ATF6 modulators and uses thereof

Abstract

The invention relates to ATF6 modulators and uses thereof. Compounds (I) are provided that are modulators of activating transcription factor 6 (ATF6). These compounds can be used as therapeutic agents for the treatment of diseases or disorders mediated by ATF6 and in particular for the treatment of viral infections, neurodegenerative diseases, vascular diseases or cancer. # imgabs0 #

Description

This application is a divisional application of the invention application with an application date of October 9, 2020, Chinese application number 2020800827982, and invention name “ATF6 regulators and their uses”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 913,126, filed on October 9, 2019, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field

[0002] The present disclosure generally relates to therapeutic agents that may be useful as modulators of activating transcription factor 6 (ATF6). ASCII Text File Sequence Listing Submission

[0003] The following content submitted as an ASCII text file is incorporated herein by reference in its entirety: Sequence Listing in Computer Readable Form (CRF) (File Name: 196052001440SEQLIST.TXT, Record Date: October 8, 2020, Size: 1KB). Background Art

[0004] The accumulation of misfolded proteins in the EP of mammalian cells causes the folding machinery to be overwhelmed and leads to a stress response. The cell attempts to reduce the ER protein load by sending signals from the ER to the nucleus, activating a large gene expression program, thereby increasing the protein folding capacity in the ER. However, if this system fails and homeostasis cannot be reestablished, the cell will die by participating in apoptosis. The unfolded protein response (UPR) is an evolutionarily conserved signal transduction pathway that maintains protein homeostasis in response to ER stress.

[0005] Three intertwined signaling pathways comprise the UPR: (1) PERK (protein kinase RNA-like ER kinase); (2) IRE1 (inositol-requiring enzyme 1α); and (3) ATF6 (activating transcription factor 6) (McKimpson, WM et al., Circ Res, 2017, 120(5):759-761). Activation of the ATF6 pathway leads to upregulation of genes such as BIP (Grp78), CHOP or XBP-1, thereby enhancing the ability of the endoplasmic reticulum to fold proteins or mediate quality control. ATF6 works in conjunction with IRE1 because one of ATF6's target genes is XBP1, a key substrate of IRE1 (Yoshida, H., et al., Cell, 2001, 107(7):881-891). PERK plays several other roles, including pausing the production of new proteins to temporarily reduce the protein folding burden.

[0006] ATF6 is a type II transmembrane protein localized in the ER that functions as an ER stress sensor and transcription factor (Adachi, Y., et al., Cell Struct Funct, 2008, 33(1):75-89; Wu, J., et al., Dev Cell, 2007, 13(3):351-64). When demand exceeds the folding capacity of the ER, ATF6 will be transferred from the ER to the Golgi apparatus, where the N-terminal domain of ATF6 (ATF6N) is released from the Golgi membrane for import into the nucleus by sequential cleavage of two Golgi-resident proteases (site 1 and site 2 proteases (S1P and S2P)), where it activates the transcription of its target genes (Ye, J., et al., Mol Cell, 2000, 6(6):1355-64). This activation involves the binding of ATF6 to a consensus sequence called the ER stress response element (ERSE). The consensus sequence of ERSE is CCAATCGGCGGCGG CCACG (SEQ ID NO. 1).

[0007] Unlike the other arms of the UPR regulated by PERK and IRE1, the ATF6 arm has not yet been substantially linked to pro-apoptotic signaling (Hetz, C. and Papa, FR 2018; Sano, R. and Reed, JC 2013). Instead, ATF6 plays a major role in the so-called "adaptive UPR," which is designed to promote protective, adaptive remodeling and recovery of cell physiology after acute physiological and pathological injury. As part of the adaptive UPR, ATF6 integrates with multiple other stress response signaling pathways to sensitively adjust cell physiology for multiple types of ER damage.

[0008] In the context of the UPR, this integration could be achieved through heterodimerization of ATF6 with other UPR-regulated bZIP transcription factors such as XBP1 (Yamamoto, K. et al. 2007; Shoulders, MD et al. 2013) or ATF6b (Thuerauf, DJ et al. 2007; Thuerauf, DJ et al. 2004; Forouhan, M. et al. 2018; Pieper, LA et al. 2017). ATF6 also has the potential to heterodimerize with other bZIP transcription factors, The other transcription factors are similarly regulated by mechanisms involving S1P / S2P-dependent proteolysis, such as CREB-H (Asada, R. et al. 2011; Zhang, K. et al. 2006). In addition to heterodimerization, ATF6 signaling is also integrated with other stress response signaling pathways that interact with other transcription factors such as NRF1, PGC1a, PPARa and ERRg (Chen, X. et al. 2016; Wu, J. et al. 2011; Misra, J. et al. 2013; Baird, L. et al. 2017).

[0009] The ability of ATF6 to integrate with other signaling pathways via multiple mechanisms reflects the unique potential of this UPR signaling arm to coordinate protective cellular responses against a range of pathological insults that induce ER stress, in addition to remodeling ER proteostasis. The establishment of new pharmacological approaches to inhibit and activate ATF6 signaling provides new opportunities to dissect the timing and extent of ATF6 signaling involved in protecting different tissues against cancer, autoimmune diseases, neurodegeneration, metabolic diseases, or I / R.

[0010] Several strategies for manipulating the UPR have been exploited to define possible links between ER stress and human disease, with significant progress in cancer and neurodegeneration.

[0011] In cancer, in addition to reshaping the tumor microenvironment and anticancer immune responses (Song, M and Cubillos-Ruiz, JR 2019), and influencing other major hallmarks of cancer (Urra, H. et al. 2016), tumor growth depends on the UPR as a selective force to drive malignant transformation (Cubillos-Ruiz, JR et al. 2016).

[0012] For example, despite high-dose chemotherapy, autologous stem cell transplantation and novel agents, multiple myeloma (MM) remains a substantially incurable malignancy. Proteasome inhibitors (PIs) such as bortezomib increase the response rate and survival rate of MM patients. The overall patient response rate of newly diagnosed MM to bortezomib and dexamethasone is about 67%. In relapsed and refractory MM, the response rate drops to about 40%-60%. Therefore, there are a large number of MM patients resistant to bortezomib. MM cells are inherently sensitive to PIs due to the constitutive expression of physiological UPR genes required for their large amounts of immunoglobulin production. This seems to reduce the threshold of inducing pro-apoptosis / terminal UPR in response to PI-induced endoplasmic reticulum (ER) stress. One of the signs of UPR induction is the increase in transcription and translation of ER chaperones. These genes are induced by UPR transcription factors XBP1 and ATF6. Although XBP1 splicing and its resulting activation have been shown to be inhibited in PI-treated MM cells, the findings showed that PI treatment did not reduce the high constitutive expression of two XBP1 target gene products, GRP78 and GRP94, and the observation that the XBP1-dependent UPR target gene ERdj4 is normally induced by PIs suggest that the UPR remains functional in PI-treated MM cells. Since both XBP1 and ATF6 can bind to ER stress response elements in the promoters of UPR target genes, it has been suggested that ATF6 can compensate for the reduced XBP1 activity in PI-treated MM cells. In line with this, it has been shown that the induction of GRP78 and GRP94 is regulated by XBP1. – / – Only slightly impaired in B cells, and GRP94 expression requires either ATF6 or XBP1, but not both. Interestingly, previous studies have shown that XBP1 predicts sensitivity to bortezomib and that its levels are proportionally correlated with sensitivity to bortezomib. Recently, Harnoss JM et al. used genetic and pharmacological disruption to demonstrate that the IRE1a-XBP1 pathway plays a key role in MM growth in vitro and in vivo. Indeed, inhibition of IRE1α kinase activity using small molecules was shown to be a potentially effective and safe therapy for the treatment of MM in the clinic.

[0013] In addition to the amount, PI sensitivity also seems to be related to the efficiency of immunoglobulin folding in MM cells. The high constitutive expression of ER resident chaperones GRP78 and GRP94 in MM cell lines is consistent with the report that specialized secretory cell functions require physiological UPR gene expression. The elevated level of ER chaperones is a feature of plasma cells, and their expression is essential for appropriate antibody assembly and secretion. It has been shown that GRP78 is stably combined with the immunoglobulin heavy chain not yet associated with immunoglobulin light chain, and contributes to immunoglobulin assembly. In addition, GRP78 and GRP94 are both important for immunoglobulin light chain folding and targeting unassembled subunits for degradation. The fact that the expression of GRP78 and GRP94 in MM cells treated with PI and classical ER stress agents is only slightly increased shows that they have expressed nearly maximum levels of cell protective UPR proteins to serve as secretory cells. Therefore, for inducing terminal UPR after any additional stress to ER, these cells may have a lower threshold (compared to non-secretory cells). Therefore, more resistant myeloma clones as well as other non-secretory malignancies may be sensitized to bortezomib by combining bortezomib with agents that interfere with the UPR, such as modulators of the ATF6 signaling pathway.

[0014] On the other hand, the protein folding capacity of specialized secretory cells is overwhelmed in several diseases, which leads to cell degeneration and death caused by terminal UPR signaling. For example, dysregulation of UPR signaling in pancreatic β cells that secrete insulin leads to premature cell loss, insulin deficiency, and diabetes. Although neurons are generally considered not to be classic secretory cells, the accumulation of abnormal aggregates may still induce terminal UPR in neurons and lead to neurodegeneration (Hetz, C. and Saxena, S. 2017). ER stress is involved in ocular diseases and in the death of neuronal photoreceptor cells (Kroeger, H. et al. 2019).

[0015] In addition, many diseases lead to impaired circulation, which may lead to ischemic conditions in various organs (including the brain, heart and kidneys) (Benjamin, EJ et al. 2018). In these cases, prolonged ischemia leads to irreversible damage, which can be partially alleviated by clinical interventions that restore blood flow via reperfusion (Hausenloy, DJ and Yellon, DM 2016). Although reperfusion is necessary to reduce the damage of persistent ischemia, it is known that reperfusion itself causes some additional damage, usually caused by reactive oxygen species (ROS) (Murphy, E. and Steenbergen, C. 2008). It has been previously demonstrated that the complex nature of cell damage associated with ischemia or reperfusion after ischemia (I / R) affects the levels and activities of multiple signal transduction pathways and transcription factors. A recently studied I / R-activated pathway involves the destruction of protein homeostasis. In order to protect against pathological ER stress induced by I / R, tissues activate endogenous adaptive stress-responsive signal transduction pathways, such as the unfolded protein response (UPR).

[0016] Recent evidence has highlighted a protective role for the ATF6 arm of the UPR in attenuating adverse outcomes associated with ischemia / reperfusion (I / R) injury in multiple disease models (Kudo, T. et al. 2008; Oida, Y. et al. 2008; Prachasilchai, W. et al. 2009; Oida, Y. et al. 2010; Blackwood, E. A. et al. 2019; Yu, Z. et al. 2017; Bi, X. et al. 2018), suggesting that ATF6 is a potential therapeutic target for pharmacological intervention with activator compounds in multiple ischemia-related disorders (Plate, L. et al. 2016; Glembotski, C. C. et al. 2019).

[0017] ATF6 activated transcriptional targets play a role in the pathogenesis and development of a variety of diseases, including viral infection, cancer, neurodegeneration, Alzheimer's disease, cerebral ischemia, hereditary cerebellar atrophy and ataxia, type 2 diabetes and diabetic nephropathy, and cardiovascular diseases (such as myocardial atrophy, heart failure, ischemic heart disease and atherosclerosis) (Chu, WS, et al., Diabetes, 2007, 56 (3): 856-62; Vekich, JA, et al., J Mol Cell Cardiol, 2012, 53 (2): 259-67; Liu, CL, et al., Int J Mol Med, 2016, 37 (2): 407-14). Therefore, regulating ATF6-mediated transcription may provide a therapeutic strategy for these diseases and other diseases involving ATF6 activity. Summary of the invention

[0018] In one aspect, a compound of formula (I) is provided: or a pharmaceutically acceptable salt thereof, wherein A, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d , and -- are as described in detail herein.

[0019] In another aspect, a method for treating a disease or disorder mediated by activating transcription factor 6 (ATF6) in an individual in need is provided, wherein the method comprises administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound. In some embodiments, the disease or disorder mediated by activating transcription factor 6 (ATF6) is a viral infection, cancer, a neurodegenerative disease, or a vascular disease. In certain embodiments, the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. In some embodiments, the disease or disorder characterized by activating transcription factor 6 (ATF6) is cancer. In some embodiments, ATF6 is ATF6α.

[0020] In another aspect, a method for treating a disease or disorder characterized by activating transcription factor 6 (ATF6) in an individual in need is provided, wherein the method comprises administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, the disease or disorder characterized by activation of ATF6 is a viral infection, cancer, a neurodegenerative disease, or a vascular disease. In certain embodiments, the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. In some embodiments, the disease or disorder characterized by activating transcription factor 6 (ATF6) is cancer. In some embodiments, ATF6 is ATF6α.

[0021] In another aspect, provided is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0022] In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, or adenocarcinoma. In some embodiments, one or more cancer cells in the individual are dormant cancer cells.

[0023] In some embodiments, the individual has undergone prior treatment. In some embodiments, the cancer is resistant or refractory to prior treatment. In some embodiments, the cancer is resistant to treatment with: ubiquitin proteasome pathway inhibitors, taxanes, Cox-2 inhibitors, platinum antineoplastic drugs, anthracyclines, pyrimidine analogs, topoisomerase inhibitors, mTOR inhibitors, immune checkpoint inhibitors, or agents used in immuno-oncology.

[0024] In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering a second anticancer agent. In some embodiments, the second anticancer agent targets an immune checkpoint protein.

[0025] In another aspect, a method of treating a disease or disorder associated with angiogenesis in an individual in need thereof is provided, wherein the method comprises administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, the method further comprises administering a second anti-angiogenic agent.

[0026] In some embodiments of the methods disclosed herein, the methods further comprise administering a second agent that modulates an unfolded protein response or an integrated stress response. In some embodiments, the second agent inhibits the IRE1 / XBP1 pathway.

[0027] In another aspect, provided is a method of modulating (activating or inhibiting) ATF6 in an individual, the method comprising administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0028] In another aspect, provided is a method for regulating (activating or inhibiting) ATF6 in a cell, the method comprising delivering a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, to the cell.

