the therapeutic potential of the cardiac alamandine / MrgD axis.

[0027] Drugs that target alternative RAS, such as blockers of receptors for alternative RAS like MRGPRD, may be useful in the treatment of portal hypertension and liver fibrosis because they increase the visceral vascular resistance in cirrhotic animals.

[0028] MRGPRD in immune cells MRGPRD has been found to be expressed in neutrophils and is thought to be involved in the inflammatory response.

[0029] Alamandine does not affect M0 macrophages via the MRGPRD receptor, but reduces the expression levels of the pro-inflammatory TNF-α, CCL2, and IL-1β transcripts in LPS+IFN-γ-stimulated macrophages.

[0030] MRGPRD in the eye MRGPRD is expressed in retinal neurons, the retinal vasculature, Müller glial cells, and RPE cells. MRGPRD-deficient mice do not show significant changes in retinal morphology and thickness during aging. In in vitro tests using human retinal cells, alamandine has been shown to attenuate the increase in inflammatory cytokine gene expression and the production of reactive oxygen species. These results support the idea that alamandine / MRGPRD is a new protective axis of RAS that may exert antioxidant and anti-inflammatory effects in the retina.

[0031] MRGPRD in the kidney Allantoin induces scratching behavior in mice and in cultured DRG neurons, and calcium influx and action potentials are significantly reduced in DRG neurons of MRGPRD KO mice, suggesting a role for MRGPRD in chronic kidney disease (CKD).

[0032] MRGPRD in the brain According to studies in the mouse brain, MRGPRD-positive cells are region-specifically identified in some forebrain regions such as the cortex, hippocampus, amygdala, hypothalamus, substantia nigra, striatum, globus pallidus, and in some midbrain nuclei. The specific localization of MRGPRD in reward and limbic-related regions may suggest a role for MRGPRD in processes such as pain perception / regulation, synaptic plasticity, learning, memory, and cognition.

[0033] Furthermore, alamandine induces antidepressant-like effects in low-brain angiotensinogen transgenic rats. The MRGPRD receptor antagonist reverses the antidepressant-like effects induced by alamandine, suggesting a role for MRGPRD in the treatment of neuropsychiatric disorders.

[0034] MRGPRD and lung cancer MRGPRD is reported to be expressed in lung cancer and to promote tumor formation. Therefore, targeting MRGPRD may lead to new treatments for lung cancer and other cancers.

[0035] In some aspects, methods for the treatment of MRGPRD-dependent cancer-related diseases are provided, including administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition as described herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In certain aspects, the cancer is lung cancer, pancreatic cancer, or skin cancer. In certain embodiments, the cancer is lung cancer. In other embodiments, the cancer is pancreatic cancer. In still other embodiments, the cancer is skin cancer. In a particular embodiment, the cancer is melanoma.

[0036] Embodiments of the present invention also relate to a method of treating an MRGPRD-dependent proliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or pharmaceutical composition as described herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.In some embodiments, the method relates to the treatment of cancers such as acute myeloid leukemia, adolescent cancer, pediatric adrenocortical cancer, AIDS-related cancers (such as lymphoma, Kaposi sarcoma, etc.), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid rhabdoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), fetal tumor, central nervous system cancer, endometrial cancer, epithelioma, esophageal cancer, neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal cavity and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular tumor, pharyngeal cancer, thymoma / thymic cancer, thyroid cancer, renal pelvis / ureter transitional cell carcinoma, trophoblastic tumor, pediatric atypical cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, viral cancer, etc.In some embodiments, the method relates to the treatment of non-cancerous proliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0037] In certain embodiments, the invention relates to a method for treating MRGPRD-dependent lung cancer, the method comprising administering to a subject in need thereof an effective amount of any of the above-described compounds (or a pharmaceutical composition comprising the same). In certain aspects, the MRGPRD-dependent lung cancer is non-small cell lung cancer (NSCLC), e.g., adenocarcinoma, squamous cell lung cancer or large cell lung cancer. In other embodiments, the MRGPRD-dependent lung cancer is small cell lung cancer. Other MRGPRD-dependent lung cancers treatable with the disclosed compounds include, but are not limited to, adenomatous tumors, carcinoid tumors and undifferentiated carcinomas.

[0038] According to the method of the present invention, the subjects that can be treated with the compounds or pharmaceutical compositions of the present invention, or pharmaceutically acceptable salts, isomers, hydrates, solvates or isotopes thereof, include, for example, acute myeloid leukemia, adolescent cancer, pediatric adrenocortical cancer, AIDS-related cancers (such as lymphoma, Kaposi's sarcoma, etc.), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid tumor, basal cell cancer, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), fetal tumor, central nervous system cancer, endometrial cancer, epithelioma, esophageal cancer, neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, fungating polyp, myelodysplastic syndrome, myelodysplastic / myeloproliferative tumor, multiple myeloma, Merkel cell cancer, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular tumor, pharyngeal cancer, thymoma / thymic cancer, thyroid cancer, renal pelvis / ureter transitional cell carcinoma, trophoblastic tumor, pediatric atypical cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer,Subjects diagnosed with viral cancer are included. In some embodiments, subjects treated with the compounds or pharmaceutical compositions of the invention include subjects diagnosed with non-cancerous proliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0039] Measurement of MRGPRD activity See Example 26.

[0040] MRGPRD utility As used herein, the phrase "MRGPRD-dependent condition" means a condition in which activation, hypersensitization, or desensitization of MRGPRD by a natural or synthetic ligand initiates, mediates, maintains, or enhances a pathological condition.

[0041] A method of treating a subject having a pathological condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof.

[0042] As described above, the present invention relates to modulators of MRGPRD, products containing them, and methods for their use and preparation. This receptor mediates diseases such as dry eye syndrome / dry keratoconjunctivitis and related diseases, chronic pruritus (such as pruritus), inflammatory diseases, autoimmune diseases, skin diseases, cardiovascular diseases, kidney diseases, cognitive impairment due to neurodegenerative diseases, age-related cognitive impairment, vascular cognitive impairment, post-stroke cognitive impairment, mental diseases, etc.

[0043] Definitions As used herein, the following terms have the meanings defined below unless the context indicates otherwise.

[0044] "Modulating" MRGPRD means that a compound interacts with MRGPRD such that it functions as an inverse agonist and / or a competitive antagonist to the receptor. In one embodiment, such modulation is partially or fully selective for other MRGPRs such as MRGPRX1, X2, X3, and / or X4.

[0045] The term "agonism" is used herein to include compounds that interact with a receptor in some way and thereby function as an agonist by binding to the receptor at the binding site of its natural ligand or at a site other than the binding site. Thus, the phrase "MRGPRD agonism" is used herein to include compounds that interact with MRGPRD in some way and thereby function as an agonist by binding to the GPCR receptor at the binding site of its natural ligand or at a site other than the binding site (i.e., allosteric binding).

[0046] The term "antagonism" is used herein to include compounds that interact with a receptor in some way and thereby function as an antagonist by binding to the receptor at the binding site of its natural ligand or at a site other than the binding site. The term "MRGPRD antagonism" is used herein to include compounds that interact with MRGPRD in some way and thereby function as an antagonist by binding to the GPCR at the binding site of its natural ligand or at a site other than the binding site (i.e., allosteric binding).

[0047] Partial agonists are compounds that bind to and activate a receptor but have reduced efficacy compared to a full agonist. In the presence of a full agonist, a partial agonist acts as an effective competitive antagonist. Inverse agonists are compounds that bind to a receptor and induce a pharmacological response opposite to that of an agonist. Allosteric modulators are compounds that bind at a site distinct from the orthosteric site, or the site of action of the primary ligand, and exert an indirect effect by influencing the binding or efficacy of the primary ligand. Pure allostery has no effect on the protein in the absence of a primary ligand that activates or inactivates the receptor.

[0048] "MRGPR" refers to one or more of the Mas-related G protein-coupled receptors, which are a group of orphan receptors with restricted expression in very specific tissues (e.g., mast cells and dorsal root ganglia) and barrier tissues. There are eight related receptors expressed in humans, only four of which have easily identifiable orthologs in other species (i.e., MRGPRD, E, F, and G). Some of the other four receptors (MRGPRX1, X2, X3, and X4) have counterparts in higher species including dogs and horses, but they do not have a single corresponding ortholog in rodents.

[0049] "MRGPRD" is also referred to as "MRGD", or "TGR7", or "MAS-related GPR family member D", and refers to a member of the MRGPR family.

[0050] "Effective amount" refers to an amount of a particular agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, the effective amount of the agent is an amount sufficient to inhibit or treat a disease without causing substantial toxicity in the subject. The effective amount of an agent will vary depending on the subject being treated, the severity of the affliction, and the method of administration of the pharmaceutical composition. Methods for determining the effective amount of the disclosed compounds sufficient to achieve the desired effect in a subject will be understood by those of ordinary skill in the art in light of the present disclosure.

[0051] In the following description, specific specific details are set forth in order to provide a thorough understanding of various embodiments of the present invention. However, those of ordinary skill in the art will understand that the embodiments of the present invention may be practiced without such details.

[0052] Unless the context requires otherwise, throughout this specification and the claims, the word "comprise", and variations such as "comprises" and "comprising", are to be construed in an open, inclusive sense, i.e., "including, but not limited to".

[0053] References to "one embodiment" or "an embodiment" in this specification mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used in this specification and the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0055] "Alkyl" means a saturated or unsaturated, straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 3 carbon atoms. Examples of saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Unsaturated alkyl includes alkenyl and alkynyl as defined below.

[0056] "Alkenyl" means a saturated or straight-chain or branched-chain alkenyl group having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon containing at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0057] "Alkynyl" means a straight-chain or branched-chain alkynyl group having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkynyl group is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0058] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0059] "Hydroxy" or "hydroxyl" refers to -OH.

[0060] "Cyano" refers to -CN.

[0061] "Carboxy" or "carboxyl" refers to -CO2H.

[0062] "Amino" or "aminyl" refers to -NH2, -NH alkyl or N(alkyl)2, where alkyl is as defined above. Examples of amino or aminyl include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, etc.

[0063] "Aminylalkyl" refers to amino or aminyl bonded via the above-described alkyl (i.e., alkyl-aminyl). Examples of aminylalkyl include, but are not limited to,

Chemical formula

[0064] "Cyanoalkyl" refers to CN bonded via alkyl as described above (i.e., -alkyl-CN). Examples of cyanoalkyl include, but are not limited to,

Chemical formula

[0065] "Haloalkyl" refers to the alkyl as defined above, in which one or more hydrogen atoms are replaced by halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, etc.

[0066] "Hydroxylalkyl" refers to the above-described hydroxyl bonded via the above-described alkyl (i.e., -alkyl-OH). Examples of hydroxylalkyl include, but are not limited to,

Chemical formula

Chem.

[0067] "Alkoxy" refers to the alkyl defined above bonded by an oxygen atom (i.e., -O-alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, etc.

[0068] "Alkoxyalkyl" refers to the alkoxy defined above bonded through the above-mentioned alkyl (i.e., -alkyl-alkoxy). Examples of alkoxyalkyl groups include, but are not limited to,

Chem.

[0069] "Alkoxyalkenyl" refers to the alkoxy defined above bonded through the above-mentioned alkenyl (i.e., alkenyl-alkoxy). Examples of alkoxyalkenyl groups include, but are not limited to,

Chem.

[0070] "Haloalkoxy" refers to the haloalkyl defined above bonded by an oxygen atom (i.e., -O-haloalkyl). Examples of haloalkoxy groups include, but are not limited to, -OCF3, etc.

[0071] "Alkylcarbonyl" refers to the alkyl bonded through a carbonyl (i.e., -C(O)-alkyl). Examples of alkylcarbonyl groups include, but are not limited to,

Chem.

[0072] "Aminylcarbonyl" refers to aminyl bonded via a carbonyl (i.e., -C(O)-aminyl). Examples of aminylcarbonyl groups include, but are not limited to,

Chemical formula

Chemical formula

[0073] "Alkylsulfonyl" refers to alkyl as described above bonded via a sulfonyl (i.e., -S(O)2-alkyl). Examples of alkylsulfonyl groups include, but are not limited to,

Chemical formula

[0074] "Aminylsulfonyl" refers to aminyl as described above bonded via a sulfonyl (i.e., -S(O)2-aminyl). Examples of aminylsulfonyl groups include, but are not limited to,

Chemical formula

Chemical formula

[0075] "Alkylsulfonylaminyl" refers to alkylsulfonyl as described above bonded via an aminyl (i.e., -aminyl-S(O)2-alkyl). Examples of alkylsulfonylaminyl groups include, but are not limited to,

Chemical formula

[0076] "Cycloalkyl" refers to an alkyl group that forms a ring structure and can be either substituted or unsubstituted. The ring can be fully saturated, partially unsaturated, or fully unsaturated. When there is unsaturation, the conjugation of Π electrons within the ring does not give rise to aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. The cycloalkyl group further includes polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphyl, isocampphyl, and carenyl groups, etc., and fused rings such as decalinyl, etc., but are not limited to these. "Carbocycle", "carboscyclic", or "carbon ring" refers to an alkyl group that forms a ring structure and can be either substituted or unsubstituted. The ring can be fully saturated, partially unsaturated, or fully unsaturated. When there is unsaturation, the conjugation of Π electrons within the ring can give rise to aromaticity. In one embodiment, the carbon ring includes cycloalkyl as defined above. In another embodiment, the carbon ring includes aryl as defined above.

[0077] "Cycloalkylalkyl" refers to the above-mentioned cycloalkyl bonded via the above-mentioned alkyl (i.e., -alkyl-cycloalkyl). Examples of cycloalkylalkyl include, but are not limited to,

Chemical formula

[0078] An "aryl" group is a cyclic aromatic hydrocarbon that does not contain a heteroatom. Representative aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylene, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings where at least one ring, although not necessarily all rings, is aromatic, such as fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, the aryl is phenyl or naphthyl, and in another embodiment, the aryl is phenyl.

[0079] "Arylalkyl" refers to the above-mentioned aryl group bonded through the above-mentioned alkyl (i.e., -alkyl-aryl). Examples of arylalkyl include, but are not limited to,

Chemical formula

[0080] "Heterocycle" or "heterocyclyl" or "heterocyclic ring" refers to aromatic and non-aromatic ring moieties containing three or more ring members, one or more of which are heteroatoms such as N, O, S, or P, but are not limited thereto. In some embodiments, the heterocyclyl contains 3 to 20 cyclic members, while other such groups have 3 to 15 cyclic members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need to contain a heteroatom. For example, both the dioxolanyl ring and the benzodioxolanyl ring system (methylenedioxyphenyl ring system) are heterocyclyl groups within the scope of the meaning of this specification.

[0081] The heterocyclyl group includes fused ring species in which an aromatic group and a non-aromatic group are fused. The heterocyclyl group also includes polycyclic ring systems containing heteroatoms such as, but not limited to, quinuclidyl, and heterocyclyl groups having substituents such as, but not limited to, alkyl, halo, amino, aminyl, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups bonded to one of the ring members. The heterocyclyl group defined herein can be a heteroaryl group or a partially or fully saturated cyclic group containing at least one ring heteroatom. Examples of the heterocyclyl group include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuran, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0082] In one embodiment, the heterocyclyl includes heteroaryl.

[0083] "Heterocyclylalkyl" refers to the above-described heterocyclyl group bonded via alkyl as described above (i.e., -alkyl-heterocyclyl).

[0084] "Heteroaryl" refers to an aromatic ring moiety containing five or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds in which, although not necessarily in all rings, at least one ring is aromatic, such as, for example, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl.

[0085] "Heteroarylalkyl" refers to the above-described heteroaryl (i.e., -alkyl-heteroaryl) bonded via an alkyl as described above. Examples of heteroarylalkyl include, but are not limited to,

Chemical formula

[0086] "Isomers" are used herein to include all chiral, diastereomeric, or racemic forms of a structure (also called stereoisomers as opposed to structural or positional isomers) unless a specific stereochemistry or isomeric form is specifically indicated. Such compounds can be optical isomers enriched or resolved at any or all asymmetric atoms, at any concentration, as is apparent from the description. Both racemic mixtures and mixtures of diastereomers, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, all of which are within the scope of certain embodiments of the present invention. Isomers arising from the presence of chiral centers include a pair of non-superimposable isomers called "enantiomers". A single enantiomer of a pure compound is optically active (i.e., they can rotate the plane of plane-polarized light and are designated as R or S).

[0087] "Isolated optical isomer" means a compound substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer can be at least about 80% by weight, at least 80% by weight, or at least 85% by weight pure. In other embodiments, the isolated isomer is at least 90% pure, at least 98% pure, or at least 99% pure.

[0088] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer over the other enantiomer or diastereomer of at least about 80%, and more specifically 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or more than 99.9%.

[0089] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it has no optical activity (i.e., the constituent enantiomers cancel each other out and do not rotate plane-polarized light in either direction). All compounds having an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers and can be synthesized from their respective racemates by purification and / or appropriate chiral synthesis.

[0090] A "hydrate" is a compound that exists in combination with water molecules. The combination may contain a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may contain water in a random amount. As used herein, the term "hydrate" refers to the solid form; i.e., a compound in an aqueous solution may be hydrated but is not a hydrate as used herein.

[0091] A "solvate" is similar to a hydrate except that a solvent other than water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to the solid form; i.e., a compound in a solvent solution may be solvated but is not a solvate as used herein.

[0092] "Isotope" refers to atoms that have the same number of protons but different numbers of neutrons, and the isotopes of the compound of structure (I) include any such compound in which one or more atoms are replaced by the isotope of that atom. For example, carbon-12 (the most common form of carbon) has 6 protons and 6 neutrons, while carbon-13 has 6 protons and 7 neutrons, and carbon-14 has 6 protons and 8 neutrons. Hydrogen has two stable isotopes, namely deuterium (1 proton and 1 neutron) and tritium (1 proton and 2 neutrons). Fluorine has many isotopes, but fluorine-19 has the longest half-life. Therefore, examples of isotopes of the compound having the structure of structure (I) include compounds of structure (I) in which one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, compounds of structure (I) in which one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or compounds of structure (I) in which one or more fluorine atoms are replaced by fluorine-19, but are not limited thereto.

[0093] "Salt" generally refers to an ionic form of an organic compound, such as a carboxylic acid or an amine, combined with a counterion. For example, a salt formed between an acid in its anionic form and a cation is called an "acid addition salt". Conversely, a salt formed between a base in its cationic form and an anion is called a "base addition salt".

[0094] The term "pharmaceutically acceptable" refers to a drug that is approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to non-toxic inorganic or organic acid and / or base addition salts (see, for example, Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0095] Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts including alkali metal, alkaline earth metal, and transition metal salts such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as, for example, N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0096] Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, embonic (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, -galacturonic acid, and galacturonic acid.

[0097] The compounds of the present disclosure (i.e., the compounds of structure (I) and embodiments thereof), or pharmaceutically acceptable salts thereof, may contain one or more geometrically asymmetric centers and, accordingly, can give rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R)- or (S)-, or in the case of amino acids, (D)- or (L)- with respect to absolute stereochemistry. Accordingly, embodiments include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using a chiral synthon or chiral reagent or resolved using prior art such as chromatography and fractional crystallization. Prior art for the preparation / isolation of individual enantiomers includes chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also included.

[0098] Pharmaceutically unacceptable salts are generally not useful as pharmaceuticals, but such salts can be useful, for example, as intermediates in the synthesis of compounds having structure (I), e.g., in their purification by recrystallization.

[0099] As used herein, the phrase "MRGPRD or MRGPRD ortholog-dependent condition" means a condition in which activation, hypersensitization, or desensitization of MRGPRD or its ortholog by a natural or synthetic ligand initiates, mediates, maintains, or exacerbates a pathological condition

[0100] In some embodiments, the MRGPRD-dependent condition is a pain-related condition, an itch-related condition, an inflammatory condition, an eye-related condition, a cardiovascular and renal disease-related condition, an inflammatory or autoimmune disorder, or a cognitive disorder-related condition.

[0101] As used herein, the phrase "pain-related condition" means any pain resulting from a medical condition. Thus, in one embodiment, the methods of the present invention are directed to acute pain, progressive prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behçet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, collapse of the lung (pneumothorax), complex regional pain syndrome (RSD), constipation, corneal neuropathic pain, Crohn's disease, degenerative disc disease, dental pain, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dry eye syndrome, dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, inflammatory bowel disease (IBD), intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatomyositis, knee injury, leg pain, lumbago-hematuria syndrome, lupus, Lyme disease, medullary spongeKidney, MSK), dysesthetic thigh pain, dermatofibroma, migraine, musculoskeletal pain, muscle / fascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, eye itching, osteoarthritis, Paget's disease, Personage-Turner syndrome, pelvic pain, pericoronitis pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney, polymyalgia rheumatica, polymyositis, porphyria, post-herniorrhaphy pain syndrome, post-mastectomy, postoperative pain, pain syndrome, post-stroke pain, post-thoracotomy pain syndrome, post-herpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (herpes zoster), Sjogren's syndrome, spasmodic torticollis, Oddi sphincter dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, lumbar spinal stenosis, syringomyelia, tarlo cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, and vulvar pain and other pain-related conditions are provided for the treatment of.

[0102] As used herein, the phrase "itching-related condition" means pruritus associated with any condition (including acute and chronic pruritus). The sensation of itching can arise, for example, from the peripheral nervous system (e.g., cutaneous or neuropathic itching) or the central nervous system (e.g., neuropathic, neurogenic or psychogenic itching). Thus, in one embodiment, the methods of the invention are provided for treating itching-related conditions such as chronic itching, contact dermatitis, allergic blepharitis, anaphylaxis, anaphylactoid drug reactions, anaphylactic shock, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, end-stage renal disease, hemodialysis, cholestatic pruritus, chronic urticaria, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, idiopathic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythema, food allergy, folliculitis, fungal skin infections, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iodinated contrast agent allergy, iron deficiency anemia, kidney disease, leukemia, porphyria, lymphoma, mast cell activation syndrome, malignancy, mastocytosis, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia vera, nodular prurigo, lichen planus, lichen sclerosus, prurigo ani, pseudoallergic reactions, pseudorabies, psoriasis, rectal prolapse, sarcoidosis granuloma, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, scabies, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, eye itching, or urticaria.

[0103] As used herein, the term "administering" refers to providing a compound, or a pharmaceutical composition comprising a compound described herein. The compound or composition can be administered to a subject by another person or it can be self-administered by the subject. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0104] As used herein, the term "treatment" refers to an intervention that ameliorates the signs or symptoms of a disease or pathological condition. As used herein, the terms "treat", "treating", and "treatment" with respect to a disease, pathological condition, or symptom also refer to any observable beneficial effect of that treatment. Beneficial effects can be demonstrated, for example, by a delay in the onset of clinical symptoms of the disease in a subject susceptible thereto, a reduction in the severity of some or all of the clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of recurrences of the disease, an improvement in the overall health or well-being of the subject, or other parameters well known in the art specific to a particular disease. Preventive treatment is treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs thereof, for the purpose of reducing the risk of developing the disease state. Therapeutic treatment is treatment administered to a subject after the signs and symptoms of the disease have manifested.

[0105] As used herein, the term "subject" refers to an animal (e.g., a mammal such as a human, dog, or horse). A subject to be treated according to the methods described herein can be a subject diagnosed with an MRGPRD-dependent condition or an MRGPRD ortholog-dependent condition, such as a pain-related condition. The diagnosis can be performed by any method or technique known in the art. One of ordinary skill in the art will understand that a subject to be treated according to the present disclosure may be subjected to standard tests as being at risk, or identified without testing, due to the presence of one or more risk factors associated with the disease or symptom. The term "patient" can be used interchangeably with the term "subject". A subject can refer to an adult subject or a pediatric subject.

[0106] The Federal Food, Drug, and Cosmetic Act defines "pediatric" as subjects under 21 years of age at the time of diagnosis or treatment. The pediatric subpopulation is further characterized as follows: (i) neonates - from birth to 28 days postnatal, (ii) infants - from 29 days to less than 2 years old, (iii) children - from 2 years to less than 12 years old, and (iv) adolescents - from 12 to 21 years old. Despite this definition, depending on the susceptible patient population and clinical trial evaluation, approved regulatory labels may include expressions that specifically modify the scope of the pediatric population, such as pediatric patients up to 22 years old, for example.

[0107] In another embodiment, a method of treating a subject having an MRGPRD-dependent condition (e.g., a pain-related condition) described herein further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent. In another embodiment, a method of treating a subject having a pain-related condition is provided, the method comprising administering to the subject a therapeutically effective amount of a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, or a pharmaceutical composition thereof.

[0108] Method MRGPRD modulator In some embodiments, compounds are provided that are active as modulators of Mas-related G protein-coupled receptor D, compounds having the following structure (I),

Chemical formula

[0109] In other embodiments, a compound having the following structure (I’),

Chemical formula

[0110] In some embodiments, compounds are provided in which A is a monocyclic carbocyclic ring. In some embodiments, compounds are provided in which A is a saturated or partially saturated monocyclic carbocyclic ring. In some embodiments, compounds are provided in which A is phenyl. In some embodiments, compounds are provided in which A is a monocyclic heterocyclic ring. In other embodiments, compounds are provided in which A is a heteroaryl ring.

[0111] In some embodiments, compounds are provided in which A is a monocyclic carbocyclic ring and y is 1. In other embodiments, compounds are provided in which A is a monocyclic carbocyclic ring and y is 2. In further embodiments, compounds are provided in which A is a monocyclic carbocyclic ring and y is 3. In still other embodiments, compounds are provided in which A is a monocyclic carbocyclic ring and y is 4.