[0029] Also provided is a pharmaceutical composition comprising: (A) a compound as described in detail herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (B) a pharmaceutically acceptable carrier or excipient. Also provided is a kit comprising a compound as described in detail herein or a salt thereof and optionally instructions for use. Also provided is a compound as described in detail herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or disorder characterized by activation of ATF6. In some embodiments, the disease or disorder is cancer, a neurodegenerative disease, or a vascular disease. In certain embodiments, the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. DETAILED DESCRIPTION definition

[0030] As used herein, the use of the terms "a", "an", etc. means one or more unless expressly stated otherwise.

[0031] References herein to "about" a value or parameter include (and describe) embodiments involving that value or parameter itself. For example, description referring to "about X" includes description of "X".

[0032] Unless otherwise indicated, as used herein, "alkyl" refers to and includes saturated straight chain (ie, unbranched) or branched monovalent hydrocarbon chains, or combinations thereof, having the specified number of carbon atoms (ie, C 1 -C 10 Specific alkyl groups are groups having 1 to 20 carbon atoms (“C 1 -C 20 alkyl”), having 1 to 10 carbon atoms (“C 1 -C 10 alkyl”), having 6 to 10 carbon atoms (“C 6 -C 10 alkyl”), having 1 to 6 carbon atoms (“C 1 -C 6 alkyl”), having 2 to 6 carbon atoms (“C 2 -C 6 alkyl") or having 1 to 4 carbon atoms ("C 1 -C 4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0033] "Alkoxy" refers to the group RO-, where R is alkyl; and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0034] As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), which may or may not be aromatic. Specific aryl groups are those having 6 to 14 ring carbon atoms ("C 6 -C 14 An aryl group having more than one ring wherein at least one ring is non-aromatic can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, an aryl group having more than one ring wherein at least one ring is non-aromatic is attached to the parent structure at an aromatic ring position.

[0035] Unless otherwise indicated, as used herein, "cycloalkyl" refers to and includes a saturated cyclic monovalent hydrocarbon structure having the specified number of carbon atoms (i.e., C 3 -C 10 Cycloalkyl groups may be composed of one ring (such as cyclohexyl) or multiple rings (such as adamantyl). Cycloalkyl groups containing more than one ring may be fused, spirocyclic, or bridged, or a combination thereof. Specific cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyl groups are those having 3 to 8 ring carbon atoms ("C 3 -C 8 cycloalkyl”), having 3 to 6 carbon atoms (“C 3 -C 6 cycloalkyl”), or having 3 to 4 ring carbon atoms (“C 3 -C 4 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0036] "Halo" or "halogen" refers to an element of the 17-group series with an atomic number of 9 to 85. Preferred halides include groups of fluorine, chlorine, bromine and iodine. In the case where a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halides, which may be, but are not necessarily, the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halide is referred to as a "perhaloalkyl". A preferred perhaloalkyl group is trifluoromethyl (-CF 3Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each H in the hydrocarbon that constitutes the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF 3 ).

[0037] The term "haloalkyl" refers to an alkyl group having one or more halo substituents, or one, two or three halo substituents. Examples of haloalkyl groups include -CF 3 、-(CH 2 )F, -CHF 2 、-CH 2 Br, -CH 2 CF 3 and -CH 2 CH 2 F.

[0038] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 ring carbon atoms and at least one ring heteroatom (including but not limited to heteroatoms, such as nitrogen, oxygen and sulfur). Heteroaryl can have a monocyclic ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which may or may not be aromatic. Specific heteroaryl is a 5 to 14-membered ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 10-membered ring having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5, 6 or 7-membered ring having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, a specific heteroaryl is a monocyclic aromatic 5, 6 or 7-membered ring having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, a specific heteroaryl is a polycyclic aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl having more than one ring and at least one of which is non-aromatic can be connected to the parent structure at an aromatic ring position or a non-aromatic ring position. In one variation, a heteroaryl having more than one ring and at least one of which is non-aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl can be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0039] As used herein, "heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings and having 1 to 14 ring carbon atoms and 1 to 6 ring heteroatoms (such as nitrogen, sulfur or oxygen, etc.). Heterocycles containing more than one ring may be fused, bridged or spirocyclic or any combination thereof, but do not include heteroaryl. Heterocyclyl may be optionally substituted independently by one or more substituents described herein. Specific heterocyclyl groups are 3 to 14 membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12 membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10 membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8 membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6 membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3, 4, 5, 6, or 7 membered rings having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] "Pharmaceutically acceptable carrier" refers to ingredients in a pharmaceutical formulation other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

[0041] As used herein, "treatment" or "treating" is a method for obtaining beneficial or desired results (including clinical results). For example, beneficial or desired results include, but are not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dose of other drugs required to treat the disease, delaying disease progression, and / or prolonging the survival of an individual. With respect to cancer or other unwanted cell proliferation, beneficial or desired results include shrinking the tumor (reducing tumor size); reducing the growth rate of the tumor (such as inhibiting tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing down and preferably stopping the infiltration of cancer cells into surrounding organs to a certain extent; inhibiting (slowing down and preferably stopping to a certain extent) tumor metastasis; inhibiting tumor growth; preventing or delaying the occurrence and / or recurrence of tumors; and / or alleviating one or more symptoms associated with cancer to a certain extent. In some embodiments, beneficial or desired results include preventing or delaying recurrence, such as recurrence of unwanted cell proliferation.

[0042] As used herein, an "effective dose" or "effective amount" of a compound or its salt or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For preventive use, beneficial or desired results include results such as: eliminating or reducing the risk of a disease, reducing the severity of a disease, or delaying the onset of a disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presented during the development of the disease. For therapeutic use, beneficial or desired results include improving, alleviating, alleviating, delaying or reducing one or more symptoms caused by the disease; improving the quality of life of those suffering from the disease; reducing the dose of other drugs required to treat the disease; such as enhancing the effect of another drug via targeting; delaying the progression of the disease; and / or prolonging survival. With respect to cancer or other unwanted cell proliferation, an effective amount includes an amount sufficient to cause a tumor to shrink and / or reduce the growth rate of a tumor (such as inhibiting tumor growth), or to prevent or delay other undesirable cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. An effective amount may be administered in one or more administrations. In the case of cancer, an effective amount of a drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow down, and preferably stop cancer cell infiltration into surrounding organs to a certain extent; (iv) inhibit (i.e., slow down, preferably stop) tumor metastasis to a certain extent; (v) inhibit tumor growth; (vi) prevent or delay the recurrence of tumors; and / or (vii) alleviate one or more symptoms associated with cancer to a certain extent. An effective dose may be administered in one or more administrations. For the purposes of this disclosure, an effective dose of a compound or its salt or pharmaceutical composition is an amount sufficient to directly or indirectly complete a preventive or therapeutic treatment. It is contemplated and understood that an effective dose of a compound or its salt or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, an "effective dose" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the desired result can be achieved or achieved in combination with one or more other agents.

[0043] As used herein, the term "subject" is a mammal, including humans. Individuals include, but are not limited to, humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is a human. The individual (such as a human) may suffer from advanced disease or a lower degree of disease, such as low tumor burden. In some embodiments, the individual is in the early stages of a proliferative disease (such as cancer). In some embodiments, the individual is in the late stages of a proliferative disease (such as advanced cancer).

[0044] It should be understood that the aspects and variations described herein also include "consisting of" and / or "consisting essentially of" the aspects and variations.

[0045] All references cited throughout the text, such as publications, patents, patent applications, and published patent applications, are incorporated herein by reference in their entirety. Compound

[0046] In one aspect, a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R d Is H or C 1 -C 6 alkyl; R 1 It is C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl or C 1 -C 6 Haloalkyl; L is -CH 2 - or does not exist; -- is a key or does not exist; R 2 , R 3 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group, wherein R 2 , R 3 , R 4 , R 5 and R 6 At least two of them are halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl, and / or wherein R 2 , R 3 , R 4 , R 5 and R 6 One of them is CN; or R 2 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C6 Alkyl, or C 1 -C 6 haloalkyl and -- is the key that makes R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, wherein the 5- or 6-membered ring is unsubstituted or substituted by one to three groups selected from the group consisting of halogen, CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 Haloalkyl; A is R a is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy, The condition is that when A is And R a is 2-furyl or 2-thiofuryl, at least one of (i.) to (vi.) One applies: (i.) L does not exist, and R 1 It is C 1 -C 6 alkyl; (ii.)--is the bond that makes R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, provided that when forming said 5-membered carbocyclic ring, R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Haloalkyl; (iii.) R 2 , R 3 , R 4 , R 5 and R 6 One of them is CN; (iv.) R 4 and R 5 are independently Cl, Br, I, CN, C 1 -C 6 Alkyl, or C 1-C 6 Haloalkyl; (v.) R 2 and R 3 Each is Cl; and (vi.) R 2 , R 3 , R 4 , R 5 and R 6 At least one of them is F, Br, I, CN, or C 1 -C 6 haloalkyl and R a is 2-thiofuranyl; and R 7 It is H, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl, The condition is that when R d It is C 1 -C 6 When alkyl, R 7 is H, and when R 7 It is C 1 -C 6 When alkyl, R d It's H.

[0047] In one variation, there is provided a compound of formula (I) or a salt thereof, wherein R 1 (i.e., C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, or C 1 -C 6 In another embodiment, a compound of formula (I) or a salt thereof is provided, wherein R 1 (i.e., C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, or C 1 -C 6 Also included are mixtures of compounds of formula (I), including racemic and non-racemic mixtures of a given compound, and mixtures of two or more compounds of different formulae.

[0048] In the description herein, it should be understood that each description, variation, embodiment or aspect of a part can be combined with each description, variation, embodiment or aspect of other parts, just as if each combination of descriptions were specifically and individually listed. For example, the R of formula (I) provided herein 1 Every description, variation, embodiment or aspect of A of formula (I) can be combined with every description, variation, embodiment or aspect of A of formula (I) as if each combination was specifically and individually listed.

[0049] In some embodiments, a compound of formula (I) is provided, wherein A is In some embodiments, a compound of formula (I) is provided, wherein A is In other embodiments, a compound of formula (I) is provided, wherein A is

[0050] In some embodiments of Formula (I), R 1 It is C 1 -C 6 In other embodiments, R 1 It is C 3 -C 8 In some embodiments, R 1 It is C 1 -C 6 In certain embodiments, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. 1 In some embodiments, R 1 In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 It is cyclopropyl.

[0051] In some embodiments of Formula (I), R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring. 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 5-membered carbocyclic ring. 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbocyclic ring. 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbocyclic ring substituted with one to three groups selected from the group consisting of halogen, CN, -OH, C1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R 3 With R 1 Together with the atoms to which they are attached, they form a 6-membered carbocyclic ring substituted with one to three groups selected from the group consisting of halo, CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is unsubstituted or substituted by one to three groups selected from the group consisting of halogen, CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 Halogenated alkyl.

[0052] In some embodiments of compounds of Formula (I), L is absent. In other embodiments, L is -CH 2 -. In some embodiments, L is absent, and R 1 It is C 1 -C 6 In other embodiments, L is absent and R 1 It is C 3 -C 8 In some embodiments, L is absent and R 1 It is C 1 -C 6 In certain embodiments, L is absent and R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, L is absent, and R 1 In some embodiments, L is absent and R 1 In some embodiments, L is absent and R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, L is absent, and R 1 It is cyclopropyl.

[0053] In some embodiments of the compound of Formula (I), L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring. In some embodiments, L is absent and R 3 With R1 Together with the atoms to which they are attached, they form an unsubstituted 5-membered carbocyclic ring. In some embodiments, L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbocyclic ring. In some embodiments, L is absent, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbocyclic ring substituted with one to three groups selected from the group consisting of halo, CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form a 6-membered carbocyclic ring substituted with one to three groups selected from the group consisting of halo, CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is unsubstituted or substituted by one to three groups selected from the group consisting of halogen, CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbocyclic ring, wherein the 5-membered carbocyclic ring is unsubstituted or substituted with halogen, CN, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl substituted and R 2 , R 4 , R 5 and R 6 One or two of them are independently selected from halogen, CN, C 1 -C 6 Alkyl and C 1 -C 6 In certain embodiments, L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 5-membered carbon ring, and R 2 , R 4 , R 5 and R6 Each is H. In one variation, L is absent, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbon ring with R 1 In another variation, L is absent and R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbon ring with R 1 The carbon is in the "R" configuration.

[0054] In some embodiments, L is -CH 2 -, and R 1 It is C 1 -C 6 In other embodiments, L is -CH 2 -, and R 1 It is C 3 -C 8 In some embodiments, L is -CH 2 -, and R 1 It is C 1 -C 6 In certain embodiments, L is -CH 2 -, and R 1 L is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, L is -CH 2 -, and R 1 In some embodiments, L is -CH 2 -, and R 1 In some embodiments, L is -CH 2 -, and R 1 In some embodiments, L is -CH 2 -, and R 1 In some embodiments of the compound of Formula (I), L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring. In some embodiments, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 5-membered carbocyclic ring. In some embodiments, L is -CH 2 -, and R 3 With R 1Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbocyclic ring. In some embodiments, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbocyclic ring substituted with one to three groups selected from the group consisting of halo, CN, -OH, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 6-membered carbocyclic ring substituted with one to three groups selected from the group consisting of halo, CN, -OH, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is unsubstituted or substituted by one to three groups selected from the group consisting of halogen, CN, -OH, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbocyclic ring, wherein the 5-membered carbocyclic ring is unsubstituted or substituted with halogen, CN, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl substituted and R 2 , R 4 , R 5 and R 6 One or two of them are independently selected from halogen, CN, C 1 -C 6 Alkyl, and C 1 -C 6 In certain embodiments, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbon ring, and R 2 , R 4 , R 5 and R6 Each is H. In one variation, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbon ring with R 1 In another variation, L is -CH 2 -, and R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbon ring with R 1 The carbon is in the "R" configuration.

[0055] In some embodiments of Formula (I), A is And R a In another embodiment of formula (I), A is And R a is 2-pyridyl. In some embodiments of Formula (I), A is And R a In other embodiments of formula (I), A is And R a In still other embodiments of formula (I), A is And R a It is 2-pyrazinyl.

[0056] In some embodiments of Formula (I), A is And R a In another embodiment of formula (I), A is And R a is 2-pyridyl. In some embodiments of Formula (I), A is And R a In other embodiments of formula (I), A is And R a In still other embodiments of formula (I), A is And R a It is 2-pyrazinyl.

[0057] In other embodiments of Formula (I), A is And R a In another embodiment of formula (I), A is And R a is 2-pyridyl. In some embodiments of Formula (I), A is And R aIn other embodiments of formula (I), A is And R a In still other embodiments of formula (I), A is And R a It is 2-pyrazinyl.

[0058] In certain embodiments of Formula (I), -- is a bond such that R 3 With R 1 Together with the atoms to which they are attached, they form a 6-membered carbocyclic ring. In some variations, the 6-membered carbocyclic ring is unsubstituted. In other variations, the 6-membered ring is substituted. In still other variations, the 6-membered carbocyclic ring is substituted with one to three groups selected from the group consisting of halo, -CN, -OH, C 1 -C 6 Alkyl, and C 1 -C 6 Halogenated alkyl.

[0059] In some embodiments of Formula (I), - is a bond such that R 3 With R 1 Together with the atoms to which they are attached, they form a 5-membered carbocyclic ring. In some variations, the 5-membered carbocyclic ring is unsubstituted. In other variations, the 5-membered carbocyclic ring is substituted. In still other variations, the 5-membered carbocyclic ring is substituted with one to three groups selected from the group consisting of halo, -CN, -OH, C 1 -C 6 Alkyl and C 1 -C 6 haloalkyl and R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, or C 1 -C 6 alkyl.

[0060] In some embodiments of Formula (I), wherein A is And R a is 2-furyl, L is absent, and R 1 It is C 1 -C 6 Alkyl; or - is a bond such that R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, provided that when a 5-membered carbocyclic ring is formed, R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, C 1 -C 6Alkyl, or C 1 -C 6 Halogenated alkyl.

[0061] In certain embodiments of Formula (I), when R d It is C 1 -C 6 When alkyl, R 7 is H. In other embodiments of Formula (I), when R 7 It is C 1 -C 6 When alkyl, R d It's H.

[0062] In some embodiments of the compound of Formula (I), R 2 , R 3 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 are independently H, Cl, CN, or CF 3 In some embodiments, R 4 and R 5 are independently Cl, Br, I, CN, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 In some embodiments, two of R are not H. 2 , R 3 , R 4 , R 5 and R 6 At least two of are not H. In some embodiments, R 2 , R 3 , R 4 , R 5and R 6 In some embodiments, R 6 is CN. In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 One of them is CF 3 In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 Two of them are CF 3 In some embodiments, R 2 and R 6 Each is CF 3 , or R 4 and R 5 Each is CF 3 , or R 3 and R 6 Each is CF 3 In some embodiments, R 2 , R 3 , R 4 , R 5 and R 6 One or two of are Cl. In some embodiments, R 4 and R 5 Each is Cl. In other embodiments, R 2 and R 3 Each is Cl. In still other embodiments, R 2 and R 3 Each is F. In some embodiments, R 2 and R 3 One of them is F and R 2 and R 3 In some embodiments, R 2 and R 6 Each is F. In other embodiments, R 2 and R 6 Each is Cl. In some embodiments, R 2 and R 6 One of them is F and R 2 and R 6 In some embodiments, R 2 , R 4 , R 5 and R 6 Each is H. In some embodiments, R 2 , R3 , R 4 , R 5 and R 6 In certain embodiments, three of R are not H. 2 , R 3 and R 6 is not H. In some embodiments, R 2 , R 3 and R 6 In certain embodiments, R 2 , R 3 and R 6 Each is F.

[0063] In some embodiments of Formula (I), yes Where R 2 and R 6 Each is C 1 -C 6 In some embodiments, yes Where R 2 and R 6 Each independently selected from halogen, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, yes Where R 2 and R 6 Each independently selected from Cl, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, yes Where R 2 and R 6 Each is independently Cl or F. In some embodiments, yes In some embodiments, yes Where R 2 and R 6 Each is independently F. In some embodiments, yes Where R 2 and R 6 One of them is F and R 2 and R 6 One of is Cl. In some embodiments, yes Where R2 and R 3 In some embodiments, yes Where R 5 and R 6 Each independently selected from Cl, Br, I, CN, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, yes In some embodiments, yes In other embodiments, yes In still other embodiments, yes

[0064] In some embodiments of the compound of Formula (I), R a is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 In some embodiments, R a is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each of which is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R a selected from 2-furanyl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, C 1 -C 6 Alkyl, and C 1 -C 6 Alkoxy.

[0065] In some embodiments, R a is a 5- or 6-membered heteroaryl group containing one heteroatom. 2 , R 3 , R 4 , R5 and R 6 At least two of them are C 1 -C 6 When alkyl halide is present, R a is a 6-membered heteroaryl group containing at least two heteroatoms. In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R d Is H or C 1 -C 6 alkyl; R 1 It is C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl or C 1 -C 6 Haloalkyl; L is -CH 2 - or does not exist; -- is a key or does not exist; R 2 , R 3 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group, wherein R 2 , R 3 , R 4 , R 5 and R 6 At least two of them are halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl, and / or wherein R 2 , R 3 , R 4 , R 5 and R 6 One of them is CN; or R 2 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl and -- is a bond such that R 3 With R 1Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, wherein the 5- or 6-membered carbocyclic ring is unsubstituted or substituted by one to three groups selected from the group consisting of halogen, CN, -OH, C 1 -C 6 alkyl Base and C 1 -C 6 Haloalkyl; A is R a is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy, The condition is that when R 2 , R 3 , R 4 , R 5 and R 6 At least two of them are C 1 -C 6 When alkyl halide is present, R a is a 6-membered heteroaryl group containing at least two heteroatoms; and The condition is that when A is And R a is 2-furyl or 2-thiofuryl, at least one of (i.) to (vi.) One applies: (i.) L does not exist, and R 1 It is C 1 -C 6 alkyl; (ii.)--is the bond that makes R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, provided that when forming said 5-membered carbocyclic ring, R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Haloalkyl; (iii.) R 2 , R 3 , R 4 , R 5 and R 6 One of them is CN; (iv.) R4 and R 5 are independently Cl, Br, I, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Haloalkyl; (v.) R 2 and R 3 Each is Cl; and (vi.) R 2 , R 3 , R 4 , R 5 and R 6 At least one of them is F, Br, I, CN, or C 1 -C 6 haloalkyl and R a is 2-thiofuranyl; and R 7 It is H, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl, The condition is that when R d It is C 1 -C 6 When alkyl, R 7 is H, and when R 7 It is C 1 -C 6 When alkyl, R d It's H.

[0066] In some embodiments, A is And R a is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, A is And R a is 2-furanyl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 In some embodiments, A is And R a It is 2-furyl.

[0067] In some embodiments of the compound of Formula (I), A is And Ra is a 5- or 6-membered heteroaryl group, wherein R a The 5- or 6-membered heteroaryl is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 In some embodiments, A is And R a is 2-furanyl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 In some embodiments, A is And R a It is 2-pyrazinyl.

[0068] In some embodiments of the compound of Formula (I), A is And R a is a 5- or 6-membered heteroaryl group, wherein R a The 5- or 6-membered heteroaryl is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 In some embodiments, A is And R a is 2-furanyl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 In some embodiments, A is And R a It is 2-furyl.

[0069] In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d is methyl, R 7 It is H, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d Yes H, R 7 is methyl, A is R a is 2-furyl, R 1is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached they form an unsubstituted 5-membered carbocyclic ring.

[0070] In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d is methyl, R 7 It is H, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d Yes H, R 7 is methyl, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 5-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7It is H, A is R a is 2-pyrazinyl, R 1 is methyl, and L is absent.

[0071] In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d is methyl, R 7 It is H, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d Yes H, R 7 is methyl, A is R a is 2-furyl, R 1 is methyl, and L is absent. In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached, they form an unsubstituted 6-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 It is H, A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached they form an unsubstituted 5-membered carbocyclic ring.

[0072] In some variations of the embodiments described herein, the compound of formula (I) is not any of the following: N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)propyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide; 5-Acetyl-N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyridin-4-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-{1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-5-tert-butyl-1,2-oxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-[3,3'-bipyridine]-5-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2,4-difluorophenyl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-imidazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,3-dihydro-2H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(4-fluorophenyl)nicotinamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-phenylnicotinamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(5-methylfuran-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(4-cyano-3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(3-chloropyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(3-chloropyridin-2-yl)isoxazole-3-carboxamide; N-(1-((2,4-bis(trifluoromethyl)phenyl)(cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(3-chloropyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-3-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyridin-2-yl)isoxazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(furan-2-yl)thiazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-2'-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6'-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyridin-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(2-methoxyphenyl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2-methoxyphenyl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrimidin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-N-methyl-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(pyridin-2-yl)thiazole-5-carboxamide; N-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-1-methyl-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(6-methylpyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(6-methylpyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-1-(pyridin-2-yl)-1H-1,2,3-triazole-4-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)oxazole-4-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)oxazole-5-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyrimidin-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazole-5-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-4-methyl-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)picolinamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-2-(furan-2-yl)thiazole-5-carboxamide; N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-4-methyl-5-(pyridin-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrimidin-4-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide; and N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0073] Representative compounds are listed in Table 1. Table 1

[0074] In some embodiments, provided herein are compounds described in Table 1 or pharmaceutically acceptable salts thereof, and uses thereof.

[0075] Where applicable, the embodiments and variations described herein apply to compounds of any formula detailed herein.

[0076] Provided herein are compounds selected from the group consisting of: N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; 5-(Furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; 5-(Furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide; 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; and N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, Or a pharmaceutically acceptable salt thereof. Where applicable, any and all stereoisomers of the compounds described herein are also provided herein, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio (including racemic mixtures).

[0077] Where applicable, the embodiments and variations described herein apply to compounds of any formula detailed herein.

[0078] All representative examples of compounds detailed herein, including intermediates and final compounds according to the present disclosure, are depicted herein. It should be understood that in one aspect, any of the compounds described can be used in the methods detailed herein, including (where applicable) intermediate compounds that can be isolated and administered to an individual.

[0079] Even if salts are not depicted, the compounds depicted herein may also exist as salts, and it should be understood that the disclosure includes all salts and solvates of the compounds depicted herein, as well as non-salt and non-solvate forms of the compounds, as fully understood by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. In the case of one or more tertiary amine moieties present in the compounds, N-oxides are also provided and described.

[0080] Where any of the compounds described herein may exist in tautomeric forms, even though only one or a few tautomeric forms may be explicitly depicted, each tautomeric form is contemplated. The specifically depicted tautomeric form may or may not be the predominant form in solution or when used according to the methods described herein.

[0081] The present disclosure also includes any or all stereochemical forms of the compound, including any enantiomeric or diastereomeric forms. Any compound of the formula given herein may have an asymmetric center and therefore exist in the form of different enantiomers or diastereoisomers. It is believed that all optical isomers and stereoisomers of the compound of the general formula and mixtures thereof in any ratio are within the scope of the formula. Therefore, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomer forms and mixtures thereof in any ratio, unless otherwise indicated by specific stereochemistry. In the case of describing the compounds of Table 1 with a specific stereochemical configuration, any alternative stereochemical configuration of the compound is also provided herein, as well as mixtures of the stereoisomers of the compound in any ratio. For example, in the case of a compound of Table 1 having a stereocenter in an "S" stereochemical configuration, enantiomers of the compound are also provided herein, wherein the stereocenter is in an "R" stereochemical configuration. Likewise, when the compounds of Table 1 have stereocenters in the "R" configuration, enantiomers of the compounds in the "S" stereochemical configuration are also provided herein. A mixture of the compounds having both "S" and "R" stereochemical configurations is also provided. In addition, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. For example, any compound of any formula given herein may contain a bond that restricts rotation, and therefore exists in different geometric configurations. Where the compounds of Table 1 are described as specific geometric isomers (e.g., E or Z isomers or cis or trans isomers), any alternative geometric configurations of the compounds are also provided herein, as well as mixtures of the geometric isomers of the compounds in any ratio. For example, where the compounds of Table 1 are depicted as "Z" isomers, "E" isomers of the compounds are also provided herein. Likewise, where the compounds of Table 1 are depicted as "E" isomers, "Z" isomers of the compounds are also provided herein. Also provided are mixtures of the compounds having both "E" and "Z" stereochemical configurations, wherein the mixtures are in any ratio. Similarly, where the compounds of Table 1 are depicted as "cis" isomers, the "trans" isomers of the compounds are also provided herein; and where the compounds are depicted as "trans" isomers, the "cis" isomers of the compounds are also provided herein. Also provided are mixtures of the compounds having both "cis" and "trans" stereochemical configurations, wherein the mixtures are in any ratio. The present invention also encompasses all forms of the compounds, such as crystalline or non-crystalline forms of the compounds.Also contemplated are compositions comprising a compound of the invention, such as a substantially pure compound (including a specific stereochemical form thereof), or a mixture of a compound of the invention in any ratio (including two or more stereochemical forms, such as in a racemic or non-racemic mixture).

[0082] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. In some embodiments, the compounds are isotopically labeled, such as isotopically labeled compounds of Formula (I) described herein or variations thereof, wherein a portion of one or more atoms is replaced by an isotope of the same element. Exemplary isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 O. 17 O. 32 P. 35 S. 18 F. 36 Cl. Certain isotopically labeled compounds (e.g. 3 H and 14 C) can be used for compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages due to greater metabolic stability (eg, increased in vivo half-life) or reduced dosage requirements, and thus may be preferred in some circumstances.

[0083] Isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures analogous to those described in the accompanying examples, using an appropriate isotopically labeled reagent in place of the corresponding non-labeled reagent.

[0084] The present invention also includes any or all metabolites of any of the compounds. Metabolites may include any chemical species produced by the biotransformation of any of the compounds, such as intermediates and products of metabolism of the compounds, such as would be produced in vivo following administration to a human.

[0085] Provided are articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container. The container may be a vial, a can, an ampoule, a preloaded syringe, an intravenous bag, etc.

[0086] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (eg, intravenous) administration.

[0087] One or more compounds described herein can be used in the preparation of a medicament by combining one or more compounds as active ingredients with a pharmacologically acceptable carrier known in the art. The carrier can be in various forms based on the therapeutic form of the drug. In one variation, the manufacture of a medicament is for any method disclosed herein, for example, for the treatment of cancer. General synthetic method

[0088] The compounds of the present invention may be prepared by a number of methods as generally described below. In the following process descriptions, the symbols when used in the depicted formulae are to be understood as representing those groups described above with respect to the formulae herein.