[0112] In some embodiments, compounds are provided in which A is a monocyclic heterocyclic ring and y is 1. In other embodiments, compounds are provided in which A is a monocyclic heterocyclic ring and y is 2. In additional embodiments, compounds are provided in which A is a monocyclic heterocyclic ring and y is 3. In still other embodiments, compounds are provided in which A is a monocyclic heterocyclic ring and y is 4.

[0113] In some embodiments, compounds are provided in which A is a heteroaryl ring and y is 1. In other embodiments, compounds are provided in which A is a heteroaryl ring and y is 2. In further embodiments, compounds are provided in which A is a heteroaryl ring and y is 3. In still other embodiments, compounds are provided in which A is a heteroaryl ring and y is 4.

[0114] In some embodiments, compounds having the following structure (I'')

Chemical formula

[0115] In certain embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring. In other embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring. In further embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring.

[0116] In some embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring and y is 0. In other embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring and y is 1. In further embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring and y is 2. In still other embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring and y is 3. In further embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring and y is 4. In some embodiments, compounds are provided wherein A is a bicyclic carbocyclic ring and y is 5.

[0117] In some embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring and y is 0. In other embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring and y is 1. In further embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring and y is 2. In still other embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring and y is 3. In further embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring and y is 4. In other embodiments, compounds are provided wherein A is a bicyclic heterocyclic ring and y is 5.

[0118] In some embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring and y is 0. In other embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring and y is 1. In further embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring and y is 2. In still other embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring and y is 3. In further embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring and y is 4. In some embodiments, compounds are provided wherein A is a bicyclic heteroaryl ring and y is 5.

[0119] In other embodiments, compounds are provided wherein A has any of the following structures.

Chemical formula

[0120] In some embodiments, compounds having the following structure (II),

Chemical formula

[0121] In some embodiments, compounds having the following structure (II’),

Chemical formula

[0122] In some embodiments, compounds having the following structure (III),

Chemical formula

[0123] In some embodiments, compounds having the following structure (IV),

Chemical formula

[0124] In some embodiments, a compound having the following structure (V),

Chemical formula

[0125] In some of the foregoing embodiments, a compound is provided wherein X1 is N, X2 is CH optionally substituted by R7, p is 0 and R6 is a heterocyclic ring. In still other embodiments, a compound is provided wherein X1 is N, X2 is CH optionally substituted by R7, p is 1 and R6 is a heterocyclic ring. In one embodiment, a compound is provided wherein R6 is a 5-membered heterocyclic ring. In other specific embodiments, a compound is provided wherein R6 is a 6-membered heterocyclic ring. In some embodiments, a compound is provided wherein R6 is a 5-membered heteroaryl ring. In other embodiments, a compound is provided wherein R6 is a 6-membered heteroaryl ring.

[0126] In some embodiments, a compound having the following structure (VA),

Chemical formula

[0127] In some embodiments, a compound having the following structure (VB), [Chemical formula] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, wherein R9 is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, n is from 0 to 4, and q is from 0 to 2.

[0128] In some embodiments, a compound having the following structure (VC), [Chemical formula] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, n is from 0 to 4, and q is from 0 to 5.

[0129] In some embodiments, a compound having the following structure (VD), [Chemical formula] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, wherein R9 is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, n is from 0 to 4, and q is from 0 to 2.

[0130] In some embodiments, a compound having the following structure (VI), [Chemical formula] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, R9 is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, n is from 0 to 2, and y is from 1 to 4.

[0131] In some embodiments, a compound having the following structure (VIA), [Chemical formula] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, R9 is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, n is from 0 to 4, and q is from 0 to 5.

[0132] In some embodiments, a compound having the following structure (VIB), [Chemical formula] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, each R9 is independently H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, n is from 0 to 2, and q is from 0 to 2.

[0133] In some embodiments, compounds having the following structure (VIC),

Chemical formula

[0134] In some embodiments, compounds having the following structure (VID),

Chemical formula

[0135] In some embodiments, compounds having the following structure (VII),

Chemical formula

[0136] In some embodiments, compounds having the following structure (VIII), [Chem.] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, y is from 1 to 4.

[0137] In some embodiments, compounds are provided wherein B is a carbocyclic ring. In certain embodiments, compounds are provided wherein B is a saturated carbocyclic ring. In other embodiments, compounds are provided wherein B is an aryl ring. In some embodiments, compounds are provided wherein B is a heterocyclic ring. In some embodiments, compounds are provided wherein B is a saturated heterocyclic ring. In certain embodiments, compounds are provided wherein B is a heteroaryl ring. In some embodiments, B has any of the following structures, [Chem.] B is optionally substituted with 0 to 4 R7, and compounds are provided wherein R9 is H, alkyl, or haloalkyl, alkoxyalkyl, aminylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0138] In some embodiments, compounds are provided wherein R1 is isopropyl. In certain embodiments, compounds are provided wherein R1 is tert-butyl. In other embodiments, compounds are provided wherein R1 is cyclopropyl. In some embodiments, compounds are provided wherein R1 is cyclobutyl. In further embodiments, compounds are provided wherein R1 is cyclopentyl.

[0139] In some embodiments, compounds are provided wherein R2 is H. In other embodiments, compounds are provided wherein R2 is alkyl. In certain embodiments, compounds are provided wherein R2 is methyl. In further embodiments, compounds are provided wherein R2 is ethyl. In further embodiments, compounds are provided wherein R2 is n-propyl. In still other embodiments, compounds are provided wherein R2 is isopropyl. In some embodiments, compounds are provided wherein R2 is bonded to B to form a ring. In certain embodiments, R2 is bonded to B to form a ring having the following structure, [Chemical formula] wherein the above structure is optionally substituted with 0-4 R7, and compounds are provided wherein R9 is H, alkyl, or haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0140] In some embodiments, compounds are provided wherein both R3 and R4 are H. In other embodiments, compounds are provided wherein both R3 and R4 are alkyl. In certain embodiments, compounds are provided wherein one of R3 and R4 is H and the other is alkyl. In some embodiments, compounds are provided wherein the alkyl is methyl. In other embodiments, compounds are provided wherein the alkyl is ethyl. In some embodiments, compounds are provided wherein the alkyl is isopropyl. In further embodiments, compounds are provided wherein R3 and R4 are bonded to each other to form a carbocyclic ring. In certain embodiments, compounds are provided wherein R3 and R4 are bonded to each other to form a 3- to 5-membered carbocyclic ring. In some embodiments, compounds are provided wherein R3 and R4 are bonded to each other to form cyclopropyl. In other embodiments, compounds are provided wherein R3 and R4 are bonded to each other to form cyclobutyl. In certain embodiments, compounds are provided wherein R3 and R4 are bonded to each other to form cyclopentyl.

[0141] In some embodiments, compounds are provided wherein R5 is a halo. In certain embodiments, compounds are provided wherein R5 is F. In other embodiments, compounds are provided wherein R5 is Cl. In additional embodiments, compounds are provided wherein R5 is Br. In further embodiments, compounds are provided wherein R5 is I. In some embodiments, compounds are provided wherein R5 is OH. In further embodiments, compounds are provided wherein R5 is CN. In some embodiments, compounds are provided wherein R5 is alkyl. In certain embodiments, compounds are provided wherein R5 is methyl. In other embodiments, compounds are provided wherein R5 is ethyl. In further embodiments, compounds are provided wherein R5 is n-propyl. In still other embodiments, compounds are provided wherein R5 is isopropyl. In some embodiments, compounds are provided wherein R5 is tert-butyl. In some embodiments, compounds are provided wherein R5 is haloalkyl. In certain embodiments, compounds are provided wherein R5 is CF3. In other embodiments, compounds are provided wherein R5 is alkoxy. In certain embodiments, compounds are provided wherein R5 is methoxy. In some embodiments, compounds are provided wherein R5 is haloalkoxy. In certain embodiments, compounds are provided wherein R5 is OCF3. In further embodiments, compounds are provided wherein R5 is alkoxyalkyl. In certain embodiments, compounds are provided wherein R5 is CH2OCH3. In some embodiments, compounds are provided wherein R5 is alkoxyalkenyl. In certain embodiments, R5 is

Chemical formula

[0142] In some embodiments, compounds are provided where R5 is heterocyclyl. In other embodiments, compounds are provided where R5 is aryl. In further embodiments, compounds are provided where R5 is heteroaryl. In some embodiments, compounds are provided where R5 has any of the following structures.

Chemical formula

[0143] In some embodiments, compounds are provided where R6 is a carbocyclic ring optionally substituted with one or more R8s. In other embodiments, compounds are provided where R6 is a heterocyclic ring optionally substituted with one or more R8s. In certain embodiments, R6 has any of the following structures,

Chemical formula

[0144] In some embodiments, compounds are provided wherein R7 is aminyl. In other embodiments, compounds are provided wherein R7 is halo. In certain embodiments, compounds are provided wherein R7 is F. In further embodiments, compounds are provided wherein R7 is Cl. In further embodiments, compounds are provided wherein R7 is Br. In further embodiments, compounds are provided wherein R7 is I. In some embodiments, compounds are provided wherein R7 is OH. In other embodiments, compounds are provided wherein R7 is CN. In further embodiments, compounds are provided wherein R7 is alkyl. In certain embodiments, compounds are provided wherein R7 is methyl. In other embodiments, compounds are provided wherein R7 is ethyl. In further embodiments, compounds are provided wherein R7 is n-propyl. In further embodiments, compounds are provided wherein R7 is isopropyl. In still further embodiments, compounds are provided wherein R7 is tert-butyl. In some embodiments, compounds are provided wherein R7 is alkenyl. In other embodiments, compounds are provided wherein R7 is alkynyl. In certain embodiments, compounds are provided wherein R7 is ethynyl. In some embodiments, compounds are provided wherein R7 is haloalkyl. In certain embodiments, compounds are provided wherein R7 is CF3. In other embodiments, compounds are provided wherein R7 is CHF2. In further embodiments, compounds are provided wherein R7 is alkoxy. In certain embodiments, compounds are provided wherein R7 is methoxy. In other embodiments, compounds are provided wherein R7 is alkoxyalkyl. In certain embodiments, R7 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0145] In some embodiments, compounds in which R8 is aminyl are provided. In one embodiment, R8 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0146] In some embodiments, compounds are provided wherein R9 is H. In other embodiments, compounds are provided wherein R9 is alkyl. In certain embodiments, compounds are provided wherein R9 is methyl. In further embodiments, compounds are provided wherein R9 is ethyl. In further embodiments, compounds are provided wherein R9 is n-propyl. In still further embodiments, compounds are provided wherein R9 is isopropyl. In some embodiments, compounds are provided wherein R9 is tert-butyl. In additional embodiments, R9 is [Chemistry] Compounds are provided wherein. In some embodiments, compounds are provided wherein R9 is haloalkyl. In certain embodiments, compounds are provided wherein R9 is CF3. In further embodiments, compounds are provided wherein R9 is CHF2. In still further embodiments, R9 is [Chemistry] Compounds are provided wherein. In some embodiments, compounds are provided wherein R9 is alkoxyalkyl. In additional embodiments, R9 is [Chemistry] Compounds are provided wherein. In other embodiments, compounds are provided wherein R9 is aminylsulfonyl. In certain embodiments, R9 is [Chemistry] Compounds are provided where R9 is cycloalkyl. In some embodiments, compounds are provided where R9 is cyclopropyl. In one embodiment, compounds are provided where R9 is cyclobutyl. In further embodiments, compounds are provided where R9 is cyclopentyl. In some embodiments, compounds are provided where R9 is cycloalkylalkyl. In one embodiment, R9 is [Chemistry] Compounds are provided where R9 is heterocyclyl. In some embodiments, compounds are provided where R9 is tetrahydropyranyl. In some embodiments, compounds are provided where R9 is heterocyclylalkyl. In other embodiments, compounds are provided where R9 is aryl. In one embodiment, compounds are provided where R9 is phenyl. In some embodiments, compounds are provided where R9 is arylalkyl. In one embodiment, R9 is [Chemistry] Compounds are provided where R9 is heteroaryl. In other embodiments, compounds are provided where R9 is heteroarylalkyl. In one embodiment, R9 is [Chemistry] Compounds are provided where R9 has any of the following structures. [Chemistry]

[0147] In some embodiments, compounds in which n is 0 are provided. In other embodiments, compounds in which n is 1 are provided. In further embodiments, compounds in which n is 2 are provided. In further embodiments, compounds in which n is 3 are provided. In still other embodiments, compounds in which n is 4 are provided.

[0148] In some embodiments, compounds in which m is 0 are provided. In other embodiments, compounds in which m is 1 are provided. In further embodiments, compounds in which m is 2 are provided. In further embodiments, compounds in which m is 3 are provided. In still other embodiments, compounds in which m is 4 are provided.

[0149] In some embodiments, compounds in which p is 0 are provided. In other embodiments, compounds in which p is 1 are provided. In further embodiments, compounds in which p is 2 are provided. In further embodiments, compounds in which p is 3 are provided. In still other embodiments, compounds in which p is 4 are provided. In some embodiments, compounds in which p is 5 are provided.

[0150] In some embodiments, compounds in which q is 0 are provided. In other embodiments, compounds in which q is 1 are provided. In further embodiments, compounds in which q is 2 are provided.

[0151] In some embodiments, compounds having activity as modulators of Mas-related G protein-coupled receptor D are provided, compounds having the following structure (IX),

Chemical formula

[0152] In other embodiments, a compound having the following structure (IX),

Chemical formula

[0153] In some embodiments, compounds are provided wherein R 10 is isopropyl. In other embodiments, compounds are provided wherein R 10 is tert-butyl. In additional embodiments, R 10Compounds in which R is cyclopropyl are provided. In further embodiments, R 10 Compounds in which R is cyclobutyl are provided. In still other embodiments, R 10 Compounds in which R is cyclopentyl are provided.

[0154] In some embodiments, compounds in which R 12 is H are provided. In other embodiments, compounds in which R 12 is alkyl are provided. In certain embodiments, compounds in which R 12 is methyl are provided. In additional embodiments, compounds in which R 12 is ethyl are provided. In further embodiments, compounds in which R 12 is n-propyl are provided. In still other embodiments, compounds in which R 12 is isopropyl are provided.

[0155] In some embodiments, compounds in which R 15 is halo are provided. In certain embodiments, compounds in which R 15 is F are provided. In other embodiments, compounds in which R 15 is Cl are provided. In further embodiments, compounds in which R 15 is Br are provided. In still further embodiments, compounds in which R 15 is I are provided. In still further embodiments, compounds in which R 15 is Cl are provided. In some embodiments, compounds in which R 15 is alkyl are provided. In certain embodiments, compounds in which R 15 is methyl are provided. In further embodiments, compounds in which R 15 is ethyl are provided. In still further embodiments, compounds in which R 15 is n-propyl are provided. In still other embodiments, compounds in which R 15 is isopropyl are provided. In some embodiments, compounds in which R 15 is tert-butyl are provided. In some embodiments, compounds in which R 15Compounds where R is CN are provided. In other embodiments, R 15 Compounds where R is OH are provided. In some embodiments, R 15 Compounds where R is alkoxy are provided. In one embodiment, R 15 Compounds where R is methoxy are provided. In some embodiments, R 15 Compounds where R is haloalkyl are provided. In one embodiment, R 15 Compounds where R is CF3 are provided. In some embodiments, R 15 Compounds where R is cyanoalkyl are provided. In one embodiment, R 15 Compounds where R is CH2CN are provided. In other embodiments, R 15 Compounds where R is alkylcarbonyl are provided. In one embodiment, R 15 Compounds where R is C(O)CH3 are provided.

[0156] In some embodiments, R 16 Compounds where R is H are provided. In other embodiments, R 16 Compounds where R is alkyl are provided. In one embodiment, R 16 Compounds where R is methyl are provided. In additional embodiments, R 16 Compounds where R is ethyl are provided. In further embodiments, R 16 Compounds where R is n-propyl are provided. In still other embodiments, R 16 Compounds where R is isopropyl are provided. In some embodiments, R 16 Compounds where R is tert-butyl are provided. In some embodiments, R 16 Compounds where R is CN are provided. In other embodiments, R 16 Compounds where R is OH are provided. In some embodiments, R 16 Compounds where R is alkoxy are provided. In one embodiment, R 16 Compounds where R is methoxy are provided. In some embodiments, R 16 Compounds where R is haloalkyl are provided. In one embodiment, R 16Compounds in which R is CF3 are provided. In some embodiments, R 16 Compounds in which R is cyanoalkyl are provided. In one embodiment, R 16 Compounds in which R is CH2CN are provided. In some embodiments, R 16 Compounds in which R is alkylcarbonyl are provided. In one embodiment, R 16 Compounds in which R is C(O)CH3 are provided.

[0157] In some embodiments, compounds in which R 17 is halo are provided. In one embodiment, R 17 Compounds in which R is F are provided. In a further embodiment, R 17 Compounds in which R is Cl are provided. In a further embodiment, R 17 Compounds in which R is Br are provided. In a further embodiment, R 17 Compounds in which R is I are provided. In some embodiments, R 17 Compounds in which R is alkyl are provided. In one embodiment, R 17 Compounds in which R is methyl are provided. In a further embodiment, R 17 Compounds in which R is ethyl are provided. In a further embodiment, R 17 Compounds in which R is n-propyl are provided. In yet other embodiments, R 17 Compounds in which R is isopropyl are provided. In some embodiments, R 17 Compounds in which R is tert-butyl are provided. In some embodiments, R 17 Compounds in which R is haloalkyl are provided. In one embodiment, R 17 Compounds in which R is CF3 are provided.

[0158] In some embodiments, compounds in which m is 0 are provided. In other embodiments, compounds in which m is 1 are provided.

[0159] In some embodiments, compounds where n is 0 are provided. In other embodiments, compounds where n is 1 are provided. In still other embodiments, compounds where n is 2 are provided.

[0160] In some embodiments, compounds are provided that are active as modulators of Mas-related G protein-coupled receptor D, compounds having the following structure (X),

Chemical formula

[0161] In some embodiments, compounds where C is cycloalkyl are provided. In one embodiment, compounds where C is cyclopentyl are provided. In a further embodiment, compounds where C is cyclohexyl are provided. In some embodiments, compounds where R 10 is alkyl are provided. In one embodiment, compounds where R 10 is methyl are provided. In a further embodiment, compounds where R 10 is ethyl are provided. In a further embodiment, compounds where R 10 is n-propyl are provided. In still other embodiments, compounds where R 10 is isopropyl are provided. In some embodiments, compounds where R 10Compounds where R is tert-butyl are provided. In some embodiments, R 10 Compounds where R is cyclopropyl are provided. In other embodiments, R 10 Compounds where R is cyclobutyl are provided. In further embodiments, R 10 Compounds where R is cyclopentyl are provided.

[0162] In some embodiments, R 12 Compounds where R is H are provided. In other embodiments, R 12 Compounds where R is alkyl are provided. In certain embodiments, R 12 Compounds where R is methyl are provided. In additional embodiments, R 12 Compounds where R is ethyl are provided. In further embodiments, R 12 Compounds where R is n-propyl are provided. In still other embodiments, R 12 Compounds where R is isopropyl are provided. In some embodiments, R 12 Compounds where R is tert-butyl are provided.

[0163] In some embodiments, R 15 Compounds where R is halo are provided. In certain embodiments, R 15 Compounds where R is F are provided. In further embodiments, R 15 Compounds where R is Cl are provided. In further embodiments, R 15 Compounds where R is Br are provided. In further embodiments, R 15 Compounds where R is I are provided. In some embodiments, R 15 Compounds where R is alkyl are provided. In certain embodiments, R 15 Compounds where R is methyl are provided. In further embodiments, R 15 Compounds where R is ethyl are provided. In further embodiments, R 15 Compounds where R is n-propyl are provided. In still other embodiments, R 15 Compounds where R is isopropyl are provided. In some embodiments, R 15Compounds in which R is tert-butyl are provided. In some embodiments, R 15 Compounds in which R is CN are provided. In other embodiments, R 15 Compounds in which R is OH are provided. In some embodiments, R 15 Compounds in which R is alkoxy are provided. In one embodiment, R 15 Compounds in which R is methoxy are provided. In some embodiments, R 15 Compounds in which R is haloalkyl are provided. In one embodiment, R 15 Compounds in which R is CF3 are provided. In some embodiments, R 15 Compounds in which R is cyanoalkyl are provided. In one embodiment, R 15 Compounds in which R is CH2CN are provided. In some embodiments, R 15 Compounds in which R is alkylcarbonyl are provided. In one embodiment, R 15 Compounds in which R is C(O)CH3 are provided.

[0164] In some embodiments, R 17 Compounds in which R is halo are provided. In one embodiment, R 17 Compounds in which R is F are provided. In further embodiments, R 17 Compounds in which R is Cl are provided. In further embodiments, R 17 Compounds in which R is Br are provided. In further embodiments, R 17 Compounds in which R is I are provided. In some embodiments, R 17 Compounds in which R is alkyl are provided. In one embodiment, R 17 Compounds in which R is methyl are provided. In further embodiments, R 17 Compounds in which R is ethyl are provided. In further embodiments, R 17 Compounds in which R is n-propyl are provided. In still other embodiments, R 17 Compounds in which R is isopropyl are provided. In some embodiments, R 17 Compounds in which R is tert-butyl are provided. In some embodiments, R 17Compounds are provided where is a haloalkyl. In certain embodiments, R 17 Compounds are provided where is CF3.

[0165] In some embodiments, compounds are provided where m is 0. In other embodiments, compounds are provided where m is 1.

[0166] In some embodiments, compounds are provided where n is 0. In other embodiments, compounds are provided where n is 1. In still other embodiments, compounds are provided where n is 2.

[0167] In some embodiments, compounds are provided that are active as modulators of Mas-related G protein-coupled receptor D, compounds having the following structure (XI),

Chemical formula

[0168] In some embodiments, compounds are provided where R 10 is isopropyl. In other embodiments, compounds are provided where R 10 is tert-butyl. In additional embodiments, R 10Compounds in which R is cyclopropyl are provided. In further embodiments, R 10 Compounds in which R is cyclobutyl are provided. In still other embodiments, R 10 Compounds in which R is cyclopentyl are provided.

[0169] In some embodiments, compounds in which R 12 is H are provided. In other embodiments, compounds in which R 12 is alkyl are provided. In one embodiment, compounds in which R 12 is methyl are provided. In additional embodiments, compounds in which R 12 is ethyl are provided. In further embodiments, compounds in which R 12 is n-propyl are provided. In still other embodiments, compounds in which R 12 is isopropyl are provided. In some embodiments, compounds in which R 12 is tert-butyl are provided.

[0170] In some embodiments, compounds in which R 17 is halo are provided. In one embodiment, compounds in which R 17 is F are provided. In further embodiments, compounds in which R 17 is Cl are provided. In further embodiments, compounds in which R 17 is Br are provided. In further embodiments, compounds in which R 17 is I are provided. In some embodiments, compounds in which R 17 is alkyl are provided. In one embodiment, compounds in which R 17 is methyl are provided. In further embodiments, compounds in which R 17 is ethyl are provided. In further embodiments, compounds in which R 17 is n-propyl are provided. In still other embodiments, compounds in which R 17 is isopropyl are provided. In some embodiments, compounds in which R 17 is tert-butyl are provided. In some embodiments, compounds in which R 17Compounds are provided where R is haloalkyl. In certain embodiments, R 17 is CF3. Compounds are provided.

[0171] In some embodiments, compounds are provided where R 18 is C1-C4 alkyl. In some embodiments, compounds are provided where R 18 is C1-C4 alkyl optionally substituted with one R 19 . In some embodiments, compounds are provided where R 18 is methyl substituted with one R 19 . In some embodiments, compounds are provided where R 18 is ethyl substituted with one R 19 .

[0172] In some embodiments, compounds are provided where R 19 is halo. In certain embodiments, compounds are provided where R 19 is F. In further embodiments, compounds are provided where R 19 is Cl. In further embodiments, compounds are provided where R 19 is Br. In further embodiments, compounds are provided where R 19 is I. In some embodiments, compounds are provided where R 19 is CN. In other embodiments, compounds are provided where R 19 is OH. In some embodiments, compounds are provided where R 19 is haloalkyl. In certain embodiments, compounds are provided where R 19 is CF3. In some embodiments, compounds are provided where R 19 is alkoxy. In certain embodiments, compounds are provided where R 19 is methoxy. In some embodiments, compounds are provided where R 19 is alkylcarbonyl. In certain embodiments, compounds are provided where R 19 is C(O)CH3.

[0173] In some embodiments, compounds where n is 0 are provided. In other embodiments, compounds where n is 1 are provided. In still other embodiments, compounds where n is 2 are provided.

[0174] For exemplary compound structures as described above, refer to Table A.

[0175] Indications Pain In one embodiment, the regulation of MRGPRD is a medically indicated disease, and the pain-related conditions are acute pain, progressive prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, cerebral ataxic paralysis, autoimmune atrophic gastritis, avascular necrosis, low back pain, Behçet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, pneumothorax, complex regional pain syndrome (RSD), constipation, corneal neuropathic pain, Crohn's disease, degenerative disc disease, dental pain, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dry eye syndrome, dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromyalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, inflammatory bowel disease (IBD), intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatomyositis (dermatomyositis), knee injury, leg pain, loin pain-hematuria syndrome, lupus, Lyme disease, medullary sponge kidney (MSK), paralytic paralysis, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, ocular pruritus, osteoarthritis, Paget's disease, Parsonage-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney, polymyalgia, polymyositis, porphyria, post-hernia pain syndrome, post-mastectomy, postoperative pain, pain syndrome, post-stroke pain, post-thoracotomy pain syndrome, post-herpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (herpes zoster), Sjogren's syndrome, spasmodic torticollis, Oddi sphincter dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, talar cysts, transverse myelitis, trigeminal neuralgia, neurogenic pain, ulcerative colitis, vascular pain or vulvar pain.