[0089] In the case of needing to obtain a specific enantiomer of a compound, this can be achieved using any suitable conventional procedure for separating or splitting enantiomers from a mixture of corresponding enantiomers. Therefore, for example, diastereomeric derivatives can be prepared by the reaction of an enantiomeric mixture (such as racemate) with a suitable chiral compound. The diastereoisomer can then be separated by any convenient means (for example, by crystallization) and the desired enantiomer can be recovered. In another method of resolution, chiral high performance liquid chromatography can be used to separate racemates. Alternatively, if desired, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the methods.

[0090] Where it is desired to obtain a specific isomer of a compound or to otherwise purify a reaction product, chromatography, recrystallization and other conventional separation procedures may also be employed with the intermediates or final products.

[0091] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and are typically formed during the crystallization process. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and / or solubility. Various factors (such as recrystallization solvents, crystallization rates, and storage temperatures) may lead to a monocrystalline form that dominates.

[0092] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 1. Solution 1 Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and A are as defined herein for Formula (I) or any variation thereof.

[0093] An exemplary embodiment of the preparation method in Scheme 1 is shown in Scheme 1a. Option 1a Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and R a is as defined herein for Formula (I) or any variation thereof.

[0094] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 2. Solution 2 Among them, A, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and n are as defined herein for Formula (I) or any variation thereof, and X is halogen.

[0095] An exemplary embodiment of the preparation method in Scheme 2 is shown in Scheme 2a. Option 2a Among them, A, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and n are as defined herein for Formula (I) or any variation thereof, and X is halogen.

[0096] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 3. Solution 3 Among them, A, R 2 , R 4 , R 5 , R 6 , R 7 and R d is as defined herein for Formula (I) or any variation thereof.

[0097] An exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3a. Option 3a Among them, A, R 2 , R 4 , R 5 , R 6 , R 7 and R d is as defined herein for Formula (I) or any variation thereof.

[0098] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 4. Solution 4 Among them, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R d is as defined herein for formula (I) or any variation thereof, and X is halogen.

[0099] Specific examples are provided in the following Examples section. It should be understood that the above schemes can be modified to obtain various compounds of the present invention by selecting appropriate reagents and starting materials. For a general description of protecting groups and their use, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006. Pharmaceutical compositions and formulations

[0100] The present disclosure includes pharmaceutical compositions of any of the compounds detailed herein. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic acid or an organic acid. The pharmaceutical composition can be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or in a form suitable for administration by inhalation.

[0101] In one aspect, the compound as described in detail herein can be in purified form, and compositions comprising the compound in purified form are described in detail herein. Compositions comprising the compound or its salt as described in detail herein, such as compositions of substantially pure compounds are provided. In some embodiments, compositions containing the compound or its salt as described in detail herein are in substantially pure form.

[0102] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the disclosure encompasses pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are applicable to any compound or form thereof detailed herein.

[0103] The compounds or salts thereof described in detail herein can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The compounds or salts thereof can be formulated with a suitable carrier to provide delivery forms, including but not limited to tablets, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, colloids, dispersions, suppositories, ointments, poultices (foam pastes), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0104] One or more compounds or their salts described herein can be used to prepare formulations, such as pharmaceutical formulations, by combining one or more compounds or their salts as active ingredients with pharmaceutically acceptable carriers (such as those mentioned above). Depending on the treatment form of the system (e.g., transdermal patch and oral tablets), the carrier can be in various forms. In addition, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for regulating osmotic pressure. The formulations comprising the compounds can also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pennsylvania, 20th edition. (2000), which are incorporated herein by reference.

[0105] Compounds as described herein can be administered to individuals in the form of commonly accepted oral compositions such as tablets, coated tablets, and gel capsules, emulsions, or suspensions in hard or soft shells. Examples of carriers that can be used to prepare such compositions are lactose, corn starch or its derivatives, talc, stearates or their salts, etc. Acceptable carriers for soft shell gel capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc. In addition, the pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for regulating osmotic pressure.

[0106] Any of the compounds described herein may be formulated in a tablet in any of the dosage forms described, for example, a compound described herein or a pharmaceutically acceptable salt thereof may be formulated as a 10 mg tablet.

[0107] Compositions comprising the compounds provided herein are also described. In one variation, the composition comprises a compound or a salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of a substantially pure compound is provided. Usage and Purpose

[0108] The compounds and compositions described in detail herein (such as pharmaceutical compositions containing compounds of any formula provided herein or salts thereof and pharmaceutically acceptable carriers or excipients) can be used for administration and treatment methods as provided herein. The compounds and compositions can also be used in in vitro methods, such as applying compounds or compositions to cells for screening purposes and / or in vitro methods for quality control determination.

[0109] In some embodiments, provided herein is a method for regulating the ATF6 pathway. In some embodiments, provided herein is a method for regulating ATF6. In some embodiments, provided herein is a method for activating the ATF6 pathway. In some embodiments, provided herein is a method for activating ATF6. In some embodiments, provided herein is a method for inhibiting the ATF6 pathway. In some embodiments, provided herein is a method for inhibiting ATF6. In some embodiments, the ATF6 is ATF6α. It is believed that the compounds described herein or their salts and the compositions described herein effectively inhibit the ATF6 pathway, ATF6 and / or ATF6α.

[0110] In some embodiments, the method of regulating the ATF6 pathway, ATF6 or ATF6α comprises administering or delivering a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein to a cell comprising ATF6 or ATF6α. In some embodiments, the method of activating the ATF6 pathway, ATF6 or ATF6α comprises administering or delivering a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein to a cell comprising ATF6 or ATF6α. In some embodiments, the method of inhibiting the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein to a cell comprising ATF6 or ATF6α. In some embodiments, the cell is a diseased cell, such as a cancer cell. In some embodiments, the cell has an activated ATF6 pathway. In some embodiments, the cell has been exposed to ER stress inducing conditions. Several ER stress inducing conditions are known in the art, such as glucose deprivation, abnormal Ca 2+ regulation, viral infection, hypoxia, and exposure to ER stress-inducing molecules (such as thapsigargin, ionomycin, or tunicamycin).

[0111] In some embodiments, the method of regulating the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering a compound as described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein to a tumor. In some embodiments, the method of activating the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering a compound as described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein to a tumor. In some embodiments, the method of inhibiting the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering a compound as described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein to a tumor.

[0112] In some embodiments, the regulation of the ATF6 pathway, ATF6, or ATF6α includes regulating the expression of ATF6 and / or ATF6α target genes. In some embodiments, the regulation of the ATF6 pathway, ATF6, or ATF6α includes regulating the expression of ATF6α target genes. In some embodiments, the expression of ATF6 and / or ATF6α target genes is regulated by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%. In some embodiments, the activation of the ATF6 pathway, ATF6, or ATF6α includes activating the expression of ATF6 and / or ATF6α target genes. In some embodiments, the activation of the ATF6 pathway, ATF6, or ATF6α includes activating the expression of ATF6α target genes. In some embodiments, the expression of ATF6 and / or ATF6α target genes is activated by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%. In some embodiments, the inhibition of ATF6 pathway, ATF6, or ATF6α includes inhibiting the expression of ATF6 and / or ATF6α target genes. In some embodiments, the inhibition of ATF6 pathway, ATF6, or ATF6α includes inhibiting the expression of ATF6α target genes. In some embodiments, the expression of ATF6 and / or ATF6α target genes is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%.

[0113] In some embodiments, the ATF6 and / or ATF6α target gene comprises a promoter containing an ER stress response element (ERSE). In some embodiments, the promoter comprises a sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to CCAATCGGCGGCGGCCACG (SEQ ID NO.1). In some embodiments, the promoter comprises SEQ ID NO.1. In some embodiments, the ATF6 and / or ATF6α target gene is GRP78, HERPUD1, or ERO1B. In some embodiments, the ATF6α target gene is GRP78. Regulation, activation or inhibition of the expression of ATF6 and / or ATF6α target genes can be determined by methods known in the art, such as by detecting the mRNA of the target gene using techniques (such as PCR, qPCR, or Northern blot) or by detecting the polypeptide gene product (such as by protein blot or mass spectrometry).

[0114] In some embodiments, the compound, salt or composition thereof modulates, activates or inhibits the ATF6 pathway, ATF6, or the IC of ATF6α. 50Less than about 10 μM, such as less than about 5 μM, 2 μM, 1 μM, 900 nM, 800 nM, 700 nM, or 600 nM. In some embodiments, the compound, salt or composition thereof inhibits the ATF6 pathway, ATF6, or ATF6α by an IC 50 Between about 10 nM and 5 μM, such as between about 50 nM and 2 μM, between 100 nM and 1 μM, or between 20 nM and 1 μM. The half maximal inhibitory concentration (IC 50 ) is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. IC 50 IC is a quantitative measure that indicates how much inhibitor is needed to inhibit a given biological process or component of a process (such as an enzyme, cell, cell receptor, or microorganism) by half. 50 Methods for this are known in the art.

[0115] In some embodiments, the compound as described herein or its salt and the composition as described herein are applied in such an amount that the ATF6β activity is not regulated (activated or inhibited) or is regulated (activated or inhibited) to a lesser extent. In some embodiments, the regulation (activation or inhibition) of ATF6α is at least or at least about 2 times higher than the inhibition of ATF6β activity, for example, at least or at least about 3 times, 4 times, 5 times, 8 times, 10 times, 15 times, 30 times, 50 times, 60 times, 75 times or 100 times higher.

[0116] Provided herein is a method of treating a disease in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or any embodiment, variation or aspect thereof (collectively, a compound of formula (I) or a compound of the invention or a compound detailed or described herein) or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, provided herein is a method for treating a disease mediated by the ATF6 pathway in an individual, the method comprising administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease mediated by activation of the ATF6 pathway in an individual, the method comprising administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease mediated by activation of ATF6 in an individual, the method comprising administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease mediated by activation of ATF6 in an individual, the method comprising administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease mediated by activation of ATF6α in an individual, the method comprising administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, provided herein is a method for treating a disease characterized by activation of the ATF6 pathway in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease characterized by activation of ATF6 in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease characterized by activation of ATF6α in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease characterized by increased expression of an ATF6 target gene in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease characterized by increased expression of an ATF6α target gene in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease characterized by increased expression of an ATF6α target gene in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the increased expression is compared to non-diseased tissue or cells.

[0119] It is believed that the compound of the present invention or its salt effectively treats various diseases and disorders, such as diseases in which the transcriptional targets activated by ATF6 play a role in the pathogenesis or development of the disease. For example, in some embodiments, the compound and composition of the present invention can be used to treat viral infection, cancer, neurodegenerative disease or vascular disease (such as cardiovascular disease). In some embodiments, the disease is viral infection, hereditary cerebellar atrophy and ataxia or Alzheimer's disease. In some embodiments, the disease is type 2 diabetes or diabetic nephropathy. In some embodiments, the disease is myocardial atrophy, heart failure, atherosclerosis or ischemia, such as ischemic heart disease or cerebral ischemia.

[0120] It has been shown that the ATF6 branch of UPR is most important for viral infection. For example, ATF6 is important for maintaining cell viability and regulating immune response during West Nile virus infection (Ambrose R J.Virol. 2013 February 87th Volume 4th Issue 2206-2214). In addition, African swine fever virus activates ATF6 branch to prevent early apoptosis and ensure viral replication (Galindo I, Cell Death Dis July 5, 2012; 3: e341.doi: 10.1038 / cddis.2012.81). Therefore, in some embodiments, compound as described herein or its salt or composition as described herein can be used in the method for treating or preventing viral infection. In some embodiments, viral infection is African swine fever virus, dengue virus, enterovirus, hepatitis B virus, hepatitis C virus, influenza virus, tick-borne encephalitis virus or West Nile virus infection. In some embodiments, viral infection is caused by the virus that activates the ATF6 in infected cells.

[0121] In some embodiments, the compounds described herein or their salts or compositions described herein can be used in methods for treating cancer, such as breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer or adenocarcinoma. In some embodiments, the compounds, salts or compositions can be used in methods for treating metastatic renal cancer, chronic lymphocytic leukemia, pancreatic adenocarcinoma or non-small cell lung cancer.

[0122] ATF6α transcriptional targets are expressed at high levels in cancer cells. For example, there is a correlation between intracellular GRP78 levels and tumor size (Cai, JW, et al., J Cell Physiol, 1993, 154 (2): 229-37). In addition, when GRP78 / BiP expression is experimentally inhibited in cancer cells and then injected into mice, the cells cannot form tumors due to increased sensitivity to cytotoxic T cell (CTL) response and tumor necrosis factor (TNF) (Jamora, C., et al., Proc Natl Acad Sci USA, 1996, 93 (15): 7690-7694; Sugawara, S., et al., Cancer Res, 1993, 53 (24): 6001-6005).

[0123] Cancer cells in cell dormancy lack proliferation markers and exist in a quiescent state. Known cells undergoing cell dormancy include diffuse tumor cells (DTC) and tumor cells located in the circulation (referred to as circulating tumor cells (CTC)) (Hensel, JA, et al., Nat Rev Clin Oncol, 2013, 10 (1): 41-51). Minimal residual disease caused by isolated DTC is a recognized event associated with unfavorable patient prognosis. DTC (usually remaining negative for proliferation markers (e.g., Ki67) staining) may be the source of tumor recurrence that may develop for decades after treating primary tumors (Meng, S., et al., Clin Cancer Res, 2004, 10 (24): 8152-8162). It is reported that ATF6α is a transduction survival signal of dormant cancer cells through the ATF6α-Rheb-mTOR pathway (Schewe, DM et al., Proc Natl Acad Sci USA, 2008, 105 (30): 10519-10524). ATF6α signaling is important for protection against ER and low glucose stress, and the interaction between ATF6α and mTOR signaling appears to confer resistance to doxorubicin and the mTOR inhibitor rapamycin in dormant cancer cells, revealing a potential resistance mechanism (Schewe, DM et al., Proc Natl Acad Sci USA, 2008, 105(30): 10519-10524).

[0124] Furthermore, a multi-cancer study showed that ATF6 expression was higher in metastases compared to primary lesions, and colon cancer patients with increased ATF6α expression in primary tumors had a higher chance of recurrence (Ramaswamy, S., et al., Proc Natl Acad Sci USA, 2001, 98(26): 15149-15154).

[0125] In some embodiments, the compounds described herein or salts thereof or compositions described herein can be used in a method of treating cancer in an individual, wherein one or more cancer cells of the individual are dormant cancer cells. In some embodiments, one or more dormant cancer cells are disseminated tumor cells or circulating tumor cells. In some embodiments, one or more dormant cancer cells are disseminated tumor cells.

[0126] In some embodiments, the compound described herein or its salt or the composition described herein can be used in a method for treating cancer in an individual, wherein the individual has received previous treatment. In some embodiments, the cancer is resistant or refractory to previous treatment. In some embodiments, the cancer has progressed in previous treatment. In the embodiment, the cancer is a recurrent cancer. In some embodiments, the previous treatment is a treatment with the following: ubiquitin proteasome pathway inhibitors (e.g., borzotimib), taxanes (e.g., paclitaxel or docetaxel), Cox-2 inhibitors (e.g., celecoxib), platinum anti-tumor drugs (e.g., cisplatin or oxaliplatin), anthracyclines (e.g., doxorubicin), pyrimidine analogs (e.g., 5-fluorouracil or gemcitabine), topoisomerase inhibitors (e.g., etoposide), mTOR inhibitors (e.g., rapamycin), immune checkpoint inhibitors, or agents for immuno-oncology. In some embodiments, the cancer is resistant to treatment with a ubiquitin proteasome pathway inhibitor (e.g., borzotimib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum antineoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune checkpoint inhibitor, or an agent for immuno-oncology. In some embodiments, the cancer is resistant to treatment with doxorubicin and / or rapamycin.

[0127] In some embodiments, the administration of the compound, salt or composition reduces tumor growth, tumor proliferation or tumorigenicity in the individual. In some embodiments, the compound, salt or composition can be used in a method for reducing tumor growth, tumor proliferation or tumorigenicity in an individual in need. In some embodiments, tumor growth is slowed or stagnant. In some embodiments, tumor growth is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the size of the tumor is reduced. In some embodiments, the size of the tumor is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, tumor metastasis is prevented or slowed. In some embodiments, tumor growth, tumor proliferation or tumorigenicity is compared with tumor growth, tumor proliferation or tumorigenicity in the individual before the administration of the compound, salt or composition. In some embodiments, tumor growth, tumor proliferation, or tumorigenicity is compared to tumor growth, tumor proliferation, or tumorigenicity in a similar individual or group of individuals. Methods of measuring tumor growth, tumor proliferation, and tumorigenicity are known in the art, for example, by repeated imaging of an individual.

[0128] It is believed that the compounds of the present invention or their salts effectively inhibit angiogenesis. The activation of ATF6 and PERK promotes the survival effect of vascular endothelial growth factor (VEGF) on endothelial cells (EC) by positively regulating the phosphorylation of Ser473 by AKT mediated by mTORC2 (which is required for the complete activity of AKT). In mouse Matrigel plugs (standard angiogenesis assay), the depletion of PLCγ, ATF6 or eIF2a significantly inhibited the vascularization induced by VEGF in vivo (Karali, E. et al., Molecular Cell, 2014, 54: 559-572). Therefore, it is believed that the compounds of the present invention or their salts effectively treat various diseases and disorders related to angiogenesis.

[0129] Angiogenesis is implicated in the pathogenesis of a variety of disease disorders, including solid tumors and metastases, atherosclerosis, retrolental fibroplasia, hemangiomas, chronic inflammation, intraocular neovascular diseases such as proliferative retinopathy (e.g., diabetic retinopathy, age-related macular degeneration (AMD), neovascular glaucoma), immune rejection of transplanted corneal tissue and other tissues, rheumatoid arthritis, and psoriasis. Thus, in some embodiments, the compounds and compositions of the invention are used in methods of treating cancer (e.g., any cancer described herein), undesirable or abnormal hypertrophy, arthritis, rheumatoid arthritis (RA), psoriasis, psoriatic plaques, sarcoidosis, atherosclerosis, atherosclerotic plaques, diabetic and other proliferative retinopathy (including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema), corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal / choroidal neovascularization , angular neovascularization (redness), neovascular eye disease, vascular restenosis, arteriovenous malformations (AVMs), meningiomas, hemangiomas, angiofibromas, thyroid hyperplasia (including Graves' disease), corneal and other tissue transplants, chronic inflammation, lung inflammation, acute lung injury / ARDS, sepsis, primary pulmonary hypertension, malignant pulmonary effusions, cerebral edema (e.g., associated with acute stroke / closed head injury / trauma), synovial inflammation, pannus formation in RA, myositis ossificans, hypertrophic bone formation, osteoarthritis (OA), refractory ascites, polycystic ovarian disease, endometriosis, 3rd space humoral disease (3rd space spacing of fluid disease) (pancreatitis, compartment syndrome, burns, intestinal disease), uterine fibroids, premature labor, chronic inflammatory conditions such as IBD (Crohn's disease and ulcerative colitis), renal allograft rejection, inflammatory bowel disease, nephrotic syndrome, unwanted or abnormal tissue mass growth (non-cancer), hemophilic joints, hypertrophic scars, hair growth inhibition, Osler-Weber syndrome, pyogenic granulomatous retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, preeclampsia, ascites, pericardial effusion (such as that associated with pericarditis), and pleural effusion.

[0130] The combination of impaired intestinal barrier defense and microbial dysbiosis appears as a key contributing factor to multiple disorders (including inflammatory bowel disease, type 1 diabetes, Alzheimer's disease and cancer). In particular, in patients with colorectal cancer (CRC), high expression levels of ATF6 in tumor tissue are associated with increased tumor size and reduced disease-free survival. On the other hand, microbial flora changes are associated with CRC. These data show the connection between the activation of UPR, microbial flora and colon tumorigenesis. A novel relationship between UPR activation via ATF6 and microbial flora-dependent colon tumorigenesis has been demonstrated. Before tumor formation, goblet cell loss and bacterial infiltration into epithelial crypts occur, and antibiotic treatment of nATF6IEC mice significantly reduces tumor burden. In the inducible mouse model activated by ATF6, the tumor incidence rate was 100% at week 26. After four days of induction of activated ATF6, the proximity of bacteria to colon epithelium increased significantly, and cell proliferation increased, indicating that these changes are early events downstream of ATF6 activation. Some researchers found that at 5 weeks of age (before the onset of tumorigenesis), there was microbial dysbiosis and reduced microbial diversity in the cecal contents of nATF6IEC mice as assessed by 16S rRNA gene amplicon sequencing. This dysbiotic microbiota enhanced tumor formation after transfer into germ-free nATF6IEC mice compared to control microbiota transferred into nATF6IEC mice. These data suggest that microbial dysbiosis in the epithelium and subsequent STAT3 signaling significantly promote tumorigenesis in this model.

[0131] Thus, in some embodiments, the compounds described herein, or salts thereof, or compositions described herein can be used in methods of preventing or treating CRC by preventing goblet cell loss and dysbiosis by inhibiting ATF6. In some embodiments, the compounds described herein, or salts thereof, or compositions described herein can be used in methods of blocking ATF6 signaling and reversing dysbiosis in a subset of CRC patients to antagonize tumor progression.

[0132] The ability of the UPR signaling arm to significantly affect ER protein homeostasis and function indicates that the selective activation of these pathways has an important potential to alleviate the pathological imbalance of ER protein homeostasis associated with human diseases of various etiologies. In particular, it has been shown that the activation of the ATF6 signaling arm can be used to improve the imbalance of ER protein homeostasis and function associated with disease. The non-stress-dependent activation of the ATF6 transcription factor using a chemical genetics approach induces the protective remodeling of the ER protein homeostasis pathway to selectively reduce the secretion and extracellular aggregation of unstable amyloid disease-related proteins (such as thyroxine transporter and immunoglobulin light chain) without significantly affecting the secretion of the endogenous proteome (Shoulders et al., 2013; Chen et al., 2014; Cooley et al., 2014; Plate et al., 2016). Therefore, the compound described herein or its salt or the composition described herein can be used in a method for correcting the pathological imbalance of ER protein homeostasis in cells and animal models of protein misfolding and aggregation diseases.

[0133] One aspect of the present invention is based on the unexpected discovery that overexpression of ATF6 in a cell prevents cell death that would otherwise occur when unwanted protein accumulation occurs in the cell. Therefore, in some embodiments, the compounds or salts thereof described herein or the compositions described herein can be used in methods for treating disorders associated with abnormal accumulation of molecules, such as Parkinson's disease (PD), which interact with parkin and are not properly disposed of within the cell.

[0134] In some embodiments, the compounds described herein or salts thereof or compositions described herein can be used in methods for preventing cell death. For example, prevention of neuronal cell death is contemplated in the present invention, including prevention of substantia nigra neuronal death in mammals (including humans).

[0135] In some embodiments, the compounds described herein or their salts or compositions described herein can be used in methods for treating neurodegenerative diseases associated with abnormal precipitation and / or aggregation of proteins. For example, the brains of patients with Alzheimer's disease exhibit neurofibrillary tangles (NFTs), senile plaques, and cerebrovascular deposits of amyloid β; the brains of patients with prion disorders exhibit plaques containing prion proteins; the brains of patients with Huntington's disease exhibit huntingtin protein deposits; patients with dominant hereditary spinocerebellar ataxia exhibit corresponding ataxia protein deposits; patients with multiple system atrophy exhibit alpha-synuclein deposits; patients with progressive supranuclear palsy exhibit tau protein deposits; and patients with familial amyotrophic lateral sclerosis exhibit SOD1 deposits (Johnson, WG, J. Anat. 4: 609-616 (2000)). Since these different diseases share common pathological mechanisms, they may share pathways that lead to abnormal aggregation and / or precipitation of proteins (Hardy, J. and Gwinn-Hardy, K., Science 282(5391): 1075-1079 (1998)).

[0136] In some embodiments, the compounds described herein or salts thereof or compositions described herein can be used as a stand-alone therapy or as a combination therapy with other palliative agents (e.g., agents that alleviate the symptoms of the disorder to be treated) and / or agents that target the cause of the disorder. For example, administering to a subject a composition that increases ATF6 expression can be combined with the administration of L-DOPA, a dopamine agonist, a monoamine oxidase B inhibitor, or any other composition that can be used to treat a neurodegenerative disease (e.g., Parkinson's disease).

[0137] It has also been demonstrated that overexpression of active ATF6 transcription factors in the heart improves cardiac performance in ischemic heart disease mouse models through mechanisms involving ATF6-dependent regulation of the antioxidant gene catalase (Jin et al., 2017). Similarly, overexpression of active ATF6 transcription factors in the liver improves insulin sensitivity in obese mice (Ozcan et al., 2016). These results show that ATF6 activation provides unique therapeutic opportunities for improving ER protein homeostasis defects involved in different diseases.

[0138] In some embodiments, the compounds described herein or salts thereof or compositions described herein can be used in methods of promoting recovery from myocardial I / R injury, particularly by activating the endogenous adaptive ATF6 gene program in the heart.

[0139] The ATF6α pathway also plays a role in stress-induced lipid accumulation. In cultured hepatocytes and kidney cells, p50ATF6 interacts with the nuclear form of SREBP-2, thereby antagonizing the transcription of SREBP-2-regulated lipogenic genes and lipid accumulation. Moreover, Atf6α-deficient mice exhibit much longer liver dysfunction and steatosis than wild-type mice in response to pharmacological induction of ER stress. This could be explained by chronic expression of CHOP and sustained repression of C / EBPα and / or a failure of ATF6α-mediated induction of genes encoding protein chaperones, transport, and ERAD functions. When fed a HFD, Atf6α - / - Mice develop hepatic steatosis and glucose intolerance associated with increased expression of SREBP-1c. On the other hand, overexpression of the functionally active nuclear fragment of ATF6 in zebrafish induces fatty liver, suggesting that fine-tuning of ATF6α may be important for preventing hepatic steatosis.

[0140] In some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used in methods of treating metabolic disorders such as obesity, type I and type II diabetes, pancreatitis, dyslipidemia, hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, acute myocardial infarction, hypertension, cardiovascular disease, atherosclerosis, peripheral arterial disease, stroke, heart failure, coronary heart disease, renal disease, diabetic complications, neuropathy, gastroparesis, disorders associated with severe inactivating mutations in the insulin receptor, and other metabolic disorders.

[0141] In some embodiments, the compounds described herein or salts thereof or compositions described herein can be used in methods of treating ischemic heart disease or myocardial ischemia / reperfusion (I / R) recovery.

[0142] According to the present disclosure, in some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, cattle, sheep, pig, horse, dog, cat, rabbit, or rodent. In some embodiments, the individual is a human. In some embodiments, the individual suffers from any disease or disorder disclosed herein. In some embodiments, the individual has a risk of suffering from any disease or disorder disclosed herein.

[0143] Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is used to treat an obstacle or disease as described herein. In some embodiments, the manufacture of a medicament is used to prevent and / or treat an obstacle or disease mediated by an ATF6 pathway, ATF6, or ATF6α. Combination therapy

[0144] As provided herein, the compounds described herein or their salts and compositions described herein can be administered with an agent to treat any disease and disorder disclosed herein. In some embodiments, the agent regulates an unfolded protein response or an integrated stress response. In some embodiments, the agent is an anti-angiogenic agent. In some embodiments, the agent is an anticancer agent. In some embodiments, the agent targets immune checkpoint proteins.

[0145] In some embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein and (b) an agent are administered sequentially, concurrently or simultaneously. In certain embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein and (b) an agent are administered at intervals of about 15 minutes or less (such as any one of about 10 minutes, 5 minutes or 1 minute or less). In certain embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein and (b) an agent are administered at intervals of about 15 minutes or more (such as any one of about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes or more). Any of (a) a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein and (b) an agent may be administered first. In certain embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein and (b) an agent are administered simultaneously.