[0176] Skin In another embodiment, the modulation of MRGPRD is a medically indicated disease, and the pruritus-related condition is chronic pruritus, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, end-stage renal failure, hemodialysis, chronic urticaria, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythema, food allergy, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iodinated contrast agent allergy, iron deficiency anemia, kidney disease, leukemia, porphyria, lymphoma, malignancy, mastocytosis, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia vera, nodular prurigo, lichen planus, lichen sclerosus, pruritus ani, pseudorabies, psoriasis, rectal prolapse, sarcoidosis granuloma, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, alcoholism, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, eye pruritus, or urticaria.

[0177] In certain embodiments, the pruritus-related condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema. Eye

[0178] Eye In another embodiment, the modulation of MRGPRD is a medically indicated disease, and the eye-related condition is dry eye syndrome / keratoconjunctivitis sicca and related conditions such as xerotalmia, meibomian gland dysfunction, lacrimal gland dysfunction, dacryadenitis, dacryocystitis, allergic conjunctivitis, blepharitis, rheumatoid arthritis, systemic erythema, scleroderma, Sjogren's syndrome, Stevens-Johnson syndrome, sarcoidosis, sympathetic ophthalmia, diabetic retinopathy, parasitic eye infection, thyroid disorder, dry eye associated with other conditions such as vitamin A deficiency, dry eye related to drugs such as antihistamines, decongestants, antidepressants, antipsychotics, diuretics, hormone replacement drugs, oral contraceptives, antihypertensive drugs, isotretinoin treatment for acne, anticholinergic drugs, and dry eye related to ophthalmic surgeries such as laser ophthalmic surgery, glaucoma surgery, corneal transplantation, cataract removal surgery.

[0179] Cardiovascular and renal In another embodiment, the modulation of MRGPRD is a disease for which medical indication exists, and the cardiovascular and renal disease-related conditions are peripheral vascular disease, cerebrovascular disease, coronary artery disease, cardiac hypertrophy, myocardial fibrosis, cardiovascular hypertension, renovascular hypertension, renal fibrosis, renal disease, nephritis, atherosclerosis, coronary atherosclerotic heart disease, acute myocardial infarction, stroke, thrombosis, coronary atherosclerotic thrombosis, pulmonary embolism, myocardial ischemia, carotid stenosis, spinal stenosis, intracranial stenosis, aneurysm, sepsis, rheumatic fever, or a treatment for cardiac dysfunction due to acute or chronic diseases that affect cardiovascular function or renal function such as diabetes.

[0180] Inflammatory / GI In another embodiment, the modulation of MRGPRD is a disease for which medical indication exists, and the chronic inflammatory and autoimmune-related conditions include chronic pulmonary allergy, asthma, chronic bronchitis, atherosclerosis, Graves' disease, Hashimoto's thyroiditis, chronic inflammatory demyelinating polyneuropathy, ankylosing spondylitis, Crohn's disease, non-alcoholic steatohepatitis, scleroderma, systemic sclerosis, diabetes, ulcerative colitis, Crohn's disease, inflammatory bowel disease, systemic lupus erythematosus, alopecia areata, temporal arteritis, chronic peptic ulcer, polymyalgia rheumatica, periodontitis, rhinitis, sinusitis, pancreatitis, nephritis, Sjogren's syndrome, dermatomyositis, polymyositis, inclusion body myositis, autoimmune necrotizing myopathy, idiopathic inflammatory myopathy, multiple sclerosis, rheumatoid arthritis, vasculitis.

[0181] As used herein, the terms "autoimmune disease" or "inflammatory disorder" refer to a disease or disorder that originates from and / or is directed against an individual's own tissues or organs, or the co-separation or expression thereof, or a condition arising therefrom. Typically, there may be various clinical and laboratory markers of autoimmune diseases, including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, deposition of antigen-antibody complexes in tissues, clinical benefit from corticosteroid or immunosuppressive therapy, and lymphocyte aggregates in affected tissues. Thus, in one embodiment, the methods of the invention are provided for treating autoimmune diseases such as chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, appendicitis, synovitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendinitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infections, allergic rhinitis, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, bowel diseases, epithelial bowel diseases, inflammatory bowel diseases, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis media, pelvic inflammatory disease, endometriosis, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, pneumonia, chronic obstructive pulmonary disease, permanent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, mast cell gastrointestinal diseases, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic sinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swimmer's itch, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, reflux nephropathy, polycystic kidney disease, hepatic fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic hepatitis B and C viruses, liver tumors and cancers, lung tumors and cancers, alcoholic liver disease, polycystic liver disease, cholangiocarcinoma, neuromyelitis optica spectrum disorder, cardiovascular diseases, and vasculitis, etc.

[0182] Cognitive indications In another embodiment, the modulation of MRGPRD is a medically indicated disease, and cognitive impairment-related conditions include neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, multiple sclerosis, age-related cognitive impairment, vascular cognitive impairment, and cognitive impairment after stroke.

[0183] Cancer In another embodiment, the modulation of MRGPRD is a medically indicated disease, and the cancer-related conditions are acute myeloid leukemia, adolescent cancer, pediatric adrenocortical cancer, AIDS-related cancers (such as lymphoma, Kaposi's sarcoma, etc.), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), fetal tumor, central nervous system cancer, endometrial cancer, epithelioma, esophageal cancer, neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, fungating polypoid tumor, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular tumor, pharyngeal cancer, thymoma / thymic cancer, thyroid cancer, renal pelvis / ureter transitional cell carcinoma, trophoblastic tumor, pediatric atypical cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, viral cancer.In some embodiments, the method relates to the treatment of non-cancerous proliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0184] In other aspects, the cancer-related condition is lung cancer, pancreatic cancer, or skin cancer. In certain embodiments, the cancer-related condition is lung cancer. In certain embodiments, the cancer-related condition is pancreatic cancer. In certain embodiments, the cancer-related condition is skin cancer. In certain embodiments, the skin cancer-related condition is melanoma.

[0185] In one embodiment, the compound is selected from any one of the compounds listed in Table A, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0186] The compounds of formula (I), and, where applicable, the representative compounds of formulas (II)-(XI), include any one of the compounds listed in Table A below, as well as pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof. For this purpose, the representative compounds are identified herein by their respective "Compound Numbers", which may also be abbreviated as "Compound No." or "Cpd. No.".

Table A-1

Table A-2

Table A-3

Table A-4

Table A-5

Table A-6

Table A-7

Table A-8

Table A-9

Table A-10

Table A-11

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

Table A-19

Table A-20

Table A-21

Table A-22

Table A-23

Table A-24

Table A-25

Table A-26

Table A-27

Table A-28

Table A-29

Table A-30

Table A-31

Table A-32

Table A-33

Table A-34

Table A-35

Table A-36

Table A-37

Table A-38

Table A-39

Table A-40

Table A-41

Table A-42

Table A-43

Table A-44

Table A-45

Table A-46

Table A-47

Table A-48

Table A-49

Table A-50

[0187] All reagents for which the synthesis is not described in the experimental part are either commercially available, known compounds, or can be formed from known compounds by methods known to those skilled in the art. Compounds and intermediates produced according to the methods of the present invention may require purification. The purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be stirred using a suitable solvent. In some cases, the compound can be purified by chromatography, particularly flash column chromatography, using a dedicated or prepacked silica gel cartridge and an eluent, such as a gradient of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, the compound can be purified by preparative HPLC using the methods described.

[0188] The purification methods described herein can provide the compounds of the invention having sufficiently basic or acidic functional groups in the form of salts, for example, in the case of compounds of the invention that are sufficiently basic, trifluoroacetates or formates can be provided, or in the case of compounds of the invention that are sufficiently acidic, ammonium salts can be provided. This type of salt can be converted into its free base or free acid form by various methods known to those skilled in the art, or can be used as a salt in subsequent biological assays. It should be understood that the specific forms of the compounds of the invention that are isolated and described herein are not necessarily the only forms in which the compounds can be applied to biological assays to quantify specific biological activities.

[0189] The chemical names were generated using the naming function of ChemDraw software (version 19.0.1.28) from PerkinElmer Informatics, Inc. In some cases, the names of generally accepted commercially available reagents were used instead of the names generated by the naming software.

[0190] Examples General methods 1 1H NMR (400 MHz) was obtained in a solution of deuterated chloroform (CDCl3), deuterated ethanol (CD3OD), or dimethyl sulfoxide-D6 (DMSO-D6).

[0191] The HPLC retention times, purities, and mass spectra (LCMS) were obtained using the following methods.

[0192] Method 1: An Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6×100 mm column was used. H2O containing 0.1% FA was used as mobile phase A, and CH3CN containing 0.1% FA was used as mobile phase B. A positive mode ESI detector was used. The gradient was 5 - 95% mobile phase B over 12 minutes, then held at 95% for 1.8 minutes, and then returned to 10% mobile phase B over 0.2 minutes. The flow rate was 1 mL / min.

[0193] Method 2: A Shimadzu SCL-10A system equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6×150 mm column and a PE Sciex API 150 EX was used. H2O containing 0.1% TFA was used as mobile phase A, and MeOH containing 0.1% TFA was used as mobile phase B. The gradient was 5 - 95% mobile phase B over 12 minutes, then held at 95% mobile phase B for 3 minutes, and then returned to 5% mobile phase B over 1 minute. The flow rate was 1 mL / min.

[0194] Method 3: A Shimadzu SCL-10A system equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6×150 mm column and a PE Sciex API 150 EX was used. H2O containing 0.1% TFA was used as mobile phase A, and MeOH containing 0.1% TFA was used as mobile phase B. The gradient was 50 - 95% mobile phase B over 4 minutes, then held at 95% mobile phase B for 4 minutes, and then returned to 50% mobile phase B over 0.1 minute. The flow rate was 1 mL / min.

[0195] Method 4: SHIMADZU LCMS-2020 System equipped with Kinetex EVO C18 2.1X30mm, (5μm particles), using H2O containing 0.0375% TFA as mobile phase A and CH3CN containing 0.01875% TFA as mobile phase B. A positive mode ESI detector was used. The gradient was 5% B at 0.00 min, 5 - 90% B from 0.00 to 0.80 min, 90 - 95% B from 0.80 to 1.12 min, then 95 - 5% B at 0.01 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0196] Method 5: SHIMADZU LCMS-2020 System equipped with Kinetex EVO C18 2.1X30mm, (5μm particles), using H2O containing 0.025% NH3·H2O as mobile phase A and CH3CN as mobile phase B. A positive mode ESI detector was used. The gradient was 5% B at 0.00 min, 5 - 95% B from 0.00 to 1.2 min, 95 - 5% B from 1.20 to 1.21 min, held at 5% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0197] Method 6: SHIMADZU LCMS-2020 System equipped with Kinetex EVO C18 2.1 X 30 mm, (5μm particles), using H2O containing 0.0375% TFA as mobile phase A and CH3CN containing 0.01875% TFA as mobile phase B. A positive mode ESI detector was used. The gradient was 0% B at 0.00 min, 0 - 60% B from 0.00 to 0.80 min, 60 - 0% B from 0.80 to 1.20 min, held at 0% B for 0.34 min, and the flow rate was 1.5 ml / min.

[0198] Method 7: LCMS-2020 System equipped with HALO C18 3.0X30mm, (2.7μm particles), using H2O containing 0.0375% TFA as mobile phase A and CH3CN containing 0.01875% TFA as mobile phase B. A positive mode ESI detector was used. The gradient was 5% B at 0.00 min, 5 - 95% B from 0.00 - 0.50 min, 95% B at 0.30 min, 95 - 5% B from 0.80 - 0.81 min, held at 5% B for 0.24 min, and the flow rate was 1.5 ml / min.

[0199] The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile, DMF, and toluene used in the procedure were from Aldrich Sure - Seal bottles or similar ones kept under nitrogen (N2). All reactions were magnetically stirred and the temperature was the external reaction temperature. Chromatography was typically performed using a Combiflash® Rf flash purification system (Teledyne Isco) equipped with a Redisep (Teledyne Isco) silica gel (SiO2) column or a similar system.

[0200] Preparative HPLC purification was typically performed using one of the following systems or similar systems: 1) Waters system equipped with a Waters 2489 uv / vis detector, Aquity QDA detector, Waters xBridge Prep C18 5u MOBD, 30×1560mm column, eluting with various gradients of H2O / CH3CN (0.1% FA) at a flow rate of 30 mL / min, or 2) Column: Phenomenex Synergi C18 150X30mm - 4μm, Mobile phase: [H2O(0.225% FA) - CH3CN], B%: 55% - 85%, 12 min) and the desired fractions were typically concentrated using a Genevac EZ - 2.

[0201] The following abbreviations are used: ethyl acetate (EA), triethylamine (TEA), dimethylformamide (DMF), diisopropylethylamine (DIEA), dichloromethane (DCM), methanol (MeOH), petroleum ether (pet ether), tetrahydrofuran (THF), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), dimethyl sulfoxide (DMSO), dichloroethane (DCE), liquid chromatography mass spectrometer (LCMS), nuclear magnetic resonance (NMR), deuterated chloroform (CDCl3), trifluoroacetic acid (TFA), reverse phase (RP), hour (h), minute (min), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), p-toluenesulfonyl azide (N3Ts), hertz (Hz), retention time (t R ), trimethylsilyl azide (TMSN3), petroleum ether (pet ether), acetonitrile (CH3CN), intermediate (INT), 1,1’-bis(diphenylphosphino)ferrocene (dppf), retention factor (R f ). Formic acid (FA), water (H2O) may be included. Other abbreviations generally known in the art may be included.

[0202] Example 1 Synthesis of Compounds 1-4 and Other Representative Compounds

Chem.

[0203] Scheme 1

Chem.

[0204] Step 1-1. 5-Cyclopropyl-N-(2-methylpyridin-4-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide (Compound 1-4)

Chem.

[0205] A sample of 5-cyclopropyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (250 mg, 1.02 mmol) was dissolved in thionyl chloride (5 mL). The mixture was heated at 75 °C for 2 hours and then concentrated to remove excess thionyl chloride. The resulting residue was dissolved in DCM (5 mL), and then DIEA (132 mg, 1.02 mmol) and 2-methylpyridin-4-amine (122 mg, 1.13 mmol) were added. After stirring for 10 minutes, the reaction mixture was diluted with DCM and H2O. The organic layer was recovered and the aqueous layer was extracted with DCM (2X). The resulting organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hexane) and triturated with MeOH / H2O to obtain the product, 270 mg (97%) of 5-cyclopropyl-N-(2-methylpyridin-4-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide (Compound 1-4). C 19 H 19 LCMS-ESI (m / z) calculated for C17H18N5O: 333.4, found 334.4 [M+H] + 、t R = 10.89 min was found (Method 2). 1 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.39 - 7.47 (m, 5H), 2.62 (s, 3H), 2.51 (s, 3H), 1.99 (m, 1H), 1.18 (d, J = 8.0 Hz, 2H), 1.03 (d, J = 8.0 Hz, 2H).

[0206] The compounds listed in Table 1 were prepared using the procedure of Scheme 1.

Table 1

[0207] Example 2 Synthesis of Compound 2-4 and Other Representative Compounds

Chem.

[0208] Scheme 2

Chem.

[0209] Step 2-1. Synthesis of 3-cyclopropyl-3-oxopropanoic acid (INT 2A)

Chem.

[0210] To a stirred solution of ethyl 3-cyclopropyl-3-oxopropanoate (1 g, 6.4 mmol) in THF (20 mL) was added 1 M aqueous NaOH (12.8 mL, 12.8 mmol). After 12 h, the reaction mixture was concentrated to afford 820 mg (99%) of crude 3-cyclopropyl-3-oxopropanoic acid (INT 2A), which was used without further purification.

[0211] Step 2-2. Synthesis of 3-cyclopropyl-3-oxo-N-(pyridin-4-yl)propanamide (INT 2B)

Chem.

[0212] A round-bottom flask containing a stirred solution of INT 2A (300 mg, 2.3 mmol), pyridin-4-amine (243 mg, 2.6 mmol), and HATU (934 mg, 2.50 mmol) was charged with DCM (7 mL) and DIEA (820 μL, 4.7 mmol). The reaction mixture was stirred for 2 h, diluted with EA, washed with H2O, Sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, concentrated, and the crude material was purified by SiO2 chromatography (EA / hexane) to afford 400 mg (84.0%) of 3-cyclopropyl-3-oxo-N-(pyridin-4-yl)propanamide (INT 2B). C 11 H 12 LCMS (m / z) calculated for N2O2: 204.1, found 205.2 [M+H] + was found (Method 3). 1 H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 8.51 (d, J = 4.0 Hz, 2H), 7.52 (d, J = 4.0 Hz, 2H), 3.77 (s, 2H), 2.03 - 2.09 (m, 1H), 1.17 - 1.25 (m, 2H), 1.09 - 1.14 (m, 2H).

[0213] Step 2 - 3. Synthesis of 5-cyclopropyl-1-(4-methoxyphenyl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 2 - 4)

Chemical Structure

[0214] To a stirred solution of (4-methoxyphenyl)boronic acid (56 mg, 0.37 mmol) in DMSO (3 mL) was added sodium azide (47.9 mg, 0.74 mmol), H2O (1 mL), and Cu(OAc)2·(H2O)2 (7.4 mg, 0.04 mmol). After stirring for 2 h, INT 2B (75 mg, 0.37 mmol) and pyrrolidine (ca. 0.1 mL) were added. After stirring for an additional 12 h, the reaction mixture was diluted with EA and washed successively with sat NaHCO3, H2O, and brine. The aqueous layer was dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hex). The resulting material was further purified by reverse phase chromatography (MeOH / H2O) to afford 4.3 mg (3%) of 5-cyclopropyl-1-(4-methoxyphenyl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 2-4). C 18 H 17 LCMS-ESI (m / z) calculated for N5O2: 335.4, found 336.5 [M+H] + 、t R = 8.97 min was found (Method 2). 1 H NMR (400 MHz, DMSO-D6) δ 10.06 (s, 1H), 8.73 (s, 2H), 8.21 (s, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 2.01 (s, 1H), 1.22 (d, J = 8.0 Hz, 2H), 1.12 (d, J = 8.0 Hz, 2H).

[0215] The compounds listed in Table 2 were prepared using the procedure of Scheme 2.

Table 2-1

Table 2-2

[0216] Example 3 Synthesis of Compound 3-1 and Other Representative Compounds

Chem.

[0217] Scheme 3 [Chem.] Reagents: (i) Cu(OAc)2, DMSO, H2O, (ii) NaOH, solvent (THF, MeOH, or DMF), (iii) a. thionyl chloride, b. base (DIEA), solvent (DCM).

[0218] Step 3-1. Synthesis of ethyl 5-cyclopropyl-1-(3-ethylphenyl)-1H-1,2,3-triazole-4-carboxylate (INT 3A) [Chem.]

[0219] To a stirred solution of (3-ethylphenyl)boronic acid (100 mg, 0.67 mmol) in DMSO (5 mL) and H2O (1 mL) were added Cu(OAc)2 (12 mg, 0.067 mmol) and sodium azide (86.7 mg, 1.3 mmol). After stirring for 2 h, ethyl 3-cyclopropyl-3-oxopropionate (104.1 mg, 0.67 mmol) and pyrrolidine (9.6 mg, 0.13 mmol) were added. The reaction mixture was stirred overnight at room temperature, then diluted with EA, washed with H2O and brine, then dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (MeOH / DCM) to give 12.9 mg (7%) of ethyl 5-cyclopropyl-1-(3-ethylphenyl)-1H-1,2,3-triazole-4-carboxylate (INT 3A). C 16 H 19 Calculated LCMS-ESI (m / z) for C15H17N3O2: 285.3, found 286.5 [M+H] + , t R = 5.65 min was found (Method 3).

[0220] Step 3-2. Synthesis of 5-cyclopropyl-1-(3-ethylphenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 3B)

Chem.

[0221] A solution of NaOH (9 mg, 0.22 mmol) in H2O (1 mL) was added to a stirred solution of INT3A (12.9 mg, 0.04 mmol) in EtOH (3 mL). The mixture was stirred at 80 °C for 12 h, then diluted with H2O and washed with EA (50 mL). The aqueous layer was acidified to pH 1-2 by adding 1N HCl and then extracted with EA (3X). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to give 11.6 mg (99%) of 5-cyclopropyl-1-(3-ethylphenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 3B) as a white solid. C 14 H 15 The LCMS-ESI (m / z) calculated for C14H15N5O2 was 257.3, and 258.3 [M+H] + 、t R = 3.99 min was found (Method 3).

[0222] Step 3-3. Synthesis of 5-cyclopropyl-1-(3-ethylphenyl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (3-1)

Chem.

[0223] A stirred solution of INT 3B (11.6 mg, 0.04 mmol) in thionyl chloride (1 mL) was refluxed at 75 °C for 1 h under a N2 atmosphere. The mixture was cooled and concentrated in vacuo. The resulting residue was dissolved in anhydrous DCM (2 mL), and DIEA (7.0 mg, 0.05 mml) and pyridin-4-amine (4.2 mg, 0.05 mmol) were added. After stirring for 2 h, the mixture was washed with H2O and brine, dried (Na2SO4), concentrated, and purified by SiO2 chromatography (EA / hex) to afford 5 mg (33%) of 5-cyclopropyl-1-(3-ethylphenyl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (3-1) as a white solid. C 19 H 19 LCMS-ESI (m / z) calculated for C18H19N5O: 333.2, found 334.4 [M+H] + 、t R = 9.94 min was found (Method 2). 1 H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.62 (s, 2H), 8.14 (s, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.36 - 7.40 (m, 2H), 2.81 (q, J = 8.0 Hz, 2H), 2.02 (quint, J = 4.0 H, 1H), 1.34 (t, J = 8.0 Hz, 3H), 1.17 - 1.28 (m, 2H), 1.09 - 1.14 (m, 2H).

[0224] The compounds listed in Table 3 were prepared using the procedure of Scheme 3.

Table 3

[0225] Example 4 Synthesis of Compound 4-2 and Other Representative Compounds

Chem.

[0226] Scheme 4

Chem.

[0227] Step 4-1. Synthesis of 1-azido-2-chloro-4-methylbenzene (INT 4A)

Chem.

[0228] To a solution of (2-chloro-4-methylphenyl)boronic acid (800 mg, 4.7 mmol) in MeOH (30 mL) were added NaN3 (610 mg, 9.4 mmol) and Cu(OAc)2 (85 mg, 0.47 mmol). After stirring at 55 °C for 3 h, the reaction mixture was partially concentrated, diluted with EA, and washed with H2O. The organic layer was dried (Na2SO4), filtered, and partially concentrated to give crude 1-azido-2-chloro-4-methylbenzene (INT 4A), which was used without further purification.

[0229] Step 4-2. Synthesis of ethyl 1-(2-chloro-4-methylphenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 4B)

[0230]

Chem.

[0231] To a solution of INT 4A (335 mg, 2.0 mmol) in DMSO (3 mL) was added ethyl 3-cyclopropyl-3-oxopropionate (218 mg, 1.4 mmol) and Et2NH (80 mg, 1.1 mmol). After stirring at 80 °C for 12 h, the reaction mixture was purified by reverse-phase SiO2 chromatography (MeOH / H2O) to afford 119 mg (28%) of ethyl 1-(2-chloro-4-methylphenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 4B). C 15 H 16 The LCMS-ESI (m / z) calculated for ClN3O2: 305.1, and 306.2 [M+H] + 、t R = 6.27 min was found (Method 3).

[0232] Step 4-3. Synthesis of 1-(2-chloro-4-methylphenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 4C)

Chemical Structure

[0233] To a solution of INT 4B (120 mg, 2.0 mmol) in EtOH (3 mL) was added a solution of NaOH (78 mg, 2.0 mmol) in H2O (1 mL). After stirring at 78 °C for 2 h, the reaction mixture was concentrated, diluted with H2O and washed with EA. The pH of the aqueous layer was adjusted to pH 1-2 by adding 1N HCl and then extracted with EA (3X). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to afford 108 mg (99%) of 1-(2-chloro-4-methylphenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 4C) as a white solid. C 13 H 12 The LCMS-ESI (m / z) calculated for ClN3O2: 277.1, and 278.0 [M+H] + 、t R = 6.04 min was found (Method 3).

[0234] Step 4-4. Synthesis of 1-(2-chloro-4-methylphenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 4-2)

Chemical formula

[0235] To a solution of INT 4C (50 mg, 0.2 mmol) in DMF (1 mL) was added HATU (75.3 mg, 0.2 mmol). After stirring for 5 minutes, 2-methylpyridin-4-amine (20 mg, 0.2 mmol) and DIEA (95 mg, 0.74 mmol) were added. After stirring for 12 hours, the reaction mixture was treated with 2 - 3 drops of TFA and purified directly by reverse-phase SiO2 chromatography (MeOH / H2O containing 0.1% TFA). The clean product and fractions were combined, washed with 1M NaOH (to remove residual TFA), and concentrated to afford 26 mg (39%) of 1-(2-chloro-4-methylphenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (4-2) as a white solid. C 19 H 18 The LCMS-ESI (m / z) calculated for ClN5O: 367.1, and 368.1 [M + H] + 、t R = 11.13 minutes was found (Method 2). 1 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.51 (s, 3H), 1.91 (m, 1H), 1.25 (d, J = 8.0 Hz, 2H), 1.03 (d, J = 8.0 Hz, 2H).