[0146] In some embodiments, the agent regulates the unfolded protein response or the integrated stress response. In some embodiments, the agent inhibits the unfolded protein response or the integrated stress response. In some embodiments, the agent regulates the PERK pathway. In some embodiments, the agent inhibits the PERK pathway. In some embodiments, the agent inhibits PERK. ATF6 is known to work in cooperation with IRE1, because one of the target genes of ATF6 is XBP1 (a key substrate of IRE1) (Yoshida, H., et al., Cell, 2001, 107 (7): 881-891), for example, ATF6 and IRE1 signaling are important for the survival of melanoma cells undergoing ER stress, which indicates the potential benefits of the combined use of ATF6 inhibitors and IRE1 inhibitors (Tay, KH, et al., Cell Signal, 2014, 26 (2): 287-294). Therefore, in some embodiments, the agent regulates the IRE1 / XBP1 pathway. In some embodiments, the agent inhibits the IRE1 / XBP1 pathway. In some embodiments, the agent inhibits IRE1 or XBP1.

[0147] In some embodiments, the agent is an anti-angiogenic agent. It is believed that the compounds of the present invention or their salts effectively inhibit angiogenesis and treat diseases and disorders associated with angiogenesis. Therefore, a method of inhibiting angiogenesis is provided herein, comprising administering to an individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an anti-angiogenic agent. A method of treating a disease or disorder associated with angiogenesis (such as any disease or disorder associated with angiogenesis disclosed herein) is also provided herein, comprising administering to an individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is a VEGF antagonist. In some embodiments, the anti-angiogenic agent is bevacizumab or ranibizumab.

[0148] The role of angiogenesis as an immunomodulator in the tumor microenvironment has recently begun to become a focus. In addition, emerging evidence indicates that immunotherapy can lead to immune-mediated vascular lesions in tumors, which indicates that the tumor vasculature may be an important interface between the tumor-directed immune response and the cancer itself. The introduction of immune checkpoint inhibition as an effective immunotherapy strategy for many cancers has given people a better understanding of this interface. Preliminary studies on the complex relationship between angiogenesis, VEGF signaling and the immune system have shown that the combination of immune checkpoint blockade and angiogenesis inhibition has potential, and efforts to enhance immunotherapy will widely affect the future of oncology. The effect of ATF6 on VEGF signaling strengthens the idea of ​​using ATF6 inhibitors in combination with immune checkpoint inhibitors (Ott, PA, FS Hodi, and EI Buchbinder, Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data. Front Oncol, 2015.5: Page 202).

[0149] Thus, in some embodiments, the agent targets immune checkpoint proteins. In some embodiments, the agent is an antibody targeting immune checkpoint proteins. In some embodiments, the agent targets PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, CCR4, OX40, OX40L, IDO, and A2AR. In some embodiments, the agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0150] Provided herein is a method for enhancing an individual's immune response, the method comprising administering to the individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein and (b) an agent targeting an immune checkpoint protein. In some embodiments, the individual suffers from cancer. In some embodiments, the enhanced immune response is directed to a tumor or cancer cell.

[0151] Also provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent targeting an immune checkpoint protein, wherein the individual's immune response is increased.

[0152] In some embodiments, the agent is an anticancer agent. In some embodiments, the anticancer agent is a ubiquitin proteasome pathway inhibitor (e.g., borzotimib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum anti-tumor drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent that regulates an unfolded protein response or an integrated stress response (e.g., an IRE1 / XBP1 inhibitor or a PERK inhibitor). In some embodiments, the anticancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anticancer agent is an immune checkpoint inhibitor or an agent for immuno-oncology.

[0153] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to one or more anti-cancer therapies.

[0154] Treatment resistance is a major obstacle to improving the outcome of patients with cancer. Radiation can induce ER stress and its downstream signaling, and appears to be associated with changes in ROS balance secondary to irradiation. Previously, the knockdown of ATF6 was sufficient to enhance radiation-induced cell death (Dadey, DY, et al., Oncotarget, 2016, 7 (2): 2080-2092). This suggests that ATF6 can enhance the efficacy of radiation therapy as a potential therapeutic target.

[0155] In some embodiments, an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein is administered to an individual with cancer to increase sensitivity to radiation. In some embodiments, provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein and (b) radiation.

[0156] In some embodiments, an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein is administered to an individual with cancer to increase sensitivity to one or more anticancer agents. In some embodiments, the anticancer agent is an inhibitor of a ubiquitin proteasome pathway (e.g., borzotimib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum anti-tumor drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent (e.g., IRE1 / XBP1 inhibitor or PERK inhibitor) that regulates an unfolded protein response or an integrated stress response. In some embodiments, the anticancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anticancer agent is an immune checkpoint inhibitor or an agent for immuno-oncology.

[0157] Provided herein is a method for treating a metabolic disease and / or fibrotic disease in an individual, the method comprising administering to the individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein and (b) an agent. In some embodiments, the agent is a proteasome inhibitor, such as bortezomib, carfilzomib, and ixazomib. In some embodiments, the agent is a monoclonal antibody, such as daratumumab and alozumab. In some embodiments, the agent is an inhibitor of histone deacetylase (HDAC) protein, such as panobinostat, romidepsin, and vorinostat. In some embodiments, the agent is an immunomodulatory drug (IMiD), such as thalidomide, lenalidomide, and pomalidomide. In some embodiments, the agent is an adrenocortical steroid, such as dexamethasone, prednisone, prednisolone, and methylprednisolone. In some embodiments, the agent is a therapy targeting IRE1-XBP1. Dosage and administration methods

[0158] The dosage of the compound administered to an individual (such as a human) may vary with the specific compound or salt thereof, the method of administration, and the specific disease being treated (such as the type and stage of cancer). In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.

[0159] In one aspect, the effective amount of the compound can be a dosage between about 0.01mg / kg and about 100mg / kg. The effective amount or dosage of the compound of the present invention can be determined by conventional methods, such as modeling, dose escalation or clinical trials, wherein multiple factors are considered, such as the mode or approach of administration or drug delivery, the pharmacokinetics of the medicament, the severity and course of the disease to be treated, the health status, condition and body weight of the subject. Exemplary dosages are in the range of about 0.1mg to 10g per day.

[0160] In one aspect, any of the methods provided herein can include administering to a subject a pharmaceutical composition containing an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.

[0161] The compound or composition of the present invention can be administered to an individual according to an effective dosing regimen for a desired time period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which may last for the duration of an individual's life in some variations. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (e.g., at least once a day) over a period of time. The frequency of administration can also be less than once a day, such as approximately once a week. The frequency of administration can be more than once a day, such as twice or three times a day. The frequency of administration can also be intermittent, including "drug holidays" (e.g., once a day administration for 7 days, then continued for 7 days without administration, repeating any 14-day time period, such as approximately 2 months, approximately 4 months, approximately 6 months or longer). Any administration frequency can be used with any compound described herein and any dosage described herein.

[0162] Compounds or salts thereof provided herein can be administered to individuals via various approaches, including, for example, intravenous, intramuscular, subcutaneous, oral and transdermal. In some embodiments, the compound or composition is orally administered. Compounds provided herein can be frequently administered at low doses, referred to as "metronomic therapy", or administered as part of a maintenance therapy using a compound alone or in combination with one or more other drugs. Metronomic therapy or maintenance therapy may include cyclic administration of compounds provided herein. Metronomic therapy or maintenance therapy may include intratumoral administration of compounds provided herein.

[0163] Also provided herein are compositions (including pharmaceutical compositions) as described herein and other methods described herein for treating, preventing, and / or delaying the onset and / or development of the diseases described herein.In certain embodiments, the composition comprises a pharmaceutical formulation in unit dosage form. Products and kits

[0164] The disclosure further provides articles comprising compounds of the disclosure described herein or salts thereof, compositions and unit doses in suitable packaging. In certain embodiments, the articles are used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampoules, bottles, cans, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0165] The disclosure further provides a kit for carrying out the method of the disclosure, the kit comprising one or more compounds described herein or a composition comprising a compound described herein. The kit may employ any compound disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kit may be used for any one or more purposes described herein, and accordingly may contain instructions for treating a disease described herein (such as cancer).

[0166] The kit generally comprises suitable packaging. The kit may comprise one or more containers containing any compound described herein. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in one container where cross-reactivity and shelf life permit.

[0167] The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or subunit dosage. For example, a kit containing a sufficient dose of a compound as disclosed herein and / or a second pharmaceutically active compound that can be used for a disease (e.g., hypertension) described herein can be provided to provide effective treatment of an individual for an extended period of time, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or any one of longer periods of time. The kit may also include multiple unit doses of the compound and instructions for use, and be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy).

[0168] The kit may optionally include a set of instructions for use of one or more components of the method of the invention, typically written instructions, but electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable. The instructions included in the kit typically include information about the components and their administration to an individual.

[0169] The invention may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting. Example Synthesis Example

[0170] The following examples are provided to illustrate rather than limit the present disclosure. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selecting appropriate starting materials and reagents to obtain other compounds of formula (I) or salts thereof. The compounds are prepared using the general method described above.

[0171] The following abbreviations are used throughout the examples: DCM (dichloromethane), DIAD (diisopropyl azodicarboxylate), DIPEA or DIEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HPLC (high pressure liquid chromatography), IPA (isopropyl alcohol), LCMS (liquid chromatography mass spectrometry), NMR (nuclear magnetic resonance), PPh 3 (triphenylphosphine), RT (room temperature), TEA (triethylamine), THF (tetrahydrofuran) and TLC (thin layer chromatography). Example S1 Example S1-1. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-1).

[0172] Step 1: Synthesis of 1-(2,6-dichlorophenyl)ethan-1-ol. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-one (1 gm, 5.28 mmol, 1.0 eq.) in methanol (5 mL) was added NaBH in portions at 0 °C. 4 The mixture was stirred for 10 minutes under room temperature at room temperature for 2 hours. The reaction mixture was stirred for 1 hour under room temperature for 2 hours. The product was confirmed to form by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate (50mL × 3). The organic extracts merged were washed with water (50mL × 2) and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain 1-(2,6-dichlorophenyl)ethan-1-ol (990 mg as a colorless liquid), 1 H NMR (400 MHz, DMSO-d 6 )δ7.47-7.63(m,2H),7.30-7.47(m,1H),5.55(br.s.,1H),4.20(br.s.,1H),1.45(d,J=6.58Hz,3H).

[0173] Step 2: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-4-nitro-1H-pyrazole. 3 4-nitro-1H-pyrazole (118.947mg, 1.05mmol, 1 equivalent) and DIAD (413mg, 1.578mmol, 1.5 equivalent) were added to a stirred solution in THF (2mL) and 1-(2,6-dichlorophenyl) 1-ol (200mg, 1.05mmol, 1.0 equivalent) was then added. The resulting reaction mixture was stirred for 1h at RT. The product was confirmed to form with TLC and LCMS. After the reaction was completed, the mixture was diluted with EtOAc (50mL) and washed with water (50mL x 3). The organic layer was purified by Na 2 SO 4 Dry and concentrate under reduced pressure to get the crude product, which was further purified by flash column chromatography to get the pure product 1-(1-(2,6-dichlorophenyl)ethyl)-4-nitro-1H-pyrazole (160 mg), 1 H NMR (400 MHz, DMSO-d 6 )δ9.14(s,1H),8.27(s,1H),7.49(d,J=7.89Hz,2H),7.29-7.44(m,1H),6.13-6.36(m,1H),1.99(d,J=7.02Hz,3H).

[0174] Step 3: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazole-4-amine. To a stirred solution of 1-(1-(2,6-dichlorophenyl)ethyl)-4-nitro-1H-pyrazole (160 mg, 0.6235 mmol, 1 eq.) in 10 mL EtOH / water (1:1) was added Fe (172.5 mg, 3.135 mmol, 5 eq.) and ammonium chloride (175.68 mg, 3.136 mmol, 5 eq.) and allowed to heat at 80 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to give 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazole-4-amine (110 mg), LCMS: 256 [M+H] + .

[0175] Step 4: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine (100 mg) in ethanol was added HCl in ethanol (1 mL) and allowed to stir at RT for 1 h. After completion of the reaction, the reaction mixture was evaporated and lyophilized to give the product 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (125 mg), LCMS: 256 [M+H] + .

[0176] Step 5: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 eq.) in DMF (1 mL) was added HATU (105.5 mg, 0.277 mmol, 1.0 eq.). The mixture was treated dropwise with DIPEA (107.99 ml, 0.831 mmol, 3.0 eq.). After stirring at RT for 15 min, the mixture was treated dropwise with a solution of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (80.55 mg, 0.555 mmol, 1 eq.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. After the reaction was completed, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL x 3). The organic layer was purified by Na 2 SO 4 Dry and concentrate under reduced pressure to obtain a crude product, which was further purified by trituration with acetone hexane (8:2) ml to obtain a precipitate as N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, LCMS: 417 [M+H] + .

[0177] Step 6: Synthesis of (R)-N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide and (S)-N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. The racemic mixture of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide was purified by chiral normal phase HPLC (Daicel HPLC). -IC, 250×20 mm, 5 μm). An isocratic program of HPLC grade n-hexane and HPLC grade isopropanol was used, total flow rate: 56 ml / min, co-solvent percentage: 10% to obtain enantiomer A (12 mg) and enantiomer B (10 mg). LCMS 417 [M+H] + ; Enantiomer A, 1 HNMR (400 MHz, DMSO-d 6 )δppm 11.03 (br.s., 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 7.89 Hz, 2H), 7.34-7.41 (m, 1H), 7.28 (d, J = 3.51 Hz, 1H), 7.12 (s, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 6.11-6.22 (m, 1H), 1.96 (d, J = 7.02 Hz, 3H). Enantiomer B, 1 H NMR (400 MHz, DMSO-d 6 )δ11.02(s,1H),8.11(s,1H),8.01(s,1H),7.66(s,1H),7.49(d,J=7.89Hz,2H),7.34-7.41(m,1H) ,7.29(d,J=3.95Hz,1H),7.14(s,1H),6.78(br.s.,1H),6.10-6.21(m,1H),1.96(d,J=7.45Hz,3H). Example S1-2. Synthesis of N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-2)

[0178] Step 1: Synthesis of 5-chloro-2,3-dihydro-1H-inden-1-ol. To a stirred solution of 5-chloro-2,3-dihydro-1H-inden-1-one (500 mg, 3.01 mmol, 1.0 equiv) in methanol (20 mL) was added NaBH in portions at 0 °C. 4 The mixture was stirred for 10 minutes under room temperature at room temperature for 2 hours.(120mg, 4.518mmol, 1.5 equivalents) and stirred for 10 minutes.Allow the reaction mixture to stir 1 hour at RT.Confirm that the product forms by TLC and NMR.After the reaction is completed, the reaction mixture is quenched with water and extracted with ethyl acetate (3x 50mL), the extracts merged are washed with water (2x 50mL), and the residue is purified by HPLC. 2 SO 4Dried and concentrated under reduced pressure to give 5-chloro-2,3-dihydro-1H-inden-1-ol (500 mg).