[0236] The compounds listed in Table 4 were prepared using the procedure of Scheme 4.

Table 4-1

Table 4-2

Table 4-3

[0237] Example 5 Synthesis of Compound 5-4 and Other Representative Compounds

Chem.

[0238] Scheme 5

Chem.

[0239] Step 5-1. Synthesis of 4-Azido-2-ethyl-1-methylbenzene (INT 5A).

Chem.

[0240] A solution of NaNO2 (85.9 mg, 1.2 mmol) in H2O (0.5 mL) was added dropwise to another solution of 3-Ethyl-4-methylaniline (139 mg, 1.03 mmol) in 15% aqueous hydrochloric acid (1 mL) at 0 °C. After stirring for 30 minutes, a solution of NaN3 (134.8 mg, 2.1 mmol) in H2O (0.5 mL) was added dropwise at 0 °C. After stirring at 0 °C for 1 hour, the reaction mixture was diluted with EA and washed with H2O. The organic layer was dried (Na2SO4) and concentrated to give 214 mg (99%) of crude INT 5A, which was used without further purification.

[0241] Step 5-2. Synthesis of 5-Cyclopropyl-1-(3-ethyl-4-methylphenyl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 5-4)

[0242]

Chem.

[0243] A solution of INT 2B (211 mg, 1.03 mmol), INT 5A (211 mg, 1.03 mmol) and Et2NH (41 mg, 0.57 mmol) in DMSO (3 ml) was heated at 80 °C for 4 h. The mixture was purified by RP-SiO2 chromatography (H2O / MeOH, 0.1% TFA). The obtained clean fractions were combined, diluted with EA, washed with NaHCO3, concentrated and further purified by SiO2 chromatography (EA / hexane) to give a residue, from which 10 mg (14%) of 5-cyclopropyl-1-(3-ethyl-4-methylphenyl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 5-4) was obtained. C 20 H 21 The LCMS-ESI (m / z) calculated for N5O: 347.2, 348.4 [M+H] + 、t R = 10.6 min was found (Method 2). 1 1H NMR (400 MHz, CDCl3) δ = 9.37 (s, 1H), 8.57 (s, 2H), 7.69 (s, 2H), 7.35 - 7.36 (m, 2H), 7.28 - 7.33 (m, 1H), 2.74 (q, J = 8.0 Hz, 2H), 2.42 (s, 3H), 1.99 - 2.04 (m, 1H), 1.29 (t, J = 8.0 Hz, 3H), 1.16 - 1.18 (m, 2H), 1.03 - 1.07 (m, 2H).

[0244] The compounds listed in Table 5 were prepared using the procedure of Scheme 5.

Table 5-1

Table 5-2

[0245] Example 6 Synthesis of Compound 6-2 and Other Representative Compounds

Chem.

[0246] Scheme 6

Chem.

[0247] Step 6-1. Synthesis of 3-Cyclopropyl-3-(naphthalen-1-ylimino)-N-(pyridin-4-yl)propanamide (INT6-A)

Chem.

[0248] To a stirred solution of INT 2B (100 mg, 0.49 mmol) and naphthalene-1-amine (77 mg, 0.54 mmol) in CHCl3 (7.5 mL), AcOH (32 mg, 0.54 mmol) was added portionwise at rt in a sealed tube. The tube was sealed and the mixture was refluxed at 61 °C for 16 h. The reaction mixture was diluted with EA, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (MeOH / DCM) to give 104 mg of 3-cyclopropyl-3-(naphthalen-1-ylimino)-N-(pyridin-4-yl)propanamide (INT 6A) (purity about 16%, yield 10%). C 22 H 19 Calculated LCMS-ESI (m / z) for C + H R N3O: 329.2, found 330.1 [M+H]

[0249] Step 6-2. Synthesis of 5-Cyclopropyl-1-(naphthalen-1-yl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 6-2)

Chemical Structure

[0250] To a stirred solution of INT 6A (about 17 mg, 0.05 mmol) in CH3CN (5 mL), DBU (48 mg, 0.32 mmol) and N3Ts solution (62 mg, 0.32 mmol in 0.3 M in toluene) were added at 0 °C. The reaction mixture was stirred for 12 h at the holding time and then heated to reflux for 1 h. After diluting the reaction mixture with DMSO, it was concentrated to remove CH3CN and purified by reverse-phase chromatography (MeOH / H2O) to give 20 mg (99%) of 5-Cyclopropyl-1-(naphthalen-1-yl)-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 6-2) as a white solid. C 21 H 17 LCMS-ESI (m / z) calculated for C19H15N5O: 355.1, found 355.9 [M+H] + 、t R = 11.02 min was found (Method 2). 1 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 8.60 (s, 2H), 8.15 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 2H), 7.57 - 7.71 (m, 4H), 7.25 (d, J = 8.0 Hz, 1H), 1.81 - 1.87 (m, 1H), 1.24 (d, J = 8.0 Hz, 2H), 0.89 (d, J = 8.0 Hz, 2H).

[0251] The compounds listed in Table 6 were prepared using the procedure of Scheme 6.

Table 6

[0252] Example 7 Synthesis of Compounds 7-12 and Other Representative Compounds

Chem.

[0253] Scheme 7

Chem.

[0254] Step 7-1. Synthesis of 1-(4-Bromophenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 7A)

Chem.

[0255] A solution of 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (250 mg, 0.81 mmol) in thionyl chloride (118 μL, 0.9 mmol) was heated at 90 °C for 30 min. The mixture was concentrated and the resulting residue was dissolved in DCM (20 mL). 2-Methylpyridin-4-amine (96 mg, 0.9 mmol) and DIEA (314 mg, 2.4 mmol) were added. After stirring for 2 h, the reaction mixture was diluted with H2O (10 mL), extracted with DCM, dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hexane) to give 280 mg (87%) of 1-(4-bromophenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 7A). C 18 H 16 Calculated LCMS-ESI (m / z) for C18H16BrN5O: 427.2, found 428 [M+H] + 、t R=5.7 was found (Method 3)

[0256] Step 7-2. Synthesis of 5-cyclopropyl-N-(2-methylpyridin-4-yl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide (Compound 7-12) [Chemical formula]

[0257] To a stirred solution of INT 7A (60 mg, 0.15 μmol) in dioxane (5 mL) and H2O (0.5 mL) (in a sealable tube), 4M K3PO4 (96 mg, 0.45 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (71.1 mg, 0.3 mmol), and Pd(dppf)2Cl2 (11 mg, 0.02 mmol) were added. The tube was sealed and the reaction mixture was stirred at 110 °C for 1 hour. The tube was cooled and opened, and further 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.15 mmol) and Pd(dppf)2Cl2 (11 mg, 0.02 mmol) were added. After heating at 110 °C for an additional 45 minutes, the reaction mixture was purified by SiO2 chromatography (EA / hexane and MeOH / DCM). The fractions containing the product were combined and concentrated, and the resulting solid was triturated with DCM / hexane to afford 42 mg (65%) of 5-cyclopropyl-N-(2-methylpyridin-4-yl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide methanamine (Compound 7-12) as a dark brown solid. C 24 H 25 The LCMS-ESI (m / z) calculated for C22H27N7O was 427.2, and 428.0 [M+H] + , t R =10.86 was found (Method 2). 11H NMR (500 Hz, DMSO-d6): 10.76 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 3.74 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.13 (t, J = 8.0 Hz, 1H), 0.97 (d, J = 8.0 Hz, 2H), 0.92 (t, J = 4.0 Hz, 2H).

[0258] The compounds listed in Table 7 were prepared using the procedure of Scheme 7. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12]

Table 7-13

Table 7-14

Table 7-15

Table 7-16

Table 7-17

Table 7-18

Table 7-19

Table 7-20

Table 7-21

Table 7-22

Table 7-23

Table 7-24

Table 7-25

Table 7-26

Table 7-27

Table 7-28

Table 7-29

Table 7-30

Table 7-31

Table 7-32

Table 7-33

Table 7-34

Table 7-35

Table 7-36

Table 7-37

Table 7-38

Table 7-39

Table 7-40

Table 7-41

Table 7-42

Table 7-43

Table 7-44

Table 7-45

Table 7-46

Table 7-47

Table 7-48

Table 7-49

Table 7-50

Table 7-51

Table 7-52

Table 7-53

Table 7-54

Table 7-55

Table 7-56

[0259] Example 8 Synthesis of Compound 8-2 and Other Representative Compounds

Chemical Structure

[0260] Scheme 8

Chemical Structure

[0261] Synthesis of (4-(5-cyclopropyl-4-((2-methylpyridin-4-yl)carbamoyl)-1H-1,2,3-triazol-1-yl)phenyl)boronic acid (INT 8A)

Chem.

[0262] Dioxane (4 mL) was added to a reaction vial containing INT 7A (400 mg, 1.04 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (528 mg, 2.1 mmol), Pd(dppf)Cl2·CH2Cl2 (85 mg, 0.1 mmol) and KOAc (306.5 mg, 3.12 mmol). The reaction mixture was deoxygenated using N2 and heated at 100 °C for 2 h, then concentrated. The resulting residue was dissolved in 1 N aqueous NaOH (20 mL) and filtered. The filtrate was washed with DCM (2X). The organic layer was back-extracted with 1 N NaOH and water. The combined aqueous layers were acidified to pH 6.5 - 7, and the solid obtained by filtration was collected, then washed with H2O and dried in vacuo at 60 °C for 2 h to give 320 mg (85%) of (4-(5-cyclopropyl-4-((2-methylpyridin-4-yl)carbamoyl)-1H-1,2,3-triazol-1-yl)phenyl)boronic acid (INT8A). C 18 H 18 LCMS-ESI (m / z) calculated for BN5O3: 363.1, 364 [M+H] + 、t R = 5.34 min was found (Method 3)

[0263] Synthesis of 1-(4-(1-cyclobutyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 8-2)

Chem.

[0264] INT 8A (30 mg, 0.08 mmol), 4-bromo-1-cyclobutyl-3,5-dimethyl-1H-pyrazole (34 mg, 0.15 mmol), Pd(dppf)Cl2 (6 mg, 0.008 mmol), and K2PO4 (52.6 mg, 0.25 mmol) were added to a sealable tube, followed by the addition of dioxane (3 mL) and H2O (1 mL). After stirring the mixture to dissolve the components, it was purged with N2, sealed, and heated at 110 °C for 3 h. Subsequently, 4-bromo-1-cyclobutyl-3,5-dimethyl-1H-pyrazole (17 mg, 0.007 mmol) and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added. The reaction mixture was purged with N2, heated, and stirred for an additional 2 h. The reaction mixture was diluted with DCM, washed with NaHCO3 and brine, dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA) and reverse-phase SiO2 chromatography (MeOH / H2O) to afford 13.1 mg (33.9%) of 1-(4-(1-cyclobutyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 8-2). C 27 H 29 LCMS-ESI (m / z) calculated for C24H27N7O: 467.6, found 468.0 [M+H] + 、t R = 11.52 min was found (Method 2). 1 1H NMR (400 MHz, CDCl3) δ = 9.21 (s, 1H), 8.31 (s, 1H), 7.44 - 7.50 (m, 3H), 7.30 - 7.33 (m, 3H), 4.55 (m, 1H), 2.61 (m, 2H), 2.49 (s, 3H), 2.32 (m, 2H), 2.20 (s, 3H), 2.15 (s, 3H), 1.93 (m, 1H), 1.88 - 1.90 (m, 2H), 1.21 (m, 2H), 0.98 (m, 2H).

[0265] The compounds listed in Table 8 were prepared using the procedure of Scheme 8.

Table 8

[0266] Example 9 Synthesis of Compound 9-1 and Other Representative Compounds

Chem.

[0267] Scheme 9

Chem.

[0268] Step 9-1. Synthesis of 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 9A)

Chem.

[0269] To a vial containing 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (450 mg, 1.46 mmol) were added 1-ethyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (365.3 mg, 1.46 mmol), Pd(dppf)Cl2·CH2Cl2 (119.3 mg, 0.15 mmol), K3PO4 (930 mg, 4.38 mmol), dioxane (4 mL) and H2O (2 mL). After degassing with N2, the reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and purified directly by RP-SiO2 chromatography (MeOH / H2O) to give 317 mg, (62%) of 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 9A) as a pale brown solid. C 19 H 21 The LCMS-ESI (m / z) calculated for C19H21N5O2: 351.4, found 352 [M+H] + 、t R = 5.71 min was found (Method 3). 1 H NMR (400 MHz, DMSO-D6) δ 13.08 (bs, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.09 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.09 (m, 1H), 1.35 (t, J = 8 Hz, 3H), 0.96 (m, 2H), 0.72 (m, 2H).

[0270] Step 9-2. Synthesis of 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 9-1)

Chemical Structure

[0271] To a stirred solution of INT9A (30 mg, 0.085 mmol) in DMF (0.8 mL) was added HATU (35.7 mg, 0.094 mmol). After stirring for 15 minutes, 2-methylpyridin-4-amine (10.2 mg, 0.094 mmol) and DIEA (33 mg, 0.26 mmol) were added. After stirring for 4 hours, the reaction mixture was diluted with EA, washed with H2O, NaHCO3 and brine, then dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hexane and MeOH / DCM) to give 13.4 mg (35.5%) of 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 9-1). C 25 H 27 LCMS-ESI (m / z) calculated for N7O: 441.2, found 442.1 [M+H] + 、t R = 10.56 min was found (Method 2). 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 3H), 7.50 (d, J = 8.0 Hz, 2H), 4.60 (m, 2H), 2.72 (s, 3H), 2.34 (s, 6H), 2.09 (m, 1H), 1.45 (t, J = 8 Hz, 3H), 01.29 (m, 2H), 1.12 (m, 2H).

[0272] The compounds listed in Table 9 were prepared using the procedure of Scheme 9.

Table 9-1

Table 9-2

Table 9-3

Table 9-4

Table 9-5

Table 9-6

Table 9-7

[0273] Example 10 Synthesis of Compound 10-1 and Other Representative Compounds

Chem.

[0274] Scheme 10

Chem.

[0275] Step 10-1. Synthesis of 1-(4-Boronophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic Acid (INT 10A)

Chem.

[0276] Dioxane (4 mL) was added to a reaction vial containing 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (1740 mg, 5.65 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (2870 mg, 11.29 mmol), Pd(dppf)Cl2·CH2Cl2 (461 mg, 0.56 mmol) and KOAc (1662 mg, 16.95 mmol). The reaction mixture was deoxygenated with N2 gas for 1 minute, stirred and heated at 100 °C for 2 hours, and then concentrated. The resulting residue was dissolved in DMSO (5 mL) and purified by RP chromatography (MeOH / H2O) to give 1200 mg (78%) of 1-(4-boronophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 10A) as an off-white solid. C 12 H 12 LCMS-ESI (m / z) calculated for CBN3O4: 273.1, found 274.1 [M+H] + , t R = 4.7 min was found (Method 3)

[0277] Step 10-2. Synthesis of 5-cyclopropyl-1-(4-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 10B)

Chemical formula

[0278] To a vial containing INT 10A (245 mg, 0.90 mmol), 4-bromo-3,5-dimethyl-1-phenyl-1H-pyrazole (269.3 mg, 1.08 mmol), Pd(dppf)Cl2-CH2Cl2 (73.3 mg, 0.090 mmol), K3PO4 (571 mg, 2.69 mmol), dioxane (3 mL) and H2O (1 mL) were added. After degassing by bubbling N2 for 1 minute, the reaction mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was purified directly by RP-SiO2 chromatography (MeOH / H2O) to afford 358 mg (72.5%) of 5-cyclopropyl-1-(4-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 10B) as a pale brown solid. C 23 H 21 The LCMS-ESI (m / z) calculated for C23H22N5O2: 399.1, found 400.0 [M+H] + 、t R = 6.0 min was found (Method 3). 1 H NMR (400 MHz, DMSO-D6) δ 7.76 (d, J = 8.0 Hz, 2H), 7.42 - 7.61 (m, 7H), 2.31 (s, 3H), 2.19 (s, 3H), 2.11 (m, 1H), 0.94 (m, 2H), 0.72 (m, 2H).

[0279] Step 10-3. Synthesis of 5-cyclopropyl-1-(4-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 10-1)

Chem.

[0280] To a stirred solution of INT10B (40 mg, 0.10 mmol) in DMF (0.8 mL) was added HATU (41.9 mg, 0.11 mmol). After stirring for 15 minutes, 2-methylpyridin-4-amine (11.9 mg, 0.11 mmol) and DIEA (38 mg, 0.30 mmol) were added. After stirring for 4 hours, the reaction mixture was diluted with EA and washed with H2O, NaHCO3 and brine, then dried (Na2SO4), filtered, concentrated and purified by SiO2 chromatography (EA / hexane and MeOH / DCM) to give 4 mg (8.2%) of 5-cyclopropyl-1-(4-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 10-1). C 29 H 27 LCMS-ESI (m / z) calculated for N7O: 489.2, found 490.0 [M+H] + 、t R = 11.96 min was found (Method 2). 1 H NMR (400 MHz, DMSO-D6) δ 9.93 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.50 - 7.79 (m, 8H), 7.42 (m, 1H), 2.96 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H), 2.05 (t, J = 8.0 Hz, 1H), 1.32 (d, J = 8.0 Hz, 2H), 1.20 (t, J = 8.0 Hz, 2H).

[0281] The compounds listed in Table 10 were prepared using the procedure of Scheme 10.

Table 10-1

Table 10-2

[0282] Example 11 Synthesis of Compound 11-1 and Other Representative Compounds

Chem.

[0283] Scheme 11

Chem.

[0284] Step 11-1. Synthesis of 2-azido-5-bromopyridine (INT 11A)

Chem.

[0285] To a solution of 5-bromo-2-fluoropyridine (1500 mg, 8.5 mmol) was added NaN3 (1.1 g, 17 mmol) in DMSO (12 mL). After stirring at 120 °C for 16 h, the reaction mixture was diluted with EA, washed with brine, dried (Na2SO4), filtered, and partially concentrated to give crude 2-azido-5-bromopyridine (INT 11A) (assuming 100% conversion). LCMS-ESI (m / z) calculated for C5H3BrN4: 197.9, found 199.2 [M+H] + , t R = 4.83 min (Method 3) was found.

[0286] Step 11-2. Synthesis of ethyl 1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 11B)

Chem.

[0287] A stirred solution of INT 11A (1.90 g, 9.54 mmol) in DMSO (6 mL) was added with K2CO3 (2.64 g, 9.54 mmol) and ethyl 3-cyclopropyl-3-oxopropionate (1.49 mg, 9.55 mmol). After heating at 50 °C for 1.5 h, the reaction mixture was cooled and acidified with 3 M HCl. The mixture was diluted with NaHCO3 and extracted with EA. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hex) to afford 690 mg (21.4%) of ethyl 1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 11B). C 13 H 13 The LCMS-ESI (m / z) calculated for BrN4O was 336, and 336.9 [M+H] + , t R = 6.21 min (Method 3) was found.

[0288] Step 11-3 Synthesis of 1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 11C)

Chemical formula

[0289] To a stirred solution of INT 11B (690 mg, 2.04 mmol) in EtOH (30 mL) and H2O (5 mL) was added 1 M aqueous NaOH (6.14 mL, 6.14 mmol). After heating at 50 °C for 40 min, the reaction mixture was cooled and concentrated to remove EtOH. The resulting solution was diluted with H2O and washed with EA. The resulting aqueous layer was neutralized with 6 M HCl and extracted with EA. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to afford 460 mg (73%) of 1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 11C). C 11 The LCMS-ESI (m / z) calculated for H9BrN4O2 was 307.9, and 309.0 [M+H] +, t R = 5.74 minutes (Method 3) was found.

[0290] Step 11-4 Synthesis of 1-(5-bromopyridin-2-yl)-5-cyclopropyl-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 11D)

Chemical Structure

[0291] HATU (129 mg, 0.34 mmol) was added to a stirred solution of INT11C (100 mg, 0.32 mmol) in DMF (2 mL). After stirring for 1 minute, DIEA (0.17 mL, 0.97 mmol) and pyridin-4-amine (33 mg, 0.36 mmol) were added to the mixture. After stirring at room temperature for 3 hours, the reaction mixture was diluted with EA, washed with 1 M NaOH and brine, then dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hexane) to give 71 mg (57%) of 1-(5-bromopyridin-2-yl)-5-cyclopropyl-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 11D). C 16 H 13 The LCMS-ESI (m / z) calculated for BrN6O: 384.2, and 385.0 [M+H] + , t R = 5.47 minutes (Method 3) was found.

[0292] Step 11-5 Synthesis of 5-cyclopropyl-N-(pyridin-4-yl)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 11-1)

Chemical Structure

[0293] To a sealable tube, INT 11D (70 mg, 0.18 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.27 mmol), Pd(dppf)Cl2 (13 mg, 0.02 mmol), and K3PO4 (116 mg, 0.55 mmol) were added, followed by addition of dioxane (2 mL) and H2O (1 mL). The tube was sealed and heated at 110 °C for 1.5 h, then the mixture was cooled to room temperature, diluted with saturated NaHCO3, and extracted with EA. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hexane and MeOH / DCM) to give 38 mg (51%) of 5-cyclopropyl-N-(pyridin-4-yl)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 11-1). C 22 H 22 LCMS-ESI (m / z) calculated for C22H23N8O: 414.2, found 415.2 [M+H] + 、t R = 9.61 min was found (Method 2). 1 1H NMR (400 MHz, DMSO-D6) δ 10.91 (s, 1H), 8.64 (s, 1H), 8.49 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H), 2.40 (m, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 0.97 (m, 4H).

[0294] The compounds listed in Table 11 were prepared using the procedure of Scheme 11.

Table 11

[0295] Example 12 Synthesis of Compound 12-1 and Other Representative Compounds

Chem.

[0296] Scheme 12

Chemical formula

[0297] Step 12-1. Synthesis of tert-butyl (4-(1,3,5-trimethyl-1H-pyrazol-4-yl) cyclohex-3-en-1-yl) carbamate (INT 12A)

Chemical formula

[0298] To a sealable tube, Pd(dppf)2Cl2 (45 mg, 0.06 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex-3-en-1-yl) carbamate (400 mg, 1.24 mmol), 4-bromo-1,3,5-trimethyl-1H-pyrazole (258 mg, 0.1.36 mmol), K3PO4 (788 mg, 3.8 mmol), dioxane (10 mL) and H2O (2 mL) were added.

[0299] After stirring at 110 °C for 1 h, the mixture was diluted with EA, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated to give a crude product. Purification by SiO2 chromatography (EA / hex, then MeOH / DCM) gave 259 mg (73%) of tert-butyl (4-(1,3,5-trimethyl-1H-pyrazol-4-yl) cyclohex-3-en-1-yl) carbamate (INT 12A). C 17 H 27The LCMS-ESI (m / z) calculated for N3O2 was 305.2, and 306.2 [M+H] + , t R = 5.86 minutes was found (Method 3).

[0300] Step 12-2. Synthesis of 4-(1,3,5-trimethyl-1H-pyrazol-4-yl) cyclohex-3-en-1-amine (INT 12B)

Chemical Structure

[0301] A solution of INT12A (175 mg, 0.57 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated, dissolved in EA, washed with brine, dried (Na2SO4), filtered and concentrated to give 33 mg (28%) of 4-(1,3,5-trimethyl-1H-pyrazol-4-yl) cyclohex-3-en-1-amine (INT 12B). C 12 H 19 The LCMS-ESI (m / z) calculated for N3 was 205.2, and 206.2 [M+H] + , t R = 3.45 minutes (Method 3) was found.

[0302] Step 12-3. Synthesis of 3-cyclopropyl-N-(2-methylpyridin-4-yl)-3-oxopropanamide (INT 12B)

Chemical Structure

[0303] A round-bottom flask containing a stirred solution of INT 2A (3.0 g, 13.8 mmol) and DIEA (5.3 g, 41.5 mmol) in DMF (10 mL) was charged with 2-methylpyridin-4-amine (1.4 g, 15.2 mmol) and HATU (5.78 g, 15.2 mmol). The reaction mixture was stirred for 12 h, diluted with EA, washed with H2O, sat aq. NaHCO3, H2O, and brine, then dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hex) to afford 2.5 g (83.0%) of 3-cyclopropyl-3-oxo-N-(pyridin-4-yl)propanamide (INT 12C). 1 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.35 (d, J = 4.0 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 4.0 Hz, 1H), 3.85 (s, 2H), 2.67 (s, 3H), 2.03 - 2.09 (m, 1H), 1.17 - 1.25 (m, 2H), 1.09 - 1.14 (m, 2H).

[0304] Step 12-4. Synthesis of 3-cyclopropyl-N-(2-methylpyridin-4-yl)-3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)imino)propanamide (INT 12D) [Chemical Structure]

[0305] To a stirred solution of INT 12B (372.5 mg, 1.8 mmol) and INT 12C (360 mg, 1.65 mmol) in CHCl3 (25 mL) was added AcOH (109 mg, 1.81 mmol). After stirring at reflux (61 °C) for 16 h, the reaction mixture was diluted with EA, washed with sat aq NaHCO3 and brine, dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hex) to afford 510 mg (76.0%) of 3-cyclopropyl-N-(2-methylpyridin-4-yl)-3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)imino)propanamide (INT 12D). C 24 H 31 LCMS-ESI (m / z) calculated for C22H29N5O: 405.2, found 406.0 [M+H] + , t R = 5.7 min (Method 3).