[0179] Step 2: Synthesis of 1-bromo-5-chloro-2,3-dihydro-1H-indene. To a stirred solution of 5-chloro-2,3-dihydro-1H-indene-1-ol (500 mg, 2.747 mmol, 1 eq) in DCM (10 mL) was added PBr dropwise at 0 °C. 3 (893 mg, 3.29 mmol, 1.2 eq.). After that, the reaction mixture was stirred at RT for 2 h. 1 HNMR confirmed the formation of the product. After the reaction was complete, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL x 3). The organic layer was purified by Na 2 SO 4 Dry and concentrate under reduced pressure to get crude product, which was further purified by flash column chromatography to get pure product 1-bromo-5-chloro-2,3-dihydro-1H-indenpyrazole (702 mg as brown liquid).

[0180] Step 3: Synthesis of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-pyrazole. To a solution of 4-nitro-1H-pyrazole (300 mg, 1.304 mmol, 1 eq.) in DMF (1 mL) was added K 2 CO 3 The mixture was stirred for 15 minutes and then treated with 1-bromo-5-chloro-2,3-dihydro-1H-indene (147 mg, 1.304 mmol, 1 equivalent) in DMF (10 mL). The reaction mixture was stirred for 24 h. The product was confirmed to be formed by TLC and LCMS and the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was purified by Na 2 O 4 '-trifluoroacetic acid (40 mL) and 4 '-trifluoroacetic acid (40 mL). 2 SO 4 Dry and concentrate under reduced pressure to get the crude product, which was further purified by flash column chromatography to get pure 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-pyrazole (225 mg as white solid), 1 H NMR (400 MHz, DMSO-d 6)δ9.00(s,1H),8.27(s,1H),7.43(s,1H),7.25(d,J=8.77Hz,1H),7.17(d,J=8.33Hz,1H),5. 92-6.03(m,1H),3.14-3.24(m,1H),2.90-3.04(m,1H),2.62-2.73(m,2H),2.41-2.48(m,1H).

[0181] Step 4: Synthesis of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine. To a stirred solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-pyrazole (150 mg, 0.566 mmol, 1 eq.) in 10 mL of EtOH / water (1:1) was added Fe (155.66 mg, 2.83 mmol, 5 eq.) and ammonium chloride (158 mg, 2.83 mmol, 5 eq.) and allowed to heat at 80°C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the filtrate was evaporated and extracted with DCM (100 ml x 2), the organic layers were collected and evaporated under reduced pressure to give 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (180 mg), LCMS: 234 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δ7.38(s,1H),7.21(d,J=6.14Hz,1H),7.02(d,J=8.33Hz,1H),6.97(s,1H),6.93(s ,1H),5.62-5.70(m,1H),3.85(br.s.,2H),3.02-3.13(m,1H),2.83-2.96(m,1H),).

[0182] Step 5: Synthesis of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (180 mg) in ethanol (1 mL) was added 4M HCl in ethanol (2 ml) at RT for 2 h. The results were analyzed by TLC and 1 HNMR confirmed product formation. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was further ground with ether and lyophilized to obtain the pure product 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-4-amine hydrochloride (150 mg, brown solid). 1H NMR (400 MHz, DMSO-d 6 )δ10.07(br.s.,2H),8.01(s,1H),7.56(s,1H),7.43(s,1H),7.25(d,J=8.33Hz,1H),7.05(d,J=8.33Hz,1H),5.87-6.0 1(m,1H),3.07-3.19(m,1H),2.95(td,J=7.73,15.68Hz,1H),2.63(dtd,J=5.26,8.17,13.48Hz,1H),2.28-2.43(m,2H).

[0183] Step 6: Synthesis of N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 eq.) in DMF (1 mL) was added HATU (105.8 mg, 0.277 mmol, 1 eq.). The mixture was treated dropwise with DIPEA (107.5 mg, 0.833 mmol, 3 eq.). After stirring at RT for 15 min, the mixture was treated dropwise with a solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine hydrochloride (64.722 mg, 0.277 mmol, 1 eq.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. The product formation was confirmed by TLC and LCMS and the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was purified by Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to afford the crude product, which was further purified by flash column chromatography to afford pure N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (50 mg, as a white solid), LCMS: 395 [M+H] + , 1 HNMR (400 MHz, DMSO-d 6)δ11.01(s,1H),8.07(s,1H),8.00(s,1H),7.66(s,1H),7.42(s,1H),7.2 8(d,J=3.07Hz,1H),7.24(d,J=7.89Hz,1H),7.14(s,1H),7.07(d,J=7.89H z,1H),6.77(dd,J=1.75,3.51Hz,1H),5.84-5.94(m,1H),3.04-3.20(m,H 1), 2.94 (td, J = 7.67, 15.35Hz, 1H), 2.56-2.70 (m, 1H), 2.28-2.42 (m, 1H).

[0184] Step 7: Separation of isomers of N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. Enantiomers of N-(1-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (50 mg, elution time 14.12 min and 15.87 min) were separated by chiral SFC (Daicel Chiralpak-IC 250×20 mm, 5 μm). An isocratic program using analytical grade liquid carbon dioxide and HPLC grade methanol, total flow rate: 4 g / min, co-solvent percentage: 40%, was used to obtain the first eluting enantiomer, Enantiomer A (8 mg), LCMS: 395 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(s,1H),8.07(s,1H),8.00(s,1H),7.66(s,1H),7.42(s,1H),7.28(d,J=3.0 7Hz,1H),7.24(d,J=7.89Hz,1H),7.14(s,1H),7.07(d,J=7.89Hz,1H),6.77(dd,J=1 .75,3.51 Hz,1H), 5.84-5.94 (m,1H), 3.04-3.20 (m,1H), 2.94 (td, J=7.67,15.35 Hz,1H), 2.56-2.70 (m,1H), 2.28-2.42 (m,1H) and the second eluting enantiomer, Enantiomer B (8 mg), LCMS: 395 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6)δ11.01(s,1H),8.07(s,1H),8.00(s,1H),7.66(s,1H),7.43(s,1H),7.2 8(d,J=3.07Hz,1H),7.24(d,J=10.09Hz,1H),7.14(s,1H),7.07(d,J=7.89 Hz,1H),6.77(dd,J=1.75,3.51Hz,1H),5.88-5.94(m,1H),3.07-3.20(m,1 H), 2.94 (td, J = 7.73, 15.68Hz, 1H), 2.55-2.69 (m, 1H), 2.29-2.44 (m, 1H). Example S1-3. Synthesis of 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (Compound 1-3).

[0185] Step 1: Synthesis of 1,2,3,4-tetrahydronaphthalen-1-ol. To a stirred solution of 3,4-dihydronaphthalen-1(2H)-one (500 mg, 3.4 mmol, 1.0 eq.) in methanol (20 mL) was added NaBH in portions at 0 °C. 4 The mixture was stirred for 10 minutes under room temperature at room temperature for 2 hours. The reaction mixture was stirred for 1 hour under room temperature for 2 hours. The product was confirmed to form by TLC and NMR. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate (3x50 mL). The organic extracts merged were washed with water (2x 50 mL), and the mixture was dried over anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure to obtain 1,2,3,4-tetrahydronaphthalen-1-ol (500 mg).

[0186] Step 2: Synthesis of 1-bromo-1,2,3,4-tetrahydronaphthalene. To a stirred solution of 1,2,3,4-tetrahydronaphthalene-1-ol (500 mg, 3.37 mmol, 1 eq.) in DCM (10 mL) was added PBr dropwise at 0 °C. 3 (1098 mg, 4.05 mmol, 1.2 eq.). Afterwards, the reaction mixture was stirred at RT for 2 h. 1 HNMR confirmed the formation of product. After the reaction was completed, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL x 3). The organic layer was purified by Na 2 SO 4Dry and concentrate under reduced pressure to get crude product which was further purified by flash column chromatography to get pure 1-bromo-1,2,3,4-tetrahydronaphthalene (632 mg crude as brown liquid). 1 H NMR (400 MHz, DMSO-d 6 ): δ8.61(d,J=5.26Hz,1H),8.15(d,J=7.45Hz,2H),7.50-7.63(m,1H),5.88(d,J=4 .38Hz,1H),,3.18-3.34(m,2H),3.01-3.15(m,2H),2.76(td,J=7.56,14.69Hz,2H).

[0187] Step 3: Synthesis of 4-nitro-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole. To a solution of 4-nitro-1H-pyrazole (161.4 mg, 1.428 mmol, 1 eq.) in DMF (1 mL) was added K 2 CO 3 The mixture was stirred for 15 minutes and the mixture was treated dropwise with 1-bromo-1,2,3,4-tetrahydronaphthalene (300 mg, 1.428 mmol, 1 equivalent) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. The product was confirmed to form with TLC and LCMS and the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was purified by Na 2 SO 4 Dry and concentrate under reduced pressure to get crude product which was further purified by flash column chromatography to get pure 4-nitro-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole (250 mg as white solid), 1 H NMR (400 MHz, DMSO-d 6 ): 1 H NMR (400 MHz, DMSO-d 6 )δ8.98(s,1H),8.26(s,1H),7.26-7.41(m,2H),7.11-7.26(m,2H),5.93-6.06(m, 1H),3.07-3.20(m,1H),2.90-3.03(m,1H),2.60-2.71(m,2H),2.40-2.48(m,2H).

[0188] Step 4: Synthesis of 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine. To a stirred solution of 4-nitro-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole (150 mg, 0.617 mmol, 1 eq.) in 10 mL of EtOH / water (1:1) was added Fe (169.7 mg, 3.085 mmol, 5 eq.) and ammonium chloride (172 mg, 3.085 mmol, 5 eq.) and allowed to heat at 80°C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the filtrate was evaporated and extracted with DCM (100 ml x 2), the organic layers were collected and evaporated under reduced pressure to give 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine (121 mg), LCMS: 214 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ): 1 H NMR (400 MHz, DMSO-d 6 )δ7.38(s,1H),7.16-7.28(m,1H),6.92-7.07(m,4H),5.57-5.74(m,1H),3. 90-3.82(br,2H),2.89-3.10(m,2H),2.83-2.89(m,2H),2.25-2.39(m,2H).

[0189] Step 5: Synthesis of 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine hydrochloride. To a solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (120 mg) in ethanol (1 mL) was added 4M HCl in ethanol (2 ml). The reaction mixture was analyzed by TLC and 1 HNMR confirmed product formation. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was further ground with ether and lyophilized to obtain the pure product 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole-4-amine hydrochloride (123 mg, brown solid). 1 H NMR (400 MHz, DMSO-d 6): δ10.16(br.s.,2H),7.81(s,1H),7.58(s,1H),7.14-7.27(m,2H),7.11(t,J=7.24Hz,1H),6.73( d,J=7.89Hz,1H),5.63(t,J=6.58Hz,1H),2.69-2.94(m,2H),2.10-2.26(m,2H),1.71-1.91(m,2H).

[0190] Step 6: Synthesis of 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 eq.) in DMF (1 mL) was added HATU (105.8 mg, 0.277 mmol, 1 eq.). The mixture was treated dropwise with DIPEA (107.5 mg, 0.833 mmol, 3 eq.). After stirring at RT for 15 min, the mixture was treated dropwise with a solution of 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine hydrochloride (68.88 mg, 0.277 mmol, 1 eq.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. The product formation was confirmed by TLC and LCMS and the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was purified by Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to afford the crude product, which was further purified by flash column chromatography to afford pure 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (40 mg, 42.59%, as a white solid), LCMS: 375 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.00(s,1H),8.00(s,1H),7.89(s,1H),7.69(s,1H),7.23-7.32(m,1H),7.15-7.23(m,2H),7.04-7.15(m,2H ),6.68-6.83(m,2H),5.52-5.66(m,1H),2.84-3.00(m,1H),2.71-2.82(m,1H),2.17(br.s.,2H),1.84(br.s,2H). Example S1-4. Synthesis of N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-4).

[0191] Step 1: Synthesis of 1-(2-chloro-6-fluorophenyl)ethan-1-ol. To a stirred solution of 1-(2-chloro-6-fluorophenyl)ethan-1-one (1 gm, 5.8 mmol, 1.0 eq.) in methanol (5 mL) was added NaBH in portions at 0°C. 4 The mixture was stirred for 10 minutes under room temperature at room temperature for 2 hours. The reaction mixture was stirred for 1 hour under room temperature for 2 hours. The product was confirmed to form by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate (50mL × 3). The organic extracts merged were washed with water (50mL × 2) and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain 1-(2-chloro-6-fluorophenyl)ethan-1-ol (1 gm as colorless liquid).

[0192] Step 2: Synthesis of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-4-nitro-1H-pyrazole. 3 4-nitro-1H-pyrazole (260mg, 2.29mmol, 1 equivalent) and DIAD (0.669ml, 3.44mmol, 1.0 equivalent) were added to a stirred solution in THF (2mL) and 1-(2-chloro-6-fluorophenyl) 2-ethanol (400mg, 2.29mmol, 1.0 equivalent). The resulting reaction mixture was stirred for 1h at RT. Confirm product formation with TLC and LCMS. After the reaction was complete, the mixture was diluted with EtOAc (50mL) and washed with water (50mL x 3). The organic layer was purified by Na 2 O 4 '-trifluoroacetic acid (400mg, 2.29mmol, 1.0 equivalent). 2 SO 4 Dry and concentrate under reduced pressure to get the crude product which was further purified by flash column chromatography to get the pure product 1-(1-(2-chloro-6-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (320 mg).

[0193] Step 3: Synthesis of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazole-4-amine. To a stirred solution of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (200 mg, 0.743 mmol, 1 eq.) in 10 mL EtOH / water (1:1) was added Fe (200 mg, 3.71 mmol, 5 eq.) and ammonium chloride (208 mg, 3.71 mmol, 5 eq.) and allowed to heat at 80 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazole-4-amine (170 mg), LCMS: 240 [M+H] + .