[0306] Step 12 - 5. Synthesis of 5-cyclopropyl-N-(2-methylpyridin-4-yl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 12 - 1) [Chemical Structure]

[0307] To a stirred solution of INT 12D (510 mg, 1.3 mmol) in CH3CN (25 mL) was added DBU (191 mg, 1.3 mmol) and 4-methylbenzenesulfonyl azide (248 mg, 1.3 mmol) at 0 °C. After stirring at room temperature for 12 h, the reaction mixture was heated and refluxed for an additional 12 h. The reaction mixture was then concentrated, diluted with EA, washed with H2O and brine, then dried (Na2SO4), filtered, concentrated and purified by SiO2 chromatography (EA / hex) and reverse phase chromatography (MeOH / H2O) to give 160 mg (29.5%) of 5-cyclopropyl-N-(2-methylpyridin-4-yl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl) cyclohex-3-en-1-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 12-1). C 24 H 29 LCMS-ESI (m / z) calculated for N7O: 431.2, found 432.1 [M+H] + , t R = 10.03 min was found (Method 2). 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 4.0 Hz, 1H), 4.91 (m, 1H), 3.74 (s, 3H), 3.0 (m, 1H), 2.70 (m, 2H), 2.65 (s, 3H), 2.55 (m, 2H), 2.47 (m, 1H), 2.21 (s, 6H), 1.85 (m, 1H, 1H), 1.29 (d, J = 8.0 Hz, 2H), 1.20 (t, J = 8.0 Hz, 2H).

[0308] The compounds listed in Table 12 were prepared using the procedure of Scheme 12.

Table 12-1

Table 12-2

[0309] Example 13 Synthesis of Compound 13-1 and Other Representative Compounds

Chem.

[0310] Scheme 13

Chem.

[0311] Step 13-1. Synthesis of 5-Cyclopropyl-N-(2-methylpyridin-4-yl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide (Compound 13-1)

Chem.

[0312] To a stirred solution of Compound 12-1 (130 mg, 0.3 mmol), 1:1 EA / MeOH was added with 5% Pd / C (39 mg, 0.3 mmol). The reaction mixture was purged with H2 gas and stirred for 12 h under an H2 (balloon) atmosphere. The reaction mixture was filtered through celite and concentrated to give 120 mg (92%) of 5-Cyclopropyl-N-(2-methylpyridin-4-yl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide (Compound 13-1). C 24 H 31 Calculated LCMS-ESI (m / z) for C22H30N7O: 433.2, found 434.2 [M+H] + , t R = 9.53 min was found (Method 2). 11H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.10 (s, 1H), 3.71 (s, 3H), 2.63 (m, 1H), 2.58 (s, 3H), 2.44 (m, 2H), 2.37 (s, 6H), 2.26 (m, 2H), 2.11 (m, 2H), 1.85 (m, 1H), 1.63 (m, 2H), 1.29 (d, J = 8.0 Hz, 2H), 1.20 (t, J = 8.0 Hz, 2H).

[0313] The compounds listed in Table 13 were prepared using the procedure of Scheme 13. [Table 13]

[0314] Example 14 Synthesis of Compound 14-15, Compound 14-16, and Other Representative Compounds [Chemical Structure]

[0315] Scheme 14 [Chemical Structure] Reagents: (i) t -BuONO, TMSN3, CH3CN, (ii) NaOH (aq), MeOH, (iii) amide coupling ([chloro(dimethylamino)methylene]-dimethylammonium hexafluorophosphate, 1-methylimidazole, DMF) or (HATU, DIEA, DMF).

[0316] Step 14-1. Synthesis of Methyl 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 14A) [Chemical Structure]

[0317] A solution of 4-phenylaniline (10 g, 59.09 mmol) in CH3CN (160 mL) was cooled to 0 °C in an ice bath. To this stirred mixture, t-BuONO (8.43 mL, 70.91 mmol) and TMSN3 (9.33 mL, 70.91 mmol) were added dropwise. The resulting solution was stirred at 25 °C for 1 h. The reaction mixture was poured into NaHCO3 (aqueous solution) at 0 °C, then diluted with EA and washed with H2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by reverse phase HPLC to give a residue, and 10 g (50.2%) of methyl 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 14A) was obtained as a yellow solid. C 19 H 17 LCMS-ESI (m / z) calculated for N3O2: 319.4, 320.0 [M+H] + 、t R = 0.919 min was found (Method 4). 1 1H NMR (400 MHz, CDCl3) δ = 7.71 - 7.65 (m, 2H), 7.59 - 7.50 (m, 4H), 7.45 - 7.38 (m, 2H), 7.36 - 7.30 (m, 1H), 3.90 (s, 3H), 1.96 - 1.89 (m, 1H), 1.00 - 0.93 (m, 2H), 0.86 - 0.80 (m, 2H).

[0318] Step 14-2. Synthesis of 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT14B)

Chemical formula

[0319] A solution of INT14A (10 g, 31.31 mmol) in MeOH (50 mL) was added with NaOH (1 M, 62.63 mL, 62.63 mmol). After stirring at 15 °C for 1 h, the reaction mixture was diluted with EA and extracted with H2O. The organic layer was discarded, the aqueous phase was poured into 1 M HCl, then diluted with EA, washed with H2O and brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain 9 g of ( [1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 14B) as a yellow solid, which was used in the next step without further purification. C 18 H 15 LCMS-ESI (m / z) calculated for N3O2: 305.3, 306.1 [M+H] + , t R = 0.854 min was found (Method 4). 1 H NMR (400 MHz, DMSO-D6) δ = 13.09 (br s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.77 (t, J = 7.8 Hz, 4H), 7.57 - 7.48 (m, 2H), 7.47 - 7.38 (m, 1H), 2.13 (tt, J = 5.4, 8.6 Hz, 1H, 0.97 - 0.83 (m, 2H), 0.77 - 0.63 (m, 2H)).

[0320] Step 14-3a. Synthesis of 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-(2-ethylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 14-15)

Chemical Structure

[0321] To a mixture of INT14B (50 mg, 0.164 mmol) and 2-ethylpyridin-4-amine (24.01 mg, 0.197 mmol) in DMF (2 mL) were added [chloro(dimethylamino)methylene]-dimethylammonium hexafluorophosphate (55.14 mg, 0.197 mmol) and 1-methylimidazole (41.68 mg, 0.51 mmol). The mixture was stirred at 60 °C for 15 h and then at 80 °C for 5 h. The mixture was diluted with aqueous NaHCO3 and extracted with EA (2X). The combined organic layers were dried (Na2SO4), filtered, concentrated under reduced pressure, and purified by reverse-phase preparative scale HPLC to give a residue, providing 3.4 mg (5.1%) of 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-(2-ethylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 14-15) as an off-white solid. C 25 H 23 LCMS-ESI (m / z) calculated for C22H21N5O: 409.5, found 410.2 [M+H] + 、t R = 0.875 min was found (Method 4). 1 1H NMR (400 MHz, CDCl3) δ = 9.51 (br s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.73 (br s, 1H), 7.69 - 7.57 (m, 5H), 7.56 - 7.48 (m, 2H), 7.48 - 7.41 (m, 1H), 3.14 - 2.85 (m, 2H), 2.06 (tt, J = 5.6, 8.5 Hz, 1H), 1.41 (t, J = 7.6 Hz, 3H), 1.24 - 1.17 (m, 2H), 1.16 - 1.08 (m, 2H).

[0322] Step 14-3b Synthesis of 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-(2-isopropylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 14-16)

Chemical formula

[0323] To a mixture of INT 14B (30 mg, 0.098 mmol) and 2-isopropylpyridin-4-amine (16.06 mg, 0.12 mmol) in DMF (1 mL), HATU (56.04 mg, 0.147 mmol) and DIEA (51.34 uL, 0.295 mmol) were added. After stirring at 20 °C for 1 hour, the mixture was diluted with aqueous NaHCO3 and extracted with EA (2X). The combined organic layers were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC to obtain a residue, providing 5.4 mg (12.8%) of 1-([1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-(2-isopropylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 14-16) as a yellow solid. C 26 H 25 The LCMS-ESI (m / z) calculated for C24H25N5O was 423.5, and 424.3 [M+H] + , t R = 0.788 min was found (Method 4). 1 H NMR (400 MHz, CDCl3) δ = 9.85 - 9.22 (m, 1H), 8.52 (d, J = 5.9 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.76 - 7.59 (m, 6H), 7.52 (t, J = 7.6 Hz, 2H), 7.48 - 7.42 (m, 1H), 3.49 - 3.17 (m, 1H), 2.11 - 2.02 (m, 1H), 1.42 (br d, J = 6.7 Hz, 6H), 1.23 - 1.17 (m, 2H), 1.15 - 1.10 (m, 2H).

[0324] The list of compounds in Table 14 was created using the procedure of Scheme 14 (final steps 14-3a or 14-3b).

Table 14-1

Table 14-2

Table 14-3

Table 14-4

Table 14-5

Table 14-6

Table 14-7

Table 14-8

Table 14-9

Table 14-10

Table 14-11

Table 14-12

Table 14-13

Table 14-14

Table 14-15

[0325] Example 15 Synthesis of Compound 15-4 and Other Representative Compounds

Chem.

[0326] Scheme 15

Chem.

[0327] Step 15-1. Synthesis of methyl 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 15A)

Chemical formula

[0328] To a solution of 4-bromoaniline (10 g, 58.13 mmol) in CH3CN (200 mL) was added tert-butyl nitrite (10.37 mL, 87.20 mmol) and azido(trimethyl)silane (9.17 mL, 69.76 mmol) at 0 °C. After stirring at 20 °C for 2 h, methyl 3-cyclopropyl-3-oxopropanoate (9.92 g, 69.76 mmol) and K2CO3 (24.10 g, 174.39 mmol) were added and the mixture was further stirred at 40 °C for 15 h. The reaction mixture was poured into H2O at 0 °C and extracted with EA. The combined organic layers were washed with brine, dried (Na2SO4), concentrated, and triturated with ethanol at 15 °C to afford a residue, giving 8.5 g (45.3%) of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15A) as a yellow solid. C 13 H 12 The LCMS-ESI (m / z) calculated for BrN3O2 was 321.0, and 321.9 [M+H] + , t R = 0.87 min was found (Method 4). 11H NMR (400 MHz, CDCl3) δ = 7.77 - 7.67 (m, 2H), 7.50 - 7.41 (m, 2H), 3.99 (s, 3H), 1.95 (tt, J = 5.5, 8.6 Hz, 1H), 1.08 - 1.02 (m, 2H), 0.88 - 0.82 (m, 2H).

[0329] Step 15-2. Synthesis of methyl 5-cyclopropyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (INT 15B) [Chemical formula]

[0330] To a stirred solution of INT 15A (500 mg, 1.55 mmol) in DMSO (4 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (600 mg, 2.36 mmol), KOAc (304.64 mg, 3.10 mmol) and Pd(dppf)Cl2 (113.56 mg, 0.15 mmol). The reaction mixture was degassed and heated at 80 °C for 15 h under a N2 atmosphere. The reaction mixture was diluted with H2O and EA. The aqueous and organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated to give 600 mg (99%) of crude methyl 5-cyclopropyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (INT 15B) as a brown oil, which was used in the next step without further purification. C 19 H 24 LCMS-ESI (m / z) calculated for C19H25BN3O4: 369.2, 370.2 [M+Na] + 、t R = 0.875 min was found (Method 5).

[0331] Step 15-3. Synthesis of methyl 5-cyclopropyl-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (INT 15C)

Chem.

[0332] To a solution of INT 15B (600 mg, 1.63 mmol) in dioxane (10 mL) and H2O (2 mL) were added 4-bromo-1,3,5-trimethyl-pyrazole (460.83 mg, 2.44 mmol), Pd(dppf)Cl2 (118.91 mg, 0.162 mmol), and K2CO3 (449.18 mg, 3.25 mmol). The reaction mixture was degassed and stirred at 80 °C for 15 h under a N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by SiO2 chromatography (EA / pet ether) to give 240 mg (34.5%) of methyl 5-cyclopropyl-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (INT 15C) as a yellow solid. C 19 H 21 The LCMS-ESI (m / z) calculated for C18H21N5O2 was 351.4, and 352.2 [M+H] + 、t R = 0.76 min was found (Method 4). 1 1H NMR (400 MHz, CDCl3) δ = 7.57 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 3.99 (s, 3H), 3.81 (s, 3H), 2.29 (d, J = 1.5 Hz, 6H), 2.05 - 2.00 (m, 1H), 1.09 - 1.02 (m, 2H), 0.99 - 0.91 (m, 2H).

[0333] Step 15-4. Synthesis of 5-cyclopropyl-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 15-D)

Chem.

[0334] To a solution of INT15C (240 mg, 683 μmol) in MeOH (20 mL) was added LiOH (1 M, 2 mL, 2 mmol). The mixture was stirred at 15 °C for 16 h and then concentrated to remove MeOH. The resulting aqueous solution was adjusted to pH = 7 using 1 M HCl to form a yellow precipitate, which was filtered and dried in vacuo to afford 200 mg (84%) of 5-cyclopropyl-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 15D) as a yellow solid. C 18 H 19 LCMS-ESI (m / z) calculated for C18H21N5O2: 337.2, 338.2 [M + H] + 、t R = 0.2 min was found (Method 5). 1H NMR (400 MHz, DMSO-d6) δ = 13.53 - 12.45 (s, 1H), 7.69 (br d, J = 8.1 Hz, 2H), 7.49 (br d, J = 8.1 Hz, 2H), 3.73 (s, 3H), 2.39 - 2.16 (m, 6H), 2.14 - 2.05 (m, 1H), 0.98 - 0.83 (m, 2H), 0.73 (br d, J = 3.9 Hz, 2H).

[0335] Step 15-5. Synthesis of 5-cyclopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide (Compound 15-4)

Chem.

[0336] To a stirred mixture of INT 15D (50 mg, 148.2 μmol) in DMF (3 mL) and 1-(1-methylpyrazol-4-yl)ethanamine (27.83 mg, 222.3 μmol), HATU (112.7 mg, 296.4 μmol) and DIEA (57.46 mg, 77.44 μL, 444.61 μmol) were added. After stirring at 15 °C for 1 h, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EA (2X). The combined organic layers were washed, dried (Na2SO4), concentrated, and purified by preparative HPLC (10 mM aqueous NH4CO3 / CH3CN) to give 32.6 mg (49.5%) of 5-cyclopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide (Compound 15-4) as a yellow solid. C 24 H 28 LCMS-ESI (m / z) calculated for C24H28N8O: 444.5, found 445.2 [M+H] + 、t R = 0.84 min was found (Method 4). 1 1H NMR (400 MHz, CDCl3) δ = 7.58 - 7.53 (m, 2H), 7.50 (s, 1H), 7.48 - 7.40 (m, 2H), 7.38 (s, 1H), 5.41 - 5.23 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 2.30 (d, J = 1.5 Hz, 6H), 2.06 - 1.95 (m, 1H), 1.62 - 1.62 (m, 1H), 1.60 (d, J = 6.9 Hz, 3H), 1.21 - 1.12 (m, 2H), 1.08 - 1.00 (m, 1H, 2H).

[0337] The compounds listed in Table 15 were prepared using the procedure of Scheme 15.

Table 15-1

Table 15-2

Table 15-3

Table 15-4

[0338] Example 16 Synthesis of Compound 16-1 and Other Representative Compounds

Chem.

[0339] Scheme 16

Chem.

[0340] Step 16-1. Synthesis of (2-Methylpyridin-3-yl)methanamine (INT 16A).

Chem.

[0341] A solution of 2-Methylpyridine-3-carbonitrile (2 g, 16.93 mmol) in THF (10 mL) was added with BH3-THF (1 M, 40.00 mL, 40 mmol) at 0 °C. The resulting solution was heated to 50 °C for 4 h. The mixture was quenched with 1 M HCl (10 mL) at 0 °C. The solution was basified with aqueous NaOH to pH > 10. The mixture was extracted with EA (3X). The combined organic extracts were dried (Na2SO4), filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC chromatography (0.1% NH3·H2O) to give 980 mg (45.5%) of (2-Methylpyridin-3-yl)methanamine (INT 16A). C7H 10 LCMS-ESI (m / z) calculated for N2: 122.2, 123.2 [M+H] + 、tR = 0.25 minutes was found (Method 5). 1 1H NMR (400 MHz, CDCl3) δ 8.41 - 8.32 (m, 1H), 7.64 (br d, J = 7.7 Hz, 1H), 7.17 - 7.11 (m, 1H), 3.89 (d, J = 4.1 Hz, 2H), 2.55 (br d, J = 7.5 Hz, 3H).

[0342] Step 16-2. Synthesis of methyl 1-(4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (16B)

Chemical Structure

[0343] To a mixture of (4-cyano-3-fluoro-phenyl)boronic acid (550 mg, 3.33 mmol) in dioxane (12 mL) and H2O (4 mL), INT 15A (1 g, 3.10 mmol), Pd(dppf)Cl2 (227.13 mg, 310.41 μmol) and K2CO3 (858 mg, 6.21 mmol) were added. The solution was degassed and then heated at 90 °C for 15 h under N2. The reaction mixture was concentrated and the residue was purified by SiO2 chromatography (EA / petroleum ether) to afford 900 mg (76%) of methyl 1-(4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 16B) as a yellow solid. C 20 H 15 LCMS-ESI (m / z) calculated for C19H14FN4O2: 362.3, found 363.2 [M+H] + 、t R = 0.917 minutes was found (Method 4).

[0344] Step 16-3. Synthesis of 1-(4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 16C) [Chemical]

[0345] To a solution of INT16B (900 mg, 2.48 mmol) in MEOH (20 mL) was added LiOH (1 M, 6 mL, 6 mmol). The reaction mixture was stirred at 25 °C for 15 h and then concentrated to remove MeOH. The resulting aqueous residue was adjusted to pH = 7 with 1 M HCl, and the yellow precipitate collected by filtration was produced to give 900 mg of crude 1-(4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 16C) as a yellow solid (purity 72%) and used without further purification. C 19 H 13 The LCMS-ESI (m / z) calculated for FN4O2: 348.3, 349.2 [M + H] + 、t R = 0.873 min was found (Method 4). 1 1H NMR (400 MHz, DMSO-D6) δ = 8.15 - 7.95 (m, 4H), 7.88 (dd, J = 1.4, 8.2 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 2.12 - 1.98 (m, 1H), 0.90 - 0.80 (m, 4H).

[0346] Step 16-4. Synthesis of 1-(4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-((2-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 16-1) [Chemical]

[0347] To a mixture of INT 16C (100 mg, 206.7 μmol, purity 72%) and INT 16A (37.9 mg, 310.1 μmol) in DMF (4 mL), HATU (157.2 mg, 413.4 μmol) and DIEA (108 μL, 620.1 μmol) were added. After stirring at 25 °C for 1 h, the mixture was concentrated and the residue was diluted with TEA (2 mL) and CH3CN (10 mL). The mixture was stirred at 25 °C for 10 min, concentrated in vacuo, and the residue was purified by preparative HPLC (aqueous NH4HCO3 / CH3CN), and then HPLC (H2O(FA) / CH3CN) was prepared to give 319 mg (33.5%) of 1-(4’-cyano-3’-fluoro-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-N-((2-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 16-1) as a yellow solid. C 26 H 21 LCMS-ESI (m / z) calculated for FN6O: 452.5, 453.0 [M+H] + 、t R = 0.969 min was found (Method 4). 1 1H NMR (400 MHz, DMSO-D6) δ = 9.12 (t, J = 6.1 Hz, 1H), 8.36 - 8.26 (m, 1H), 8.10 - 8.04 (m, 3H), 8.03 (d, J = 1.5 Hz, 1H), 7.88 (dd, J = 1.6, 8.1 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.63 - 7.55 (m, 1H), 7.20 (dd, J = 4.9, 7.6 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.18 - 1.97 (m, 1H), 0.95 - 0.72 (m, 4H).

[0348] The compounds listed in Table 16 were prepared using the procedure of Scheme 16.

Table 16

[0349] Example 17 Synthesis of Compound 17-3 and Other Representative Compounds [Chemistry]

[0350] Scheme 17 [Chemistry] Reagents: (i) HATU, DIEA, DMF.

[0351] Step 17-1. Synthesis of 1-(4'-Cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-((6-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 17-3)

[0352] [Chemistry]

[0353] To a solution of INT 16C (60 mg, 172 μmol) and (6-methyl-3-pyridyl)methanamine (31.57 mg, 258.38 μmol) in DMF (3 mL), HATU (131 mg, 344 μmol) and DIEA (90 μL, 258.4 μmol) were added. After stirring at 25 °C for 1 h, the mixture was concentrated to give a residue which was diluted with TEA (2 mL) and CH3CN (10 mL). The mixture was stirred at 25 °C for 10 min and concentrated in vacuo, and the residue was purified by preparative-HPLC (aqueous NH4HCO3 / CH3CN), then preparative-HPLC (H2O(FA) / CH3CN) to give 31.7 mg (39.8%) of 1-(4'-Cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-((6-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 17-3) as a yellow solid. C 26 H 21 LCMS-ESI (m / z) calculated for C22H20FN6O: 452.5, found 453.0 [M+H] + , t R = 0.811 min was found (Method 4).1 1H NMR (400 MHz, DMSO-D6) δ = 9.15 (t, J = 6.2 Hz, 1H), 8.42 - 8.26 (m, 1H), 8.13 - 8.00 (m, 3H), 7.88 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 1.6, 8.6 Hz, 1H), 7.86 - 7.63 (m, 2H), 7.63 - 2.2 (m, 1H), 7.21 (dd, J = 4.9, 7.9 Hz, 1H), 4.44 (d, J = 6.2 Hz, 2H), 2.44 (s, 3H), 2.12 - 2.01 (m, 1H), 0.91 - 0.81 (m, 4H).

[0354] The compounds listed in Table 17 were prepared using the procedure of Scheme 17. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7]

[0355] Example 18 Synthesis of Compound 18-3 and Other Representative Compounds [Chemical Structure]

[0356] Scheme 18 [Chemical Structure] Reagents: (i) Ethylmagnesium bromide, titanium tetraisopropoxide, BF3·Et2O in THF at 0 - 25°C, (ii) Pd(dppf)Cl2, K2CO3, dioxane, H2O at 90°C, (iii) base (NaOH(aq) or LiOH(aq)), MeOH, (iv) HATU, DIEA, DMF.

[0357] Step 18 - 1. Synthesis of 1-(pyridin - 3 - yl)cyclopropane - 1 - amine (INT 18A).

Chem.

[0358] To a mixture of pyridine - 3 - carbonitrile (500 mg, 4.80 mmol) in THF (10 mL) was added ethylmagnesium bromide (3 M, 4.00 mL) and titanium tetraisopropoxide (2.13 mL, 7.20 mmol) at - 70°C. The mixture was slowly warmed to 25°C and stirred for 3 hours. After cooling to 0°C, BF3·Et2O (1.19 mL, 9.61 mmol) was added and the mixture was stirred at 25°C for 15 hours. The mixture was quenched with 1 M aqueous NaOH and extracted with EA (3X). The combined organic extracts were dried (Na2SO4), filtered, concentrated under reduced pressure, and the residue was purified by SiO2 chromatography (MeOH / EA) to afford 200 mg (18.6%) of 1-(pyridin - 3 - yl)cyclopropane - 1 - amine (INT 18A). C8H 10 LCMS - ESI (m / z) calculated for N2: 134.1, 135.2 [M + H] + 、t R = 0.358 min was found (Method 5). 1 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 1.9 Hz, 1H), 8.37 (dd, J = 1.6, 4.8 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.16 (ddd, J = 0.8, 4.8, 8.0 Hz, 1H), 2.28 (br s, 2H), 1.09 - 1.04 (m, 2H), 0.98 - 0.92 (m, 2H).

[0359] Step 18-2. Synthesis of methyl 1-(4’-cyano-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (18B)

Chemical formula

[0360] To a mixture of (4-cyanophenyl)boronic acid (900 mg, 3.33 mmol, 1.52 eq) in dioxane (15 mL) and H2O (3 mL), INT 15A (1.3 g, 4.04 mmol), Pd(dppf)Cl2 (295.3 mg, 403 μmol, 0.1 eq) and K2CO3 (1.12 g, 8.1 mmol) were added. The solution was degassed and then heated at 90 °C for 15 h under N2. The reaction mixture was concentrated on the residue purified by SiO2 chromatography (EA / petroleum ether), and 1.3 g (90.7%) of methyl 1-(4’-cyano-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 18B) was obtained as a yellow solid. C 20 H 16 The LCMS-ESI (m / z) calculated for C19H14N4O2: 344.4, and 345.1 [M+H] + 、t R = 0.846 min was found (Method 5).

[0361] Step 18-3. Synthesis of 1-(4’-cyano-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 18C)

Chemical formula

[0362] To a solution of INT 18B (1.3 g, 3.78 mmol) in MeOH (20 mL) was added LiOH (1 M, 7.55 mL, 7.55 mmol). The reaction mixture was stirred at 25 °C for 20 h and then concentrated to remove MeOH. The resulting aqueous residue was adjusted to pH = 7 with 1 M HCl, and the yellow precipitate collected by filtration was generated to give 1.2 g of crude 1-(4’-cyano-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 18C) as a yellow solid (purity 47%) and used without further purification. C 19 H 14 LCMS-ESI (m / z) calculated for N4O2: 330.3, 331.2 [M+H] + 、t R = 0.97 min was found (Method 4).

[0363] Step 18-4. Synthesis of 1-(4’-cyano-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-N-(1-(pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 18-3)

Chemical Structure

[0364] To a solution of INT 18C (100 mg, 143 μmol, purity 47%) and INT 18A (103.3 mg, 605.4 μmol) in DMF (3 mL), HATU (230 mg, 605.4 μmol) and DIEA (210 μL, 1.21 μmol) were added. After stirring at 25 °C for 1 h, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EA. The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford a residue purified by preparative-HPLC (aqueous NH4HCO3 / CH3CN), then preparative HPLC (H2O(FA) / CH3CN), giving 37.6 mg (27.5%) of 1-(4’-cyano-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-N-(1-(pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 18-3) as a yellow solid. C 27 H 22 LCMS-ESI (m / z) calculated for N6O: 446.5, found 447.2 [M+H] + 、t R = 0.817 min was found (Method 4). 1 1H NMR (400 MHz, CDCl3) δ = 8.65 (br s, 1H), 8.58 - 8.42 (m, 1H), 8.15 - 8.01 (m, 1H), 7.84 - 7.74 (m, 7H), 7.68 (br d, J = 8.3 Hz, 2H), 7.44 (br s, 1H), 2.03 - 1.93 (m, 1H), 1.55 (br s, 2H), 1.46 (br s, 2H), 1.10 (br d, J = 4.0 Hz, 2H), 1.03 (brd, J = 8.4 Hz, 2H).

[0365] The compounds listed in Table 18 were prepared using the procedure of Scheme 18.

Table 18-1

Table 18-2

Table 18-3

Table 18-4

Table 18-5

[0366] Example 19 Synthesis of Compound 19-2 and Other Representative Compounds

Chem.

[0367] Scheme 19

Chem.

[0368] Step 19-1. Synthesis of 4-bromo-1-ethyl-3,5-dimethyl-1H-pyrazole (INT 19A).

Chem.

[0369] To a solution of 4-bromo-3,5-dimethyl-1H-pyrazole (2 g, 11.43 mmol) in CH3CN (20 mL) were added K2CO3 (4.74 g, 34.28 mmol) and iodoethane (1.83 mL, 22.85 mmol). The mixture was stirred at 80 °C for 15 h and then filtered. The filtrate was concentrated and purified by SiO2 chromatography (EA / petroleum ether) to afford 1.8 g (77.6%) of 4-bromo-1-ethyl-3,5-dimethyl-1H-pyrazole (INT 19A). C7H 11 Calculated LCMS-ESI (m / z) for C7HBrN2: 203.1, found 205.1 [M+H] + 、t R= 0.908 min (Method 5) was found (Method 5). 1 1H NMR (400 MHz, CDCl3) δ 4.02 (q, J = 7.3 Hz, 2H), 2.20 (d, J = 9.8 Hz, 6H), 1.35 (t, J = 7.2 Hz, 3H).

[0370] Step 19-2. Synthesis of methyl 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (INT 19B)

Chemical Structure

[0371] To a solution of INT 15B (2 g, 2.98 mmol) in dioxane (20 mL) and H2O (5 mL) were added INT 19A (1 g, 4.92 mmol), Pd(dppf)Cl2 (218 mg, 0.298 mmol) and K2CO3 (823 mg, 5.92 mmol). The reaction mixture was degassed and heated at 90 °C for 15 h under a N2 atmosphere. The reaction mixture was concentrated and the residue was purified by SiO2 chromatography (EA / pet ether) to give 900 mg (83%) of methyl 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (INT 19B) as a yellow solid. C 20 H 23 The LCMS-ESI (m / z) calculated for C19H22N5O2: 365.4, found 366.1 [M+H] + , t R = 0.867 min (Method 5) was found. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 2.30 (s, 6H), 2.07 - 1.99 (m, 1H), 1.46 (t, J = 7.3 Hz, 3H), 1.09 - 1.02 (m, 2H), 1.00 - 0.93 (m, 2H).

[0372] Step 19-3. Synthesis of 5-Cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 19C)

Chemical Structure

[0373] To a solution of INT 19B (900 mg, 2.46 mmol) in MeOH (30 mL) was added LiOH (1 M, 6 mL, 6 mmol). The mixture was stirred at 25 °C for 15 h and then concentrated to remove MeOH. The resulting aqueous solution was adjusted to pH = 5 using 1 M HCl to form a yellow precipitate, which was filtered and dried in vacuo to afford 600 mg (68%) of 5-Cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 19C) as a yellow solid. C 19 H 21 LCMS-ESI (m / z) calculated for C19H21N5O2: 351.4, found 352.0 [M+H] + 、t R = 0.815 min was found (Method 4). 1 1H NMR (400 MHz, DMSO-D6) δ = 7.68 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.17 - 3.98 (m, 2H), 2.29 (s, 3H), 2.29 (s, 3H), 2.16 - 2.05 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 0.95 - 0.87 (m, 2H), 0.77 - 0.68 (m, 2H).

[0374] Step 19-4. Synthesis of 5-Cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-N-(1-(pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 19-2)

Chemical Structure

[0375] To a stirred mixture of INT19C (80 mg, 227.7 μmol) and INT18A (61 mg, 455.3 μmol) in DMF (3 mL) were added HATU (173.1 mg, 455.3 μmol) and DIEA (119 μL, 683 μmol). After stirring at 25 °C for 1 h, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EA (2X). The combined organic layers were washed with brine, dried (Na2SO4), concentrated, and purified by preparative HPLC (10 mM aqueous NH4CO3 / CH3CN) to give 53.29 mg (50%) of 5-cyclopropyl-1-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-N-(1-(pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 19-2) as a white solid. C 27 H 29 LCMS-ESI (m / z) calculated for N7O: 467.6, found 468.0 [M+H] + , t R = 0.778 min was found (Method 4). 1 H NMR (400 MHz, CDCl3) δ = 8.61 (d, J = 1.7 Hz, 1H), 8.47 (dd, J = 1.6, 4.9 Hz, 1H), 8.04 (s, 1H), 7.70 (td, J = 2.0, 8.0 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.47 - 7.41 (m, 2H), 7.30 - 7.25 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.31 (s, 6H), 1.98 (tt, J = 5.4, 8.6 Hz, 1H), 1.50 - 1.40 (m, 7H), 1.20 - 1.13 (m, 2H), 1.05 - 0.96 (m, 2H).

[0376] The compounds listed in Table 19 were prepared using the procedure of Scheme 19.

Table 19

[0377] Example 20 Synthesis of Compound 20-1 and Other Representative Compounds [Chemical formula]

[0378] Scheme 20 [Chemical formula] Reagents: (i) tert-Butyl nitrite, azido(trimethyl)silane, K2CO3, C3CN 25 - 40 °C, (ii) base (NaOH(aq) or LiOH(aq), MeOH, (iii) HATU, DIEA, DMF, (iv) Pd(dppf)Cl2, K2CO3, dioxane, H2O, 90 °C, (v) Cs2CO3, NMP, 60 °C.

[0379] Step 20-1. Synthesis of ethyl 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 20A). [Chemical formula]

[0380] To a solution of 4-bromoaniline (5 g, 29.07 mmol) in CH3CN (100 mL) was added tert-butyl nitrite (5.19 mL, 43.6 mmol) and azido(trimethyl)silane (4.59 mL, 34.9 mmol) at 0 °C. After stirring at 25 °C for 2 h, methyl 3-cyclopropyl-3-oxopropanoate (4.96 g, 34.89 mmol) and K2CO3 (12.05 g, 87.20 mmol) were added and the reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was poured into saturated aqueous NaHCO3 at 0 °C and extracted with EA (3X). The combined organic layers were washed with brine (2X), dried (Na2SO4), filtered, and concentrated under vacuum. The resulting residue was purified by SiO2 chromatography (EA / petroleum ether) to give 5.2 g (55.5%) of methyl 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 20A) as a yellow solid. C 13 H 12LCMS-ESI (m / z) calculated for BrN3O2: 322.2, 323.7 [M+H] + , t R = 0.244 min was found (Method 7). 1 1H NMR (400 MHz, DMSO-D6) δ = 7.85 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 2.09 (ddd, J = 3.1, 5.5, 8.6 Hz, 1H), 0.99 - 0.83 (m, 2H), 0.68 - 0.52 (m, 2H).

[0381] Step 20-2. Synthesis of 1-(4-bromophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 20B)

Chemical Structure

[0382] LiOH·H2O (390.8 mg, 9.3 mmol) was added to a solution of INT 20A (1.0 g, 3.1 mmol) in MeOH (6 mL) and H2O (2 mL). After stirring the reaction at 25 °C for 2 h, the reaction mixture was adjusted to pH 6 - 7 using 1 M HCl solution and concentrated in vacuo to give 950 mg (99.3%) of 1-(4-bromophenyl)-5-cyclopropyl-1H-1H-1,2,3-triazole-4-carboxylic acid (INT 20B) as a yellow solid, which was used without further purification in the next step. C 12 H 12 LCMS-ESI (m / z) calculated for BrN3O2: 308.1, 310.0 [M+H] + , t R = 0.437 min was found (Method 7).

[0383] Step 20-3. Synthesis of 1-(4-bromophenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 20C)

Chemical Structure

[0384] To a solution of INT 20B (1.13 g, 3.67 mmol) and 2-methylpyridin-4-amine (436.24 mg, 4.03 mmol) in DCE (10 mL) were added 2-chloro-1-methyl-pyridin-1-iodide (2.34 g, 9.17 mmol) and triethylamine (2.04 mL, 14.67 mmol). The reaction mixture was stirred at 80 °C for 1.5 h and then purified by SiO2 chromatography (EA / petroleum ether) to afford 585 mg (40%) of 1-(4-bromophenyl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 20C) as a yellow solid. C 18 H 16 Calculated LCMS-ESI (m / z) for BrN5O: 398.3, found 399.7 [M+H] + 、t R = 0.484 min was found (Method 7). 1 1H NMR (400 MHz, DMSO-D6) δ = 10.77 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.81 (s, 1H), 7.72 - 7.63 (m, 3H), 2.45 (s, 3H), 2.14 - 2.05 (m, 1H), 0.93 (br dd, J = 2.3, 8.5 Hz, 2H), 0.78 (br dd, J = 1.9, 5.4 Hz, 2H).

[0385] Step 20-4. Synthesis of 5-cyclopropyl-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 20D)

Chemical Structure

[0386] A solution of INT 20C (200 mg, 502.19 μmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (167.3 mg, 753.3 μmol) in dioxane (2 mL) and H2O (0.2 mL) was added with Na2CO3 (159.7 mg, 1.5 mmol) and Pd(dppf)Cl2 (36.8 mg, 50.2 μmol) under N2 atmosphere. The reaction mixture was stirred at 100 °C for 1.5 h. The reaction mixture was diluted with H2O and extracted with EA (2X). The combined organic layers were washed with brine, dried (Na2SO4), concentrated, and purified by SiO2 chromatography (MeOH / DCM) to give 120 mg (46%) of 5-cyclopropyl-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 20D) as a white solid. C 23 H 23 The LCMS-ESI (m / z) calculated for N7O: 413.5, 414.2 [M+H] + 、t R = 0.387 min was found (Method 7). 1 H NMR (400 MHz, DMSO-D6) δ = 10.76 - 10.72 (m, 1H), 8.32 (s, 1H), 7.79 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.67 - 7.62 (m, 1H), 7.56 (br d, J = 8.5 Hz, 3H), 2.52 (br s, 6H), 2.45 (s, 3H), 2.15 - 2.12 (m, 1H), 0.96 (td, J = 2.6, 8.5 Hz, 2H), 0.91 (td, J = 2.7, 5.4 Hz), 2H).

[0387] Step 20-5. Synthesis of 5-cyclopropyl-1-(4-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 20-1)

Chemical Structure

[0388] To a solution of INT 20D (30 mg, 72.6 μmol) in NMP (1 mL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (25.3 mg, 108.8 μmol, 1.5 eq), Cs2CO3 (70.9 mg, 217.7 μmol) was added. After stirring the reaction mixture at 60 °C for 2 h, the reaction mixture was purified by preparative-HPLC chromatography (H2O(FA) / CH3CN) to give 15.3 mg (43%) of 5-cyclopropyl-1-(4-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 20-1) as an off-white solid. C 25 H 24 The LCMS-ESI (m / z) calculated for F3N7O: 495.55, and 496.3 [M+H] + 、t R = 0.451 min was found (Method 7). 1 H NMR (400 MHz, DMSO-D6) δ = 11.72 (s, 1H), 8.63 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.18 (dd, J = 2.1, 6.8 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.63 - 7.55 (m, 2H), 5.09 (br d, J = 9.1 Hz, 2H), 2.67 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.20 - 2.12 (m, 1H), 1.03 - 0.96 (m, 2H), 0.95 - 0.88 (m, 2H).

[0389] The compounds listed in Table 20 were prepared using the procedure of Scheme 20.

Table 20

[0390] Example 21 Synthesis of Compound 21-1 and Other Representative Compounds

Chem.

[0391] Scheme 21

Chem.

[0392] Step 21-1. Synthesis of methyl 1-(4-bromo-2-fluorophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 21A).

Chem.

[0393] To a solution of 4-bromo-2-fluoroaniline (5 g, 26.3 mmol) in CH3CN (200 mL) was added tert-butyl nitrite (4.69 mL, 39.5 mmol) and azido(trimethyl)silane (4.15 mL, 31.6 mmol) at 0 °C. After stirring at 25 °C for 3 h, methyl 3-cyclopropyl-3-oxopropionate (4.49 g, 31.6 mmol) and K2CO3 (10.91 g, 78.9 mmol) were added and the reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was poured into saturated aqueous NaHCO3 at 0 °C and extracted with EA (3X). The combined organic layers were washed with brine (2X), dried (Na2SO4), filtered, and concentrated under vacuum. The resulting residue was purified by SiO2 chromatography (EA / petroleum ether) to give 997 mg (10.1%) of methyl 1-(4-bromo-2-fluorophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 21A) as a brown solid. C 13 H 11The LCMS-ESI (m / z) calculated for BrFN3O2 was 339.0, 339.9 [M+H] + , t R = 0.499 min was found (Method 7). 1 1H NMR (400 MHz, DMSO-D6) δ = 8.05 - 7.99 (m, 1H), 7.79 - 7.72 (m, 2H), 3.88 (s, 3H), 1.97 - 1.91 (m, 1H), 0.90 - 0.85 (m, 2H), 0.71 (br dd, J = 1.6, 5.3 Hz, 2H).

[0394] Step 21-2. Synthesis of 1-(4-bromo-2-fluorophenyl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 21B)

Chemical Structure

[0395] To a solution of INT 21A (100 mg, 0.29 mmol) in THF (1 mL) and H2O (1 mL) was added LiOH·H2O (24.7 mg, 0.59 mmol). After stirring the reaction mixture at 25 °C for 2 h, the reaction mixture was adjusted to pH 6 - 7 using 1 M HCl solution and concentrated in vacuo to afford 87 mg (90.7%) of 1-(4-bromo-2-fluorophenyl)-5-cyclopropyl-1H-1H-1,2,3-triazole-4-carboxylic acid (INT 21B) as a brown solid, which was used without further purification in the next step. C 12 The LCMS-ESI (m / z) calculated for H9BrFN3O2 was 325.0, 327.9 [M+H] + , t R = 0.442 min was found (Method 7).

[0396] Step 21-3. Synthesis of 1-(4-bromo-2-fluorophenyl)-5-cyclopropyl-N-((6-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (INT 21C)

Chemical Structure

[0397] To a solution of INT 21B (87 mg, 0.27 mmol) and 2-methylpyridin-4-amine (32.6 mg, 0.27 mmol) in DMF (1 mL), HATU (152.2 mg, 0.40 mmol) and DIEA (139.4 μL, 0.80 mmol) were added. After stirring the reaction mixture at 25 °C for 2 h, the mixture was diluted with H2O and extracted with EA (3X). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated, and purified by preparative TLC chromatography (EA, R f = 0.7 to collect the peak) to afford 68 mg (47%) of 1-(4-bromo-2-fluorophenyl)-5-cyclopropyl-N-((6-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (INT 21C) as a brown oil. C 19 H 17 Calculated LCMS-ESI (m / z) for C16H15BrFN5O: 429.1, found 430.0 [M+H] + 、t R = 0.401 min was found (Method 7).

[0398] Step 21-4. Synthesis of 5-cyclopropyl-1-(2-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-((6-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 21-1)

Chemical Structure

[0399] To a solution of dioxane (1 mL) and H2O (0.1 mL) containing INT 21C (68 mg, 0.16 mmol) and (1,3,5-trimethylpyrazol-4-yl)boronic acid (29.20 mg, 0.19 mmol), Na2CO3 (50.25 mg, 0.47 mmol) and Pd(dppf)Cl2 (11.6 mg, 0.016 mmol) were added under a N2 atmosphere. The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with 10 mL of MeOH, then 30 mg of thiourea resin was added and the mixture was stirred at 25 °C for 4 h. The residue was purified by preparative HPLC chromatography (H2O(FA)-CH3CN) to give 22.6 mg (31.1%) of 5-cyclopropyl-1-(2-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-((6-methylpyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 21-1) as a white solid. C 25 H 26 LCMS-ESI (m / z) calculated for FN7O: 459.2, 460.3 [M+H] + 、t R = 0.39 min (Method 7) was found. 1 1H NMR (400 MHz, DMSO-D6) δ = 9.19 (br t, J = 6.1 Hz, 1H), 8.42 (s, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.63 (dd, J = 1.8, 7.8 Hz, 1H), 7.47 (br d, J = 11.6 Hz, 1H), 7.35 (br d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.43 (br d, J = 6.0 Hz, 2H), 3.73 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.01 - 1.86 (m, 1H), 1.00 - 0.94 (m, 2H), 0.92 - 0.84 (m, 2H).

[0400] The compounds listed in Table 21 were prepared using the procedure of Scheme 21.

Table 21

[0401] Example 22 Synthesis of Compound 22-1 and Other Representative Compounds

Chem.

[0402] Scheme 22

Chem.

[0403] Step 22-1. Synthesis of Methyl 1-(4'-Cyano-3-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (INT 22A)

Chem.

[0404] To a solution of INT 21A (800 mg, 2.35 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (538.8 mg, 2.35 mmol) in dioxane (15 mL) and H2O (1.5 mL) were added Na2CO3 (747.8 mg, 7.06 mmol) and Pd(dppf)Cl2 (172.1 mg, 0.24 mmol). The reaction was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O and extracted with EA (3X). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to give a residue purified by SiO2 chromatography (EA / petroleum ether) to afford 450 mg (52.8%) of methyl 1-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 22A) as a yellow solid. C 20 H15 LCMS-ESI (m / z) calculated for FN4O2: 362.4, 363.0 [M+H] + , t R = 0.44 min was found (Method 7). 1 1H NMR (400 MHz, DMSO-D6) δ = 8.04 - 8.12 (m, 3H), 8.00 - 8.04 (m, 2H), 7.91 (d, J = 4.00 Hz, 2H), 3.89 (s, 3H), 1.95 - 2.05 (m, 1H), 0.88 - 0.96 (m, 2H), 0.73 - 0.80 (m, 2H).

[0405] Step 22-2. Synthesis of 1-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 22B)

Chemical Structure

[0406] To a solution of INT 22A (400 mg, 1.1 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH·H2O (139 mg, 3.31 mmol). After stirring the reaction mixture at 25 °C for 4 h, the reaction mixture was adjusted to pH 7 with 1 M HCl solution and concentrated in vacuo to give a residue which was purified by preparative HPLC chromatography (H2O(FA) / CH3CN) to afford 300 mg (78%) of 1-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (INT 22B) as a white solid. C 19 H 13 LCMS-ESI (m / z) calculated for FN4O2: 348.3, 349.2 [M+H] + , t R = 0.522 min was found (Method 7). 11H NMR (400 MHz, DMSO-D6) δ = 8.05 - 8.11 (m, 3H), 7.99 - 8.03 (m, 2H), 7.89 - 7.92 (m, 2H), 1.96 - 2.05 (m, 1H), 0.86 - 0.94 (m, 2H), 0.74 - 0.81 (m, 2H).

[0407] Step 22-3. Synthesis of 1-(4'-Cyano-3-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 22-1) [Chemical formula]

[0408] To a solution of INT 22B (50 mg, 0.14 mmol) and 2-methylpyridin-4-amine (18.6 mg, 0.17 mmol) in DCE (2 mL), 2-chloro-1-methyl-pyridin-1-iodide (110 mg, 0.43 mmol) and TEA (50 μL, 0.36 mmol) were added. After stirring the reaction mixture at 83 °C for 2 hours, the mixture was filtered, concentrated, and purified by preparative HPLC chromatography (H2O(FA) / CH3CN) to afford 24.6 mg (39%) of 1-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 22-1) as a yellow solid. C 25 H 19 Calculated LCMS-ESI (m / z) for C22H16FN6O: 438.5, found 439.2 [M+H] + , t R = 0.48 min was found (Method 7). 11H NMR (400 MHz, DMSO-D6) δ = 10.92 (s, 1H), 8.37 (d, J = 5.75 Hz, 1H), 8.05 - 8.12 (m, 3H), 8.00 - 8.04 (m, 2H), 7.89 - 7.98 (m, 2H), 7.85 (s, 1H), 7.71 (br d, J = 5.63 Hz, 1H), 2.47 (s, 3H), 2.02 (quin, J = 6.97 Hz, 1H), 0.92 - 1.00 (m, 4H).

[0409] The compounds listed in Table 22 were prepared using the procedure of Scheme 22. [Table 22]

[0410] Example 23 Synthesis of Compound 23-1 and Other Representative Compounds [Chemical Structure]

[0411] Scheme 23 [Chemical Structure] Reagents: (i) Pd(dppf)Cl2, K3PO4, dioxane, H2O, (ii) TFA, DCM, (iii) HATU, DIEA, DMF, (iv) AcOH, CHCl3, (v) DBU, 4-methylbenzenesulfonyl azide, CHCl3, reflux.

[0412] Step 23-1. Synthesis of tert-butyl (4'-cyano-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl) carbamate (INT 23A) [Chemical Structure]

[0413] To a solution of dioxane (2 mL) and H2O (2 mL) containing INT 21A tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohexas-3-en-1-yl) carbamate (200 mg, 0.62 mmol) and 4-iodobenzonitrile (170 mg, 0.74 mmol), K3PO4 (394 mg, 1.9 mmol) and Pd(dppf)Cl2 (45 mg, 0.06 mmol) were added. The reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled to retention time, diluted with EA, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, concentrated, and the residue was purified by SiO2 chromatography (MeOH / DCM) to give 165 mg (89.4%) of tert-butyl (4'-cyano-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl) carbamate (INT 23A). C 18 H 22 LCMS-ESI (m / z) calculated for N2O2: 298.4, 299.2 [M+H] + 、t R = 6.32 min (Method 3) was found.

[0414] Step 23-2. Synthesis of 4'-amino-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carbonitrile (INT 23B)

Chemical Structure

[0415] TFA (1 mL) was added to a solution of INT 23A (165 mg, 0.55 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 h, then concentrated in vacuo, dissolved in DCM, washed with 1M NaOH and brine, then dried (Na2SO4), filtered and concentrated to give 97 mg (89%) of 4'-amino-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carbonitrile (INT 23B), which was used without further purification. C 13 H 14LCMS-ESI (m / z) calculated for N2: 198.3, 199.1 [M+H] + , t R = 4.92 min (Method 3) was found.

[0416] Step 23-3. Synthesis of 3-cyclopropyl-N-(2-methylpyridin-4-yl)-3-oxopropanamide (INT 23C) [Chemical Structure]

[0417] To a solution of INT 2A (1.7 g, 13.8 mmol) and 2-methylpyridin-4-amine (1.43 g, 15.2 mmol) in DMF (10 mL) were added HATU (5.79 g, 15.2 mmol) and DIEA (5.35 g, 41.4 mmol). After stirring the reaction mixture at room temperature for 12 h, the mixture was diluted with EA and washed with H2O, saturated aqueous NaHCO3, H2O, and brine, then dried (Na2SO4), concentrated, and purified by SiO2 chromatography (EA / hexane) to afford 2.5 g (83%) of 3-cyclopropyl-N-(2-methylpyridin-4-yl)-3-oxopropanamide (INT 23C). C 12 H 14 LCMS-ESI (m / z) calculated for N2O2: 218.2, 219.0 [M+H] + (Method 3) was found. 1 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.35 (d, J = 4.0 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 4.0 Hz, 1H), 3.85 (s, 2H), 2.67 (s, 3H), 2.03 - 2.09 (m, 1H), 1.17 - 1.25 (m, 2H), 1.09 - 1.14 (m, 2H).

[0418] Step 23-4. Synthesis of 3-((4’-cyano-2,3,4,5-tetrahydro-[1,1’-biphenyl]-4-yl)imino)-3-cyclopropyl-N-(2-methylpyridin-4-yl)propanamide (INT 23D) [Chemistry]

[0419] AcOH (58 mg, 0.97 mmol) was added to a solution of INT 23C (71 mg, 0.33 mmol) and INT 23B (95 mg, 0.36 mmol) in CHCl3 (20 mL). After stirring at reflux for 36 h, the mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), filtered and concentrated to give 129 mg of crude 3-((4’-cyano-2,3,4,5-tetrahydro-[1,1’-biphenyl]-4-yl)imino)-3-cyclopropyl-N-(2-methylpyridin-4-yl)propanamide (INT 23D), which was used in the next step without further purification. C 25 H 26 LCMS-ESI (m / z) calculated for N4O: 398.5, 398.9 [M+H] + 、t R = 5.95 min (Method 3) was found.

[0420] Step 23-5. Synthesis of 1-(4’-cyano-2,3,4,5-tetrahydro-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 23-1) [Chemistry]

[0421] A solution of crude INT 23D (129 mg, 0.32 mmol) and 2-methylpyridin-4-amine (1.43 g, 15.2 mmol) in CH3CN (10 mL) was added with DBU (49 mg, 0.32 mmol) and tosyl azide (213 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux for 2.5 hours. Additional tosyl azide (213 mg, 0.32 mmol) was added and the mixture was stirred at reflux for an additional 19 hours. The mixture was cooled, diluted with EA, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), concentrated, purified by SiO2 chromatography (EA / hexane, then MeOH / DCM), and further purified by reverse-phase C-18 chromatography (MeOH / H2O) to afford 8 mg (5.8%) of 1-(4’-cyano-2,3,4,5-tetrahydro-[1,1’-biphenyl]-4-yl)-5-cyclopropyl-N-(2-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 23-1). C 25 H 24 The LCMS-ESI (m / z) calculated for N6O: 424.5, found 424.6 [M+H] + 、t R = 10 min (Method 2) was found. 1 H NMR (400 MHz, DMSO-D6) δ 10.59 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 4.0 Hz, 1H), 7.59 (d, J = 4.0 Hz, 1H), 6.45 (s, 1H), 4.97 (m, 1H), 2.86 (m, 2H), 2.68 (m, 2H), 2.49 (s, 3H), 2.43 (m, 2H), 2.07 (m, 1H), 1.12 (m, 2H), 1.02 (m, 2H).

[0422] The compounds listed in Table 23 were prepared using the procedure of Scheme 23.

Table 23

[0423] Example 24 Synthesis of Compound 24-1 and Other Representative Compounds

Chem.

[0424] Scheme 24

Chem.

[0425] Step 24-1. Synthesis of Methyl 5-Isopropyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylate (INT 24A)

Chem.

[0426] To a solution of 4-methylaniline (2.06 mL, 18.66 mmol) in CH3CN (40 mL) was added TMSN3 (2.95 mL, 22.40 mmol) and t BuONO (3.33 mL, 28.00 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 2 h, then K2CO3 (7.74 g, 55.99 mmol) and methyl 4-methyl-3-oxo-pentanoate (3.20 mL, 22.40 mmol) were added and the mixture was stirred at 40 °C for 12 h. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EA (2X). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated, and the residue was purified by SiO2 chromatography (EA / petroleum ether) to give 4.4 g (88.6%) of methyl 5-isopropyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 24A). C 14 H 17The LCMS-ESI (m / z) calculated for N3O2 was 259.3, 260.0 [M+H] + , t R = 0.55 min was found (Method 7). 1 1H NMR (400 MHz, DMSO-D6) δ = 7.47 - 7.41 (m, 4H), 3.89 (s, 3H), 3.19 (spt, J = 7.1 Hz, 1H), 2.43 (s, 3H), 1.24 (d, J = 7.1 Hz, 6H).

[0427] Step 24-2. Synthesis of 5-isopropyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 24B)

Chemical Structure

[0428] To a solution of INT 24A (200 mg, 0.75 mmol) in H2O (1 mL) and MeOH (1 mL) was added LiOH (126 mg, 3.01 mmol). After the reaction mixture was stirred at 25 °C for 12 h, 1 M HCl was added to adjust the reaction mixture to pH = 7. The resulting mixture was concentrated to afford 184 mg (99%) of crude 5-isopropyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (INT 24B) as a yellow solid, which was used without further purification. C 13 H 15 The LCMS-ESI (m / z) calculated for N3O2 was 245.3, 246.3 [M+H] + , t R = 4.74 min was found (Method 7).

[0429] Step 24-3. Synthesis of 5-isopropyl-1-(p-tolyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 24-1)

Chemical Structure

[0430] To a solution of INT 24B (184 mg, 0.75 mmol) and 2-(trifluoromethyl)pyridin-4-amine (121.6 mg, 0.75 mmol) in DCE (5 mL) was added 2-chloro-1-methyl-pyridin-1-iodide (479.14 mg, 1.88 mmol) and TEA (261.04 uL, 1.88 mmol). After stirring the reaction at 80 °C for 2 h, the mixture was concentrated, dissolved in DMF, and filtered through a filter membrane. The filtrate was purified by preparative HPLC (H2O(FA) / CH3CN) and lyophilized to give 100.6 mg (34.4%) of 5-isopropyl-1-(p-tolyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 24-1) as a yellow solid. C 19 H 18 LCMS-ESI (m / z) calculated for F3N5O2: 389.4, found 390.1 [M+H] + 、t R = 0.61 min was found (Method 7). 1 1H NMR (400 MHz, DMSO-D6) δ = 11.34 (s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.19 (dd, J = 1.8, 5.4 Hz, 1H), 7.48 (s, 4H), 3.23 (td, J = 6.9, 14.0 Hz, 1H), 2.45 (s, 3H), 1.31 (d, J = 7.0 Hz, 6H).

[0431] The compounds listed in Table 24 were prepared using the procedure of Scheme 24.

Table 24

[0432] Example 25 Synthesis of Compound 25-1 and Other Representative Compounds

Chem.

[0433] Scheme 25 [Chemical formula] Reagents: (i) a. Thionyl - Cl, 90 °C, b. DIEA, DCM, (ii) Pd(dppf)Cl2·CH2Cl2, K3PO4, dioxane, H2O, (iii) Pd(dppf)Cl2·CH2Cl2, K3PO4, dioxane, H2O.

[0434] Step 25 - 1. Synthesis of 1-(3 - bromo - 4 - iodophenyl)-5 - cyclopropyl - N-(pyridin - 4 - yl)-1H - 1,2,3 - triazole - 4 - carboxamide (INT 25A) [Chemical formula]

[0435] A solution of 1-(3 - bromo - 4 - iodophenyl)-5 - cyclopropyl - 1H - 1,2,3 - triazole - 4 - carboxylic acid (1.0 g, 2.3 mmol) in thionyl chloride (335 μL, 4.6 mmol) was heated at 90 °C for 30 minutes. The mixture was cooled, concentrated, and dissolved in DCM (10 mL). DIEA (891.6 mg, 6.9 mmol) and pyridin - 4 - amine (238.5 mg, 2.53 mmol) were added. After stirring the reaction mixture for 2 hours, it was diluted with H2O. The organic layer was isolated, concentrated, and purified by SiO2 chromatography (MeOH / DCM) to prepare 880 mg (75%) of 1-(3 - bromo - 4 - iodophenyl)-5 - cyclopropyl - N-(pyridin - 4 - yl)-1H - 1,2,3 - triazole - 4 - carboxamide (INT 25A). C 17 H 13 The LCMS - ESI (m / z) calculated for BrIN5O was 508.9, and 510.0 [M + H] + , t R = 10.88 minutes (Method 3) was found. 11H NMR (400 MHz, DMSO-D6) δ = (s, 1H), 8.47 (d, J = 8 Hz, 2H), 8.22 (d, J = 8 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J = 8 Hz, 2H), 7.51 (d, J = 8 Hz, 1H), 2.12 (m, 1H), 0.93 (m, 2H), 0.78 (m, 2H).

[0436] Step 25-2. Synthesis of 1-(3-bromo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-5-cyclopropyl-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 25B) [Chemical formula]

[0437] INT 25A (250 mg, 0.49 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (104.5 mg, 0.49 mmol), Pd(dppf)Cl2·CH2Cl2 (40 mg, 0.05 mmol) and K3PO4 (312.2 mg, 1.47 mmol) were added to a vial, followed by addition of dioxane (4.0 mL) and H2O (1.5 mL). The mixture was degassed by N2 bubbling and then heated at 110 °C for 12 h. The organic layer was separated from the aqueous layer and purified by SiO2 chromatography (MeOH / EA / hexane) to afford 87 mg (36%) of 1-(3-bromo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-5-cyclopropyl-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (INT 25B) as a yellowish brown solid. C 23 H 22 Calculated LCMS-ESI (m / z) for C19H20BrN7O: 491.1, found 492.5 [M+H] + , t R = 5.62 min (Method 3) was found.

[0438] Step 25-3. Synthesis of 1-(3’-acetyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-[1,1’-biphenyl]-3-yl)-5-cyclopropyl-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 25-1)

Chemical formula

[0439] INT 25B (41 mg, 0.08 mmol), (3-acetylphenyl)boronic acid (20.5 mg, 0.13 mmol), Pd(dppf)Cl2·CH2Cl2 (6.8 mg, 0.008 mmol) and K3PO4 (53.07 mg, 0.25 mmol) were added to a vial, followed by addition of dioxane (1.0 mL) and H2O (0.5 mL). The organic layer was separated from the aqueous phase and purified by SiO2 chromatography (MeOH / EA / hexane) to obtain 1-(3’-acetyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-[1,1’-biphenyl]-3-yl)-5-cyclopropyl-N-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 25-1) as a yellowish brown solid (24.6 mg, 55%). C 31 H 29 The LCMS-ESI (m / z) calculated for C + H R N7O2 was 531.2, and 532 [M+H]

[0440] The compounds listed in Table 25 were prepared using the procedure of Scheme 25.

Table 25

[0441] Example 26 MRGPRD activity Chinese Hamster Ovary (CHO) cells (Eurofins, San Diego, CA) that stably express human MRGPRD were seeded at 20,000 cells per well in a 384-well plate in 12 μL of Optimem (Fisher Scientific 11-058-021). The plates were stored overnight at 37°C in an incubator. Antagonists were solubilized in DMSO at a concentration of 10 mM, and agonists were solubilized to a stock concentration of 50 mM H2O (β-alanine) or 10 mM DMSO (for all others), and then diluted with assay buffer (final concentration 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH = 8). The concentration of DMSO was normalized across the plate. Antagonists were added to the plate in nanoliter / picoliter volumes using a Tecan D300 digital dispenser, and 2 μL of agonist in assay buffer was added to each well to bring the final assay volume to 14 μL. The plates were covered and incubated at 37°C for 1 hour and then at room temperature for 1 hour. IP-1 standard and HTRF detection reagent were added according to the IP-One-Gq kit (part number 62IPAPEJ) purchased from Cisbio and incubated in the dark at room temperature for 1 hour. The assay plates were read on either a Molecular Devices SpectraMax iD5 plate reader or a BMG ClarioStar plate reader. The HTRF ratio was calculated from the raw data, graphed using GraphPad Prism, and the IC 50 value was calculated. The data were presented as mean IC 50 values, and mean antagonism was calculated as a percentage of the maximal efficacy response. In these studies, the variability of the data was evaluated by determining the standard error of the mean (SEM).

[0442] The activity data of the selected MRGPRD antagonists (versus 100 μM β-alanine agonist) are shown in Table 26. The activity ranges are shown as follows. "+++++" indicates antagonist activity of less than 100 nM, "++++" indicates antagonist activity of 100 - 500 nM, "+++" indicates activity of 500 - 1000 nM, "++" indicates activity of 1000 - 3000 nM, and "+" indicates activity greater than 3000 nM.

[0443] Table 26: Activity data of the selected MRGPRD antagonists [Table 26-1] [Table 26-2] [Table 26-3] [Table 26-4] [Table 26-5] [Table 26-6] [Table 26-7] [Table 26-8]

[0444] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and / or non-patent publications mentioned in this application and / or described in the datasheet of this application are hereby incorporated by reference in their entirety into this specification. Further, the terms used in the following claims should not be construed as limited to the specific embodiments disclosed in the specification, but should be interpreted to include all possible embodiments and the full scope of equivalents to which such claims are entitled.

[0445] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 367,012, filed on Jun. 24, 2022, which is hereby incorporated by reference in its entirety into this application.

Claims

1. A compound having the following structure (I), 【Chemical 1】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein when A is a monocyclic carbocyclic or monocyclic heterocyclic ring, y is 1 to 4; when A is a bicyclic carbocyclic or bicyclic heterocyclic ring, y is 0 to 5, B is a carbocyclic or heterocyclic ring, R １ is isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and R ２ is H or alkyl, or R ２ is bonded to B to form a ring, R ３ and R ４ are each independently H or alkyl, or R ３ and R ４ are joined to form a carbocyclic ring, R ５ is halo, OH, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkenyl, cyanoalkyl, alkylcarbonyl, aminylcarbonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and R ６ is a carbocyclic or heterocyclic group, optionally substituted with one or more R ８ groups, R ７ is aminyl, halo, OH, CN, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, cycloalkyl, heterocyclyl, heteroaryl, alkylsulfonyl or alkylsulfonylaminyl, R ８ is aminyl, halo, OH, CN, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxyalkyl, aminylalkyl, cyanoalkyl, carboxyl, alkylcarbonyl, aminylcarbonyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylsulfonyl, aminylsulfonyl, cycloalkylalkyl, and two Rs ８ can combine to form a carbocyclic or heterocyclic ring, n is 0 to 4, m is 0 to 4, and p is 0 to 5, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

2. The compound according to Claim 1, having the following structure (I'), [Chemical Formula 2] or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein when A is a monocyclic carbocyclic or monocyclic heterocyclic ring, y is 1 to 4, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

3. The compound according to Claim 1 or 2, wherein A is a monocyclic carbocyclic ring.

4. The compound according to Claim 3, wherein A is a saturated or partially saturated monocyclic carbocyclic ring.

5. The compound according to Claim 3, wherein A is aryl.

6. The compound according to Claim 5, wherein A is phenyl.

7. The compound according to Claim 1 or 2, wherein A is a monocyclic heterocyclic ring.

8. The compound according to Claim 7, wherein A is a heteroaryl ring.

9. The compound according to Claim 1, having the following structure (I''), 【Chemical 3】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein when A is a bicyclic carbocyclic or bicyclic heterocyclic ring, y is 0 to 5, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

10. The compound according to Claim 1 or 9, wherein A is a bicyclic carbocyclic ring.

11. The compound according to Claim 1 or 3, wherein A is a bicyclic heterocyclic ring.

12. The compound according to Claim 1 or 3, wherein A is a bicyclic heteroaryl ring.

13. The compound according to Claim 1, wherein A has any of the following structures 【Chemical 4】

14. The compound according to Claim 1, having the following structure (II), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, 【Chemical Formula 5】 the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. X １ and X ２ are both C, or X １ is N and X ２ is C, or X １ is C and X ２ is N, and y is from 1 to 4

15. ​ The compound according to claim 14, having the following structure (II’), 【Chemical Formula 6】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, where y is from 1 to 4, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

16. The compound according to claim 1, having the following structure (III), 【Chemical Formula 7】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, where q is from 0 to 5, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

17. The compound according to claim 1, having the following structure (IV), 【Chemical 8】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R ９ is H, alkyl, haloalkyl, alkoxyalkyl, aminylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where q is from 0 to 2, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

18. The compound according to claim 1, having the following structure (V), 【Chemical Formula 9】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, X １ and X ２ one of which is N and the other is R ７ which is optionally replaced by CH where n is from 0 to 4, and where y is from 1 to 4, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

19. X １ is N, and X ２ is R ７ is CH optionally replaced by R, p is 0, and R ６ is a heterocyclic ring, the compound according to claim 18

20. X １ is N, and X ２ is R ７ is CH optionally replaced by R, p is 1, and R ６ is a heterocyclic ring, the compound according to claim 18.

21. R ６ The compound according to claim 19 or 20, wherein R is a 5-membered heterocyclic ring.

22. R ６ The compound according to claim 19 or 20, wherein R is a 6-membered heterocyclic ring.

23. R ６ The compound according to claim 19 or 20, wherein R is a 5-membered heteroaryl ring.

24. R ６ The compound according to claim 19 or 20, wherein R is a 6-membered heteroaryl ring.

25. The compound according to claim 18, having the following structure (VA), 【Chemical 10】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, where n is from 0 to 4, and where q is from 0 to 5, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

26. The compound according to claim 18, having the following structure (VB), 【Chemical Formula 11】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R ９ is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 4, and where q is from 0 to 2, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

27. The compound according to claim 18, having the following structure (VC), 【Chemical Formula 12】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, where n is from 0 to 4, and where q is from 0 to 5, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

28. The compound according to claim 18 having the following structure (VD), 【Chemical Formula 13】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R ９ is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 4, and q is from 0 to 2, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 29** The compound according to claim 1 having the following structure (VI), 【Chemical 14】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R ９ is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 2, and y is from 1 to 4, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 30** The compound according to claim 29 having the following structure (VIA), 【Chemical Formula 15】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R ９ is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 4, and q is from 0 to 5, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 31** The compound according to claim 29 having the following structure (VIB), 【Chemical 16】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, Each R ９ is independently H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 2, and q is from 0 to 2, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 32** The compound according to claim 29 having the following structure (VIC), 【Chemical 17】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R ９ is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 2, and q is from 0 to 5, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 33** The compound according to claim 29 having the following structure (VID), 【Chemical 18】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, Each R ９ is independently H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and where n is from 0 to 2, and q is from 0 to 2, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 34** The compound according to claim 1 having the following structure (VII), 【Chemical Formula 19】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, where y is from 1 to 4, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 35** The compound according to claim 1 having the following structure (VIII), 【Chemical 20】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, provided that y is from 1 to 4, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. **Claim 36** The compound according to any one of claims 1 to 17 or 35, wherein B is a carbocyclic ring. **Claim 37** The compound according to claim 36, wherein B is a saturated carbocyclic ring. **Claim 38** The compound according to claim 36, wherein B is an aryl ring. **Claim 39** The compound according to any one of claims 1 to 17 or 35, wherein B is a heterocyclic ring. **Claim 40** The compound according to claim 39, wherein B is a saturated heterocyclic ring. **Claim 41** The compound according to claim 39, wherein B is a heteroaryl ring. **Claim 42** B has any one of the following structures, 【Chemical 21】 B is 0 to 4R ７ is arbitrarily replaceable, and R ９ is H, alkyl, haloalkyl, alkoxyalkyl, aminylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, The compound according to any one of claims 1 to 17 or 35. **Claim 43** R １ The compound according to any one of claims 1 to 42, wherein R is isopropyl. **Claim 44** R １ The compound according to any one of claims 1 to 42, wherein R is tert-butyl. **Claim 45** R １ The compound according to any one of claims 1 to 42, wherein R is cyclopropyl. **Claim 46** R １ The compound according to any one of claims 1 to 42, wherein R is cyclobutyl. **Claim 47** R １ The compound according to any one of claims 1 to 42, wherein R is cyclopentyl. **Claim 48** R ２ The compound according to any one of claims 1 to 47, wherein R is H. **Claim 49** R ２ The compound according to any one of claims 1 to 47, wherein R is alkyl. **Claim 50** R ２ The compound according to claim 49, wherein R is methyl. **Claim 51** R ２ The compound according to any one of claims 1 to 47, wherein R is bonded to B to form a ring. **Claim 52** R ２ is bonded to B to form a ring having the following structure, 【Chemical 22】 The above structure is arbitrarily replaced with 0 to 4R ７ and R ９ is H, alkyl, haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, The compound according to claim 51. **Claim 53** R ３ and R ４ are both H, the compound according to any one of claims 1 to 24, 27 to 29, or 32 to 52. **Claim 54** R ３ and R ４ wherein both are alkyl, the compound according to any one of claims 1 to 24, 27 to 29, or 32 to 52. **Claim 55** R ３ and R ４ wherein one of R and R is H and the other is alkyl, the compound according to any one of claims 1 to 24, 27 to 29, or 32 to 52. **Claim 56** The compound according to claim 54 or 55, wherein the alkyl is methyl. **Claim 57** The compound according to claim 54 or 55, wherein the alkyl is ethyl. **Claim 58** The compound according to claim 54 or 55, wherein the alkyl is isopropyl. **Claim 59** R ３ and R ４ are joined to each other to form a carbocyclic ring, the compound according to any one of claims 1 to 24, 27 to 29, or 32 to 52. **Claim 60** R ３ and R ４ are combined with each other to form a 3- to 5-membered carbocyclic ring, the compound according to claim 59. **Claim 61** R ３ and R ４ which are joined to each other to form a cyclopropyl, the compound according to claim 60. **Claim 62** R ３ and R ４ which are joined to each other to form cyclobutyl, the compound according to claim 60. **Claim 63** R ３ and R ４ are joined to each other to form cyclopentyl, the compound according to claim 60. **Claim 64** R ５ The compound according to any one of claims 1 to 63, wherein R is halo. **Claim 65** R ５ The compound according to claim 64, wherein R is F. **Claim 66** R ５ The compound according to claim 64, wherein R is Cl. **Claim 67** R ５ The compound according to any one of claims 1 to 63, wherein R is OH. **Claim 68** R ５ The compound according to any one of claims 1 to 63, wherein R is CN. **Claim 69** R ５ The compound according to any one of claims 1 to 63, wherein R is alkyl. **Claim 70** R ５ The compound according to claim 69, wherein R is methyl. **Claim 71** R ５ The compound according to claim 69, wherein R is ethyl. **Claim 72** R ５ The compound according to any one of claims 1 to 63, wherein R is haloalkyl. **Claim 73** R ５ is CF ３ The compound according to claim 72, wherein **Claim 74** R ５ The compound according to any one of claims 1 to 63, wherein R is alkoxy. **Claim 75** R ５ The compound according to claim 74, wherein R is methoxy. **Claim 76** R ５ The compound according to any one of claims 1 to 63, wherein R is haloalkoxy. **Claim 77** R ５ is OCF ３ The compound according to claim 76, wherein **Claim 78** R ５ The compound according to any one of claims 1 to 63, wherein R is an alkoxyalkyl. **Claim 79** R ５ is CH ２ OCH ３ The compound according to claim 78, wherein **Claim 80** R ５ The compound according to any one of claims 1 to 63, wherein R is alkoxyalkenyl. **Claim 81** R ５ is 【Chemical 23】 The compound according to claim 80, provided that it is as follows. **Claim 82** R ５ The compound according to any one of claims 1 to 63, wherein R is cyanoalkyl. **Claim 83** R ５ is CH ２ The compound according to claim 82, wherein R is CN. **Claim 84** R ５ The compound according to any one of claims 1 to 63, wherein R is alkylcarbonyl. **Claim 85** R ５ is C(O)CH ３ The compound according to claim 84, wherein **Claim 86** R ５ The compound according to any one of claims 1 to 63, wherein R is aminocarbonyl. **Claim 87** R ５ is C(O)NH ２ The compound according to claim 86, wherein **Claim 88** R ５ The compound according to any one of claims 1 to 63, wherein R is cycloalkyl. **Claim 89** R ５ is C ３ -C ５ The compound according to claim 88, wherein the cycloalkyl is cycloalkyl. **Claim 90** R ５ The compound according to claim 89, wherein R is cyclopropyl. **Claim 91** R ５ The compound according to any one of claims 1 to 63, wherein R is heterocyclyl. **Claim 92** R ５ The compound according to any one of claims 1 to 63, wherein R is aryl. **Claim 93** R ５ The compound according to any one of claims 1 to 63, wherein R is heteroaryl. **Claim 94** R ５ The compound according to any one of claims 1 to 63, wherein R has any one of the following structures. 【Chemical 24】 **Claim 95** R ６ is a carbocyclic ring optionally substituted with one or more R ８ The compound according to any one of claims 1 to 17, 18, 25, 27, 29 to 30, 32, or 34 to 94, which is a carbocyclic ring optionally substituted with one or more R **Claim 96** R ６ where one or more R ８ is optionally replaced by a heterocyclyl, a compound according to any one of claims 1 to 15, 17 to 24, 26, 28 to 29, 31, or 33 to 94. **Claim 97** R ６ has one of the following structures, 【Chemical 25】 R ６ where one or more R ８ are optionally replaced by and R ９ is H, alkyl, or haloalkyl, aminylsulfonyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, The compound according to any one of claims 1 to 94. **Claim 98** R ７ The compound according to any one of claims 1 to 97, wherein R is aminyl. **Claim 99** R ７ The compound according to any one of claims 1 to 97, wherein R is halo. **Claim 100** R ７ The compound according to claim 99, wherein R is F. **Claim 101** R ７ The compound according to claim 99, wherein R is Cl. **Claim 102** R ７ The compound according to any one of claims 1 to 97, wherein R is OH. **Claim 103** R ７ The compound according to any one of claims 1 to 97, wherein R is CN. **Claim 104** R ７ The compound according to any one of claims 1 to 97, wherein R is alkyl. **Claim 105** R ７ The compound according to claim 104, wherein R is methyl. **Claim 106** R ７ The compound according to claim 104, wherein R is ethyl. **Claim 107** R ７ The compound according to claim 104, wherein R is n-propyl. **Claim 108** R ７ The compound according to claim 104, wherein R is isopropyl. **Claim 109** R ７ The compound according to claim 104, wherein R is tert-butyl. **Claim 110** R ７ The compound according to any one of claims 1 to 97, wherein R is alkenyl.

111. R ７ The compound according to any one of claims 1 to 97, wherein R is alkynyl.

112. R ７ The compound according to claim 111, wherein R is ethynyl.

113. R ７ The compound according to any one of claims 1 to 97, wherein R is haloalkyl.

114. R ７ is CF ３ and is the compound according to claim 113.

115. R ７ is CHF ２ The compound according to claim 113, wherein

116. R ７ The compound according to any one of claims 1 to 97, wherein R is alkoxy.

117. R ７ The compound according to claim 116, wherein R is methoxy.

118. R ７ The compound according to any one of claims 1 to 97, wherein R is alkoxyalkyl.

119. R ７ is 【Chemical 26】 The compound according to claim 118, which is

120. R ７ The compound according to any one of claims 1 to 97, wherein R is alkylcarbonyl.

121. R ７ is C(O)CH ３ The compound according to claim 120, wherein

122. R ７ The compound according to any one of claims 1 to 97, wherein R is cycloalkyl.

123. R ７ The compound according to claim 122, wherein R is cyclopropyl.

124. R ７ The compound according to claim 122, wherein R is cyclobutyl.

125. R ７ The compound according to claim 122, wherein R is cyclopentyl.

126. R ７ The compound according to any one of claims 1 to 97, wherein R is heterocyclyl.

127. R ７ The compound according to claim 126, wherein R is morpholino.

128. R ７ The compound according to any one of claims 1 to 97, wherein R is heteroaryl.

129. R ７ The compound according to claim 128, wherein R is triazolyl.

130. R ７ The compound according to any one of claims 1 to 97, wherein R is alkylsulfonyl.

131. R ７ is 【Chemical 27】 The compound according to claim 130, which is

132. R ７ The compound according to any one of claims 1 to 97, wherein R is alkylsulfonylaminyl.

133. R ７ is 【Chemical 28】 The compound according to claim 132, which is

134. R ７ The compound according to any one of claims 1 to 97, wherein R has any one of the following structures. 【Chemical 29】

135. R ８ The compound according to any one of claims 1 to 134, wherein R is aminyl.

136. R ８ is 【Chemical 30】 The compound according to claim 135, which is

137. R ８ The compound according to any one of claims 1 to 134, wherein R is halo.

138. R ８ The compound according to claim 134, wherein R is F.

139. R ８ The compound according to claim 134, wherein R is Cl.

140. R ８ The compound according to any one of claims 1 to 134, wherein R is OH.

141. R ８ The compound according to any one of claims 1 to 134, wherein R is CN.

142. R ８ The compound according to any one of claims 1 to 134, wherein R is alkyl.

143. R ８ The compound according to claim 142, wherein R is methyl.

144. R ８ The compound according to claim 142, wherein R is ethyl.

145. R ８ The compound according to claim 142, wherein R is n-propyl.

146. R ８ The compound according to claim 142, wherein R is isopropyl.

147. R ８ The compound according to claim 142, wherein R is tert-butyl.

148. R ８ is 【Chemical 31】 The compound according to claim 142, which is

149. R ８ The compound according to any one of claims 1 to 134, wherein R is alkenyl.

150. R ８ The compound according to any one of claims 1 to 134, wherein R is alkynyl.

151. R ８ The compound according to claim 150, wherein R is ethynyl.

152. R ８ The compound according to any one of claims 1 to 134, wherein R is haloalkyl.

153. R ８ is CF ３ The compound according to claim 152, wherein

154. R ８ is CHF ２ The compound according to claim 152, wherein

155. R ８ is CH ２ CF ３ and the compound according to claim 152, wherein

156. R ８ The compound according to any one of claims 1 to 134, wherein R is haloalkoxy.

157. R ８ is OCF ３ The compound according to claim 156, wherein

158. R ８ The compound according to any one of claims 1 to 134, wherein R is alkoxy.

159. R ８ is OCH ３ and is the compound according to claim 158.

160. R ８ is 【Chemical Formula 32】 The compound according to claim 158, which is

161. R ８ The compound according to any one of claims 1 to 134, wherein R is an alkoxyalkyl.

162. R ８ is 【Chemical Formula 33】 The compound according to claim 161, which is

163. R ８ The compound according to any one of claims 1 to 134, wherein R is a hydroxylalkyl.

164. R ８ is 【Chemical 34】 The compound according to claim 163, which is

165. R ８ is 【Chemical 35】 The compound according to claim 163, which is

166. R ８ The compound according to any one of claims 1 to 134, wherein R is aminylalkyl.

167. R ８ is 【Chemical 36】 The compound according to claim 166, which is

168. R ８ The compound according to any one of claims 1 to 134, wherein R is cyanoalkyl.

169. R ８ is 【Chemical 37】 The compound according to claim 168, which is

170. R ８ The compound according to any one of claims 1 to 134, wherein R is carboxyl.

171. R ８ The compound according to any one of claims 1 to 134, wherein R is alkylcarbonyl.

172. R ８ is 【Chemical 38】 The compound according to claim 171, which is

173. R ８ is 【Chemical 39】 The compound according to claim 171, which is

174. R ８ The compound according to any one of claims 1 to 134, wherein R is aminocarbonyl.

175. R ８ is 【Chemical 40】 The compound according to claim 174, which is

176. R ８ is 【Chemical Formula 41】 The compound according to claim 174, which is

177. R ８ The compound according to any one of claims 1 to 134, wherein R is cycloalkyl.

178. R ８ The compound according to claim 177, wherein R is cyclopropyl.

179. R ８ The compound according to claim 177, wherein R is cyclobutyl.

180. R ８ The compound according to claim 177, wherein R is cyclopentyl.

181. R ８ The compound according to any one of claims 1 to 134, wherein R is heterocyclyl.

182. R ８ The compound according to claim 181, wherein R is tetrahydropyranyl.

183. R ８ The compound according to any one of claims 1 to 134, wherein R is aryl.

184. R ８ The compound according to claim 183, wherein R is phenyl.

185. R ８ The compound according to any one of claims 1 to 134, wherein R is arylalkyl.

186. R ８ is 【Chemical Formula 42】 The compound according to claim 185, which is

187. R ８ The compound according to any one of claims 1 to 134, wherein R is heteroaryl.

188. R ８ The compound according to any one of claims 1 to 134, wherein R is heteroarylalkyl.

189. R ８ is 【Chemical 43】 The compound according to claim 188, which is

190. R ８ The compound according to any one of claims 1 to 134, wherein R is alkylsulfonyl.

191. R ８ is 【Chemical 44】 The compound according to claim 190, which is

192. R ８ The compound according to any one of claims 1 to 134, wherein R is aminylsulfonyl.

193. R ８ is 【Chemical 45】 The compound according to claim 192.

194. R ８ is 【Chemical Formula 46】 The compound according to claim 192.

195. R ８ The compound according to any one of claims 1 to 134, wherein R is cycloalkylalkyl.

196. R ８ is 【Chemical 47】 The compound according to claim 195.

197. Two Rs ８ The compound according to any one of claims 1 to 134, wherein two Rs are bonded to each other to form a carbocyclic ring.

198. Two Rs ８ The compound according to any one of claims 1 to 134, wherein two Rs are bonded to each other to form a heterocyclic ring.

199. R ８ The compound according to any one of claims 1 to 134, wherein R has any one of the following structures. 【Chemical 48】

200. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is H.

201. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is alkyl.

202. R ９ The compound according to claim 201, wherein R is methyl.

203. R ９ The compound according to claim 201, wherein R is ethyl.

204. R ９ The compound according to claim 201, wherein R is n-propyl.

205. R ９ The compound according to claim 201, wherein R is isopropyl.

206. R ９ The compound according to claim 201, wherein R is tert-butyl.

207. R ９ is 【Chemical 49】 The compound according to claim 201.

208. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is haloalkyl.

209. R ９ is CF ３ The compound according to claim 208, wherein

210. R ９ is CHF ２ The compound according to claim 208, wherein

211. R ９ is 【Chemical Formula 50】 The compound according to claim 208.

212. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is an alkoxyalkyl.

213. R ９ is 【Chemical Formula 51】 The compound according to claim 212.

214. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is aminylsulfonyl.

215. R ９ is 【Chemical 52】 The compound according to claim 214.

216. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is cycloalkyl.

217. R ９ The compound according to claim 216, wherein R is cyclopropyl.

218. R ９ The compound according to claim 216, wherein R is cyclobutyl.

219. R ９ The compound according to claim 216, wherein R is cyclopentyl.

220. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is cycloalkylalkyl.

221. R ９ is 【Chemical 53】 The compound according to claim 220.

222. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is heterocyclyl.

223. R ９ The compound according to claim 222, wherein R is tetrahydropyranyl.

224. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is heterocyclylalkyl.

225. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is aryl.

226. R ９ The compound according to claim 225, wherein R is phenyl.

227. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is arylalkyl.

228. R ９ is 【Chemical 54】 The compound according to claim 227.

229. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is heteroaryl.

230. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R is heteroarylalkyl.

231. R ９ is 【Chemical Formula 55】 The compound according to claim 230.

232. R ９ The compound according to any one of claims 17, 26, 28 to 33, 36 to 199, wherein R has any one of the following structures. 【Chemical Formula 56】

233. The compound according to any one of claims 1 to 232, wherein n is 0.

234. The compound according to any one of claims 1 to 232, wherein n is 1.

235. The compound according to any one of claims 1 to 232, wherein n is 2.

236. The compound according to any one of claims 1 to 232, wherein n is 3.

237. The compound according to any one of claims 1 to 232, wherein n is 4.

238. The compound according to any one of claims 1 to 237, wherein m is 0.

239. The compound according to any one of claims 1 to 237, wherein m is 1.

240. The compound according to any one of claims 1 to 237, wherein m is 2.

241. The compound according to any one of claims 1 to 237, wherein m is 3.

242. The compound according to any one of claims 1 to 237, wherein m is 4.

243. The compound according to any one of claims 1 to 242, wherein p is 0.

244. The compound according to any one of claims 1 to 242, wherein p is 1.

245. The compound according to any one of claims 1 to 242, wherein p is 2.

246. The compound according to any one of claims 1 to 242, wherein p is 3.

247. The compound according to any one of claims 1 to 242, wherein p is 4.

248. The compound according to any one of claims 1 to 242, wherein p is 5.

249. The compound according to any one of claims 1 to 248, wherein q is 0.

250. The compound according to any one of claims 1 to 248, wherein q is 1.

251. The compound according to any one of claims 1 to 248, wherein q is 2.

252. A compound having the following structure (IX), 【Chemical 57】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R １０ is isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and R １２ is H or alkyl, R １５ is halo, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, and R １６ is H, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, and R １７ is halo, alkyl or haloalkyl, and where m is 0 to 4, n is 0 to 4, R １６ is methyl and R １ is cyclopropyl, m or n is not 0, and R １６ is H, R １ is cyclopropyl, when m is 1, R １５ is not F the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

253. A compound having the following structure (IX), 【Chemical Formula 58】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, (A) R １６ is H, R １０ is isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and R １２ is H or alkyl, R １５ is Cl, Br, I, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, and R １７ is halo, alkyl or haloalkyl, and where m is 0 to 4, and n is 0 to 4, (B) R １６ is methyl and R １０ is cyclopropyl, R １２ is H or alkyl, R １５ is halo, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, and R １７ is halo, alkyl or haloalkyl, and m is 1 to 4 and n is 0 to 4, or m is 0 to 4 and n is 1 to 4, (C) R １６ is methyl, and R １０ is tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, R １２ is H or alkyl, R １５ is halo, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, R １７ is halo, alkyl or haloalkyl, and m is 0 to 4, and n is 0 to 4, or (D) R １６ is C ２ to C ６ alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, R １０ is isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and R １２ is H or alkyl, R １５ is halo, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, R １７ is halo, alkyl or haloalkyl, and m is 0 to 4, and n is 0 to 4, the compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

254. R １０ The compound according to claim 252 or 253, wherein R is isopropyl.

255. R １０ The compound according to claim 252 or 253, wherein R is tert-butyl.

256. R １０ The compound according to claim 252 or 253, wherein R is cyclopropyl.

257. R １０ The compound according to claim 252 or 253, wherein R is cyclobutyl.

258. R １０ The compound according to claim 252 or 253, wherein R is cyclopentyl.

259. R １２ The compound according to any one of claims 252 to 258, wherein R is H.

260. R １２ The compound according to any one of claims 252 to 258, wherein R is alkyl.

261. R １５ The compound according to any one of claims 252 to 260, wherein R is halo.

262. R １５ The compound according to claim 261, wherein R is F.

263. R １５ The compound according to claim 261, wherein R is Cl.

264. R １５ The compound according to any one of claims 252 to 260, wherein R is alkyl.

265. R １５ The compound according to claim 264, wherein R is methyl.

266. R １５ The compound according to claim 264, wherein R is ethyl.

267. R １５ The compound according to any one of claims 252 to 260, wherein R is CN.

268. R １５ The compound according to any one of claims 252 to 260, wherein R is OH.

269. R １５ The compound according to any one of claims 252 to 260, wherein R is alkoxy.

270. R １５ The compound according to claim 269, wherein R is methoxy.

271. R １５ The compound according to any one of claims 252 to 260, wherein R is haloalkyl.

272. R １５ is CF ３ The compound according to claim 271, wherein

273. R １５ The compound according to any one of claims 252 to 260, wherein R is cyanoalkyl.

274. R １５ is CH ２ CN, the compound according to claim 273.

275. R １５ The compound according to any one of claims 252 to 260, wherein R is alkylcarbonyl.

276. R １５ is C(O)CH ３ The compound according to claim 275, wherein

277. R １６ The compound according to any one of claims 252 to 276, wherein R is H.

278. R １６ The compound according to any one of claims 252 to 276, wherein R is alkyl.

279. R １６ The compound according to claim 278, wherein R is methyl.

280. R １６ The compound according to claim 278, wherein R is ethyl.

281. R １６ The compound according to any one of claims 252 to 276, wherein R is CN.

282. R １６ The compound according to any one of claims 252 to 276, wherein R is OH.

283. R １６ The compound according to any one of claims 252 to 276, wherein R is alkoxy.

284. R １６ The compound according to claim 283, wherein R is methoxy.

285. R １６ The compound according to any one of claims 252 to 276, wherein R is haloalkyl.

286. R １６ is CF ３ and is the compound according to claim 285.

287. R １６ The compound according to any one of claims 252 to 276, wherein R is cyanoalkyl.

288. R １６ is CH ２ The compound according to claim 287, wherein it is CN.

289. R １６ The compound according to any one of claims 252 to 276, wherein R is alkylcarbonyl.

290. R １６ is C(O)CH ３ The compound according to claim 289, wherein

291. R １７ The compound according to any one of claims 252 to 290, wherein R is halo.

292. R １７ The compound according to claim 291, wherein R is F.

293. R １７ The compound according to claim 291, wherein R is Cl.

294. R １７ The compound according to any one of claims 252 to 290, wherein R is alkyl.

295. R １７ The compound according to claim 294, wherein R is methyl.

296. R １７ The compound according to any one of claims 252 to 290, wherein R is haloalkyl.

297. R １７ is CF ３ The compound according to claim 296, wherein

298. The compound according to any one of claims 252 to 297, wherein m is 0.

299. The compound according to any one of claims 252 to 297, wherein m is 1.

300. The compound according to any one of claims 252 to 299, wherein n is 0.

301. The compound according to any one of claims 252 to 299, wherein n is 1.

302. The compound according to any one of claims 252 to 299, wherein n is 2.

303. A compound having the following structure (X), 【Chemical 59】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein C is a saturated carbocyclic ring, R １０ is alkyl, cyclopropyl, cyclobutyl or cyclopentyl, and R １２ is H or alkyl, R １５ is halo, alkyl, CN, OH, alkoxy, haloalkyl, cyanoalkyl or alkylcarbonyl, R １７ is halo, alkyl or haloalkyl, and m is from 0 to 4, and n is from 0 to 4, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

304. The compound according to claim 303, wherein C is cycloalkyl.

305. The compound according to claim 304, wherein C is cyclopentyl.

306. The compound according to claim 304, wherein C is cyclohexyl.

307. R １０ The compound according to any one of claims 303 to 306, wherein R is alkyl.

308. R １０ The compound according to any one of claims 303 to 306, wherein R is cyclopropyl.

309. R １０ The compound according to any one of claims 303 to 306, wherein R is cyclobutyl.

310. R １０ The compound according to any one of claims 303 to 306, wherein R is cyclopentyl.

311. R １２ The compound according to any one of claims 303 to 310, wherein R is H.

312. R １２ The compound according to any one of claims 303 to 310, wherein R is alkyl.

313. R １５ The compound according to any one of claims 303 to 312, wherein R is halo.

314. R １５ The compound according to claim 313, wherein R is F.

315. R １５ The compound according to claim 313, wherein R is Cl.

316. R １５ The compound according to any one of claims 303 to 312, wherein R is alkyl.

317. R １５ The compound according to claim 316, wherein R is methyl.

318. R １５ The compound according to claim 316, wherein R is ethyl.

319. R １５ The compound according to any one of claims 303 to 312, wherein R is CN.

320. R １５ The compound according to any one of claims 303 to 312, wherein R is OH.

321. R １５ The compound according to any one of claims 303 to 312, wherein R is alkoxy.

322. R １５ The compound according to claim 321, wherein R is methoxy.

323. R １５ The compound according to any one of claims 303 to 312, wherein R is haloalkyl.

324. R １５ is CF ３ The compound according to claim 323, wherein

325. R １５ The compound according to any one of claims 303 to 312, wherein R is cyanoalkyl.

326. R １５ is CH ２ The compound according to claim 325, wherein it is CN.

327. R １５ The compound according to any one of claims 303 to 312, wherein R is alkylcarbonyl.

328. R １５ is C(O)CH ３ The compound according to claim 327, wherein

329. R １７ The compound according to any one of claims 303 to 328, wherein R is halo.

330. R １７ The compound according to claim 329, wherein R is F.

331. R １７ The compound according to claim 329, wherein R is Cl.

332. R １７ The compound according to any one of claims 303 to 328, wherein R is alkyl.

333. R １７ The compound according to claim 332, wherein R is methyl.

334. R １７ The compound according to any one of claims 303 to 328, wherein R is haloalkyl.

335. R １７ is CF ３ The compound according to claim 334, wherein

336. The compound according to any one of claims 303 to 335, wherein m is 0.

337. The compound according to any one of claims 303 to 335, wherein m is 1.

338. The compound according to any one of claims 303 to 337, wherein n is 0.

339. The compound according to any one of claims 303 to 337, wherein n is 1.

340. The compound according to any one of claims 303 to 337, wherein n is 2.

341. A compound having the following structure (XI), 【Chemical Formula 60】 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, R １０ is isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and R １２ is H or alkyl, R １７ is halo, alkyl or haloalkyl, R １８ is an alkyl group optionally replaced by one or more R １９ and is R １９ is halo, CN, OH, alkoxy, haloalkyl, or alkylcarbonyl, and wherein n is from 0 to 4, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

342. R １０ The compound according to claim 341, wherein R is isopropyl.

343. R １０ The compound according to claim 341, wherein R is tert-butyl.

344. R １０ The compound according to claim 341, wherein R is cyclopropyl.

345. R １０ The compound according to claim 341, wherein R is cyclobutyl.

346. R １０ The compound according to claim 341, wherein R is cyclopentyl.

347. R １２ The compound according to any one of claims 341 to 346, wherein R is H.

348. R １２ The compound according to any one of claims 341 to 346, wherein R is alkyl.

349. R １７ The compound according to any one of claims 341 to 346, wherein R is halo.

350. R １７ The compound according to claim 349, wherein R is F.

351. R １７ The compound according to claim 349, wherein R is Cl.

352. R １７ The compound according to any one of claims 341 to 346, wherein R is alkyl.

353. R １７ The compound according to claim 352, wherein R is methyl.

354. R １７ The compound according to any one of claims 341 to 346, wherein R is haloalkyl.

355. R １７ is CF ３ and is the compound according to claim 354.

356. R １８ is one R １９ C optionally replaced by １ ~C ４ is alkyl, and the compound according to any one of claims 341 to 355.

357. R １８ wherein one R １９ is replaced by methyl, the compound according to claim 356.

358. R １８ wherein one R １９ is replaced by ethyl, the compound according to claim 356.

359. R １９ The compound according to any one of claims 341 to 358, wherein R is halo.

360. R １９ The compound according to claim 359, wherein R is F.

361. R １９ The compound according to claim 359, wherein R is Cl.

362. R １９ The compound according to any one of claims 341 to 358, wherein R is CN.

363. R １９ The compound according to any one of claims 341 to 358, wherein R is OH.

364. R １９ The compound according to any one of claims 341 to 358, wherein R is haloalkyl.

365. R １９ is CF ３ The compound according to claim 364, wherein

366. R １９ The compound according to any one of claims 341 to 358, wherein R is alkoxy.

367. R １９ The compound according to claim 366, wherein R is methoxy.

368. R １９ The compound according to any one of claims 341 to 358, wherein R is alkylcarbonyl.

369. R １９ is C(O)CH ３ The compound according to claim 368, wherein

370. A compound according to any one of claims 341 to 369, wherein n is 0.

371. A compound according to any one of claims 341 to 369, wherein n is 1.

372. A compound according to any one of claims 341 to 369, wherein n is 2.

373. A compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein the compound has any of the structures found in Table A.

374. A pharmaceutical composition comprising a compound according to any one of claims 1 to 373, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, and at least one pharmaceutically acceptable excipient.

375. A method of modulating Mas-related G protein receptor (MRGPR) D by contacting an effective amount of a compound according to any one of claims 1 to 373 or the pharmaceutical composition according to claim 374 with MRGPRD.

376. A method of treating an MRGPRD-dependent condition by administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 373 or the pharmaceutical composition according to claim 374.

377. The method according to claim 376, wherein the MRGPRD-dependent condition is a pain-related condition, an itch-related condition, an eye-related condition, a cardiovascular and kidney disease-related condition, an inflammatory or autoimmune disorder, a cognitive disorder-related condition, or a cancer-related condition.

378. The pain-related condition is acute pain, progressive prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, cerebral ataxic paralysis, autoimmune atrophic gastritis, avascular necrosis, low back pain, Behçet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, pneumothorax, complex regional pain syndrome (RSD), constipation, corneal neuropathic pain, Crohn's disease, degenerative disc disease, dental pain, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromyalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, inflammatory bowel disease, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatomyositis, knee injury, leg pain, loin pain-hematuria syndrome, lupus, Lyme disease, medullary sponge kidney (MSK), paralytic paralysis, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney, polymyalgia, polymyositis, porphyria, post-hernia pain syndrome, post-mastectomy, postoperative pain, pain syndrome, post-stroke pain, post-thoracotomy pain syndrome, post-herpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (herpes zoster), Sjogren's syndrome, spasmodic torticollis, Oddi sphincter dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, talarophalangeal cyst, transverse myelitis, trigeminal neuralgia, neurogenic pain, ulcerative colitis, vascular pain or vulvar pain, the method according to claim 377.

379. The method according to claim 377, wherein the itching-related condition is chronic itching, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, end-stage renal failure, hemodialysis, chronic urticaria, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry eye syndrome, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermal blistering disease, erythema, food allergy, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iodinated contrast agent allergy, iron deficiency anemia, kidney disease, leukemia, porphyria, lymphoma, malignancy, mastocytosis, multiple myeloma, neurodermatitis, itching of the eyes, onchocerciasis, Paget's disease, pediculosis, polycythemia vera, prurigo nodularis, lichen planus, lichen sclerosus, pruritus ani, pseudorabies, psoriasis, rectal prolapse, sarcoidosis granuloma, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, alcoholism, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, itching of the eyes, or urticaria.

380. The method according to claim 377, wherein the itching-related condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.

381. The method according to claim 377, wherein the eye-related condition is dry eye associated with dry eye syndrome / sicca keratoconjunctivitis and xerotalmia, meibomian gland dysfunction, lacrimal gland dysfunction and other related conditions, dacryoadenitis, dacryocystitis, allergic conjunctivitis, blepharitis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, Stevens-Johnson syndrome, sarcoidosis, sympathetic ophthalmia, diabetic retinopathy, parasitic eye infections, thyroid disorders, other conditions related to dry eye such as vitamin A deficiency, dry eye related to drugs such as antihistamines, decongestants, antidepressants, antipsychotics, diuretics, hormone replacement drugs, oral contraceptives, antihypertensive drugs, isotretinoin treatment for acne, anticholinergic drugs, and dry eye related to ophthalmic surgeries such as laser eye surgery, glaucoma surgery, corneal transplantation, cataract removal surgery.

382. The method according to claim 377, wherein the cardiovascular and renal disease-related conditions are for the treatment of myocardial dysfunction caused by acute or chronic diseases affecting cardiovascular function and renal function, such as peripheral vascular disease, cerebrovascular disease, coronary artery disease, cardiac hypertrophy, myocardial fibrosis, cardiovascular hypertension, renovascular hypertension, renal fibrosis, kidney disease, nephritis, atherosclerosis, coronary atherosclerotic heart disease, acute myocardial infarction, stroke, thrombosis, coronary atherosclerotic thrombosis, pulmonary embolism, myocardial ischemia, carotid stenosis, spinal stenosis, intracranial stenosis, aneurysm, sepsis, rheumatic fever, or diabetes.

383. The method according to claim 377, wherein the inflammatory or autoimmune disease is chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, appendicitis, synovitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (RSD / CRPS), rhinitis, tendinitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, allergy, intestinal disease, epithelial intestinal disease, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis media, pelvic inflammatory disease, endometriosis, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, pneumonia, chronic obstructive pulmonary disease, cardiovascular disease, or vasculitis.

384. The method according to claim 377, wherein the cognitive impairment-related conditions include neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, multiple sclerosis, age-related cognitive impairment, vascular cognitive impairment, and post-stroke cognitive impairment.

385. wherein the cancer-related condition is acute myeloid leukemia, cancer in adolescence, pediatric adrenocortical cancer, AIDS-related cancer (such as lymphoma, Kaposi's sarcoma, etc.), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), fetal tumor, central nervous system cancer, endometrial cancer, epithelioma, esophageal cancer, neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular tumor, pharyngeal cancer, thymoma / thymic cancer, thyroid cancer, renal pelvis / ureter transitional cell carcinoma, trophoblastic tumor, pediatric atypical cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, viral cancer, the method according to claim 377. In some embodiments, the method is the method of claim 377, relating to the treatment of non-cancerous proliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

386. The method of claim 377, wherein the cancer-related condition is lung cancer, pancreatic cancer, or skin cancer.

387. The method of claim 377, wherein the cancer-related condition is lung cancer.

388. The method of claim 377, wherein the cancer-related condition is pancreatic cancer.

389. The method of claim 377, wherein the cancer-related condition is skin cancer.

390. The method of claim 389, wherein the skin cancer-related condition is melanoma.

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