[0194] Step 4: Synthesis of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine (150 mg) in ethanol was added HCl in ethanol (1 mL) and allowed to stir at RT for 1 h. After 1 hour the reaction mixture was evaporated and lyophilized to give the product 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (155 mg). LCMS: 240 [M+H] + .

[0195] Step 5: Synthesis of N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 eq.) in DMF (1 mL) was added HATU (105.5 mg, 0.277 mmol, 1.0 eq.) and DIPEA (107.99 ml, 0.831 mmol, 3.0 eq.). After stirring at room temperature for 15 min, a solution of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (77 mg, 0.555 mmol, 1 eq.) in DMF (1 mL) was added. The reaction mixture was kept under stirring for 24 h. After the reaction was completed, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL x 3). The organic layer was purified by Na 2 SO 4Dry and concentrate under reduced pressure to obtain a crude product, which was further purified by trituration with acetone: hexane (8:2) to give a precipitate as N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg). LCMS: 401 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.01(s,1H),8.14(s,1H),8.00(d,J=1.32Hz,1H),7.64(s,1H),7.35-7.48(m,2H),7.19-7.33( m, 2H), 7.14 (s, 1H), 6.77 (dd, J = 1.75, 3.51Hz, 1H), 6.02 (q, J = 7.31Hz, 1H), 1.92 (d, J = 7.45Hz, 3H). Example S1-5. Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-5)

[0196] Step 1: Synthesis of 1-(2,4-difluorophenyl)ethan-1-ol. To a stirred solution of 1-(2,4-difluorophenyl)ethan-1-one (1 gm, 6.4 mmol, 1.0 eq.) in methanol (5 mL) was added NaBH in portions at 0 °C. 4 The mixture was stirred for 10 minutes under room temperature at room temperature for 2 hours. The reaction mixture was stirred for 1 hour under room temperature for 2 hours. The product was confirmed to form by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate (50mL × 3). The organic extracts merged were washed with water (50mL × 2) and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain 1-(2,4-difluorophenyl)ethan-1-ol (1 gm as colorless liquid). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.45-7.61(m,1H),7.00-7.20(m,2H),5.33(d,J=4.38Hz,1H),4.87-5.00(m,1H),1.31(d,J=6.58Hz,3H).

[0197] Step 2: Synthesis of 1-(1-(2,4-difluorophenyl)ethyl)-4-nitro-1H-pyrazole. 34-nitro-1H-pyrazole (286mg, 2.53mmol, 1 equivalent) and DIAD (0.511ml, 2.53mmol, 1.0 equivalent) were added to a stirred solution in THF (2mL), followed by addition of 1-(2,4-difluorophenyl) 2-ethanol (400mg, 2.53mmol, 1.0 equivalent). The resulting reaction mixture was stirred for 1h at RT. Confirm product formation with TLC and LCMS. After the reaction was complete, the mixture was diluted with EtOAc (50mL) and washed with water (50mL x 3), and the organic layer was purified by Na 2 SO 4 Dry and concentrate under reduced pressure to get the crude product, which was further purified by flash column chromatography to get the pure product 1-(1-(2,4-difluorophenyl)ethyl)-4-nitro-1H-pyrazole (170 mg), 1 H NMR (400 MHz, DMSO-d 6 ): δ9.10(s,1H),8.30(s,1H),7.51(dd,J=2.63,8.77Hz,1H),7.42(dd,J=6.14,8.77H z, 1H), 7.26 (dt, J = 2.41, 8.44Hz, 1H), 6.00 (q, J = 6.87Hz, 1H), 1.83 (d, J = 7.02Hz, 3H).

[0198] Step 3: Synthesis of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazole-4-amine. To a stirred solution of 1-(1-(2,4-difluorophenyl)ethyl)-4-nitro-1H-pyrazole (100 mg, 0.395 mmol, 1 eq.) in 10 mL EtOH / water (5:5) was added Fe (106 mg, 1.976 mmol, 5 eq.) and ammonium chloride (111 mg, 1.976 mmol, 5 eq.) and allowed to heat at 80 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazole-4-amine (89 mg). LCMS: 224 [M+H] + .

[0199] Step 4: Synthesis of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine (89 mg) in ethanol was added HCl in ethanol (1 mL) and allowed to stir at RT for 1 h. After completion of the reaction, the reaction mixture was evaporated and lyophilized to give the product 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (60 mg), LCMS: 224 [M+H] + .

[0200] Step 5: Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (31.09 mg, 0.171 mmol, 1 eq.) in DMF (1 mL) was added HATU (65.2 mg, 0.171 mmol, 1.0 eq.) and DIPEA (0.089 ml, 0.515 mmol, 3.0 eq.). After stirring at RT for 15 min, a solution of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (50 mg, 0.171 mmol, 1 eq.) in DMF (1 mL) was added dropwise. The reaction mixture was kept under stirring for 24 h. After the reaction was completed, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL x 3). 2 SO 4 Dry and concentrate under reduced pressure to obtain a crude product, which was further purified by trituration with acetone hexane (8:2) ml to obtain a precipitate as N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg). LCMS: 385 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.02(s,1H),8.14(s,1H),8.00(d,J=0.88Hz,1H),7.69(s,1H),7.22-7.38(m,3H),7.14(s,1H) ,7.03-7.10(m,1H),6.77(dd,J=1.75,3.51Hz,1H),5.85(q,J=7.02Hz,1H),1.80(d,J=7.02Hz,3H). Example S1-6. Synthesis of N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-6).

[0201] Step 1: Synthesis of 1-(2-chloro-4-fluorophenyl)ethan-1-ol. To a stirred solution of 1-(2-chloro-4-fluorophenyl)ethan-1-one (0.5 gm, 3.205 mmol, 1.0 eq.) in methanol (5 mL) was added NaBH in portions at 0°C. 4 The mixture was stirred for 10 minutes under room temperature at room temperature for 2 hours.The reaction mixture was stirred for 1 hour under room temperature for 2 hours.The product was confirmed to form by TLC and LCMS.After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate (50mL × 3), the organic extracts merged were washed with water (50mL × 2), and the residue was purified by HPLC. 2 SO 4 Dry and concentrate under reduced pressure to obtain 1-(2-chloro-4-fluorophenyl)ethan-1-ol (0.4 gm as colorless liquid). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.43-7.64(m,1H),6.97-7.19(m,2H),5.33(d,J=4.38Hz,1H),4.84-5.00(m,1H),1.31(d,J=6.58Hz,3H).

[0202] Step 2: Synthesis of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole. 3 4-nitro-1H-pyrazole (260mg, 2.29mmol, 1 equivalent) and DIAD (0.460mg, 2.29mmol, 1 equivalent) were added to a stirred solution in THF (2mL) and 1-(2-chloro-4-fluorophenyl) 2-ethanol (400mg, 2.29mmol, 1.0 equivalent). The resulting reaction mixture was stirred for 1h at RT. Confirm product formation with TLC and LCMS. After the reaction was complete, the mixture was diluted with EtOAc (50mL) and washed with water (50mL × 3), and the organic layer was purified by Na 2 SO 4 Dry and concentrate under reduced pressure to get the crude product which was further purified by flash column chromatography to get the pure product 1-(1-(2-chloro-4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (220 mg), 1H NMR (400 MHz, DMSO-d 6 ): δ9.10(s,1H),8.30(s,1H),7.51(dd,J=2.63,8.77Hz,1H),7.42(dd,J=6.14,8.77H z, 1H), 7.26 (dt, J = 2.41, 8.44Hz, 1H), 6.00 (q, J = 6.87Hz, 1H), 1.83 (d, J = 7.02Hz, 3H).

[0203] Step 3: Synthesis of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazole-4-amine. To a stirred solution of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (100 mg, 0.395 mmol, 1 eq.) in 10 mL EtOH / water (1:1) was added Fe (107 mg, 1.97 mmol, 5 eq.) and ammonium chloride (111 mg, 1.976 mmol, 5 eq.) and allowed to heat at 80°C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazole-4-amine (89 mg), 1 H NMR (400 MHz, DMSO-d 6 ): δ7.15-7.24(m,1H),6.97-7.15(m,2H),6.93(s,1H),5.74(br.s.,1H),5.59(m,J=6.58Hz,1H),3.82(br.s.,2H),1.68(d,J=7.45Hz,3H).

[0204] Step 4: Synthesis of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazole-4-amine hydrochloride. To a stirred solution of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazole-4-amine (118 mg) in ethanol was added HCl in ethanol (2 mL) and allowed to stir at room temperature for 1 h. The reaction mixture was evaporated and lyophilized to give the product 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazole-4-amine hydrochloride (80 mg). 1 H NMR (400 MHz, DMSO-d 6): δ9.9(s,2H),8.04(s,1H),7.60(s,1H),7.49(dd,J=2.63,8.77Hz,1H),7.18-7.41(m,2H),5.95(q,J=6.87Hz,1H),1.78(d,J=7.02Hz,3H).

[0205] Step 5: Synthesis of N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (32.72 mg, 0.181 mmol, 1 eq.) in DMF (1 mL) was added HATU (69.72 mg, 0.181 mmol, 1.0 eq.) and DIPEA (0.094 ml, 0.54 mmol, 3.0 eq.). After stirring at RT for 15 min, a solution of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (50 mg, 0.181 mmol, 1 eq.) in DMF (1 mL) was added. The reaction mixture was kept under stirring for 24 h. After the reaction was completed, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL x 3). 2 SO 4 Dry and concentrate under reduced pressure to obtain a crude product, which was further purified by trituration with acetone hexane (8:2) ml to obtain a precipitate as N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg). LCMS: 401 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.04(s,1H),8.14(s,1H),8.00(d,J=1.75Hz,1H),7.71(s,1H),7.46-7.55(m,1H),7.19-7.30( m,3H),7.14(s,1H),6.77(dd,J=1.75,3.51Hz,1H),5.91(q,J=6.87Hz,1H),1.79(d,J=7.02Hz,3H).

[0206] Example S1-7. Synthesis of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (Compound 1-11).

[0207] Step 1: Synthesis of N'-hydroxypyrazine-2-carboximidamide. To a mixture of pyrazine-2-carbonitrile (1 gm, 9.5 mmol, and 1 eq.) was added NH 2 OH.HCl (1.32 gm, 0.018 mol, 2 eq.) was added with Na 2 CO 3 (2 gm, 0.018 mole, 2 eq.). The reaction mixture was refluxed for 16 hours. The reaction mixture was cooled to RT. The obtained suspension was filtered off. The obtained precipitate was identified as our product N′-hydroxypyrazine-2-carboximidamide (1.1 gm, white precipitate). 1 H NMR (400 MHz, DMSO-d 6 )δ10.23(s,1H),9.06(d,J=0.88Hz,1H),8.63(q,J=2.63Hz,2H),5.95(br.s.,2H).

[0208] Step 2: Synthesis of N-hydroxypyrazine-2-carboximidoyl chloride. N'-hydroxypyrazine-2-carboximidamide (200 mg, 1.449 mmol, and 1 equivalent) was reacted with H at 0 °C. 2 To a solution of 1% N-butylene oxide (256.34 mg, 4.34 mmol, and 3 equivalents), 0.1 N HCl (0.4 ml) and acetic acid (1 ml) were added. The reaction mixture was stirred until it became transparent. NaNO 2 (100 mg, 1.449 mmol, and 1 equivalent) and kept stirring at zero degrees Celsius for half an hour. And the obtained suspension was filtered off. The obtained precipitate was confirmed to be our product N-hydroxypyrazine-2-carbonimidoyl chloride (180 mg, white precipitate). 1 H NMR (400 MHz, DMSO-d 6 )δ13.04(s,1H),9.09(s,1H),8.70-8.78(m,2H).

[0209] Step 3: Synthesis of ethyl 3-(pyrazin-2-yl)isoxazole-5-carboxylate. To a mixture of N-hydroxypyrazine-2-carboximidoyl chloride (100 mg, 0.632 mmol, 1 eq.) and ethyl propionate (124.05 mg, 1.265 mmol, 2 eq.) in DCM (20 mL) was added K in portions at room temperature over 60 min. 2 CO 3To the solution of (218.3mg, 2.5 mmoles, 2 equivalents) in DCM (20mL). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was concentrated to dryness, and processed by adding water (10ml), and extracted with ethyl acetate (2X 25ml X 2 times), which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane to obtain 3- (pyrazine-2-yl) isoxazole-5-ethyl formate (80mg) as a white solid. LCMS: 220 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δ9.27-9.39(m,1H),8.76-8.92(m,2H),7.82(s,1H),4.42(q,J=7.02Hz,2H),1.36(t,J=7.24Hz,H 3H).

[0210] Step 4: Synthesis of 3-(pyrazine-2-yl)isoxazole-5-carboxylic acid. To a solution of ethyl 3-(pyrazine-2-yl)isoxazole-5-carboxylate (60 mg, 0.272 mmol, 1 eq.) in THF (2 mL) and water (2 mL) was slowly added lithium hydroxide (13.05 mg, 0.326 mmol, 1.2 eq.). The resulting mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was acidified with 1N HCl and the obtained suspension was lyophilized. The obtained crude product was ground with ether. The obtained precipitate (ppt.) 3-(pyrazine-2-yl)isoxazole-5-carboxylic acid was our product (52 mg, off-white solid). LCMS: 192 [M+H] + .

[0211] Step 5: Synthesis of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide. To a solution of 3-(pyrazin-2-yl)isoxazole-5-carboxylic acid (50 mg, 0.2613 mmol, 1 eq.) in DMF (2 mL) was added HATU (100.2 mg, 0.261 mmol, 1 eq.). The mixture was treated dropwise with DIPEA (0.183 ml, 0.783 mmol, 3 eq.). After stirring at RT for 15 min, the mixture was treated dropwise with a solution of 1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-amine (84.56 mg, 0.261 mmol, 1 eq.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. Reactant mixture is diluted with water (50mL).Gained precipitate is filtered out.The crude material obtained is purified by grinding with DCM: hexane (2:8) using the flash silica gel chromatography of the mixture of ethyl acetate in hexane to obtain N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazine-2-yl)isoxazole-5-carboxamide (40mg).LCMS:497[M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δ11.23(s,1H),9.32(s,1H),8.85(d,J=7.02Hz,2H),8.21(s,1H),8.02-8.1 2(m,2H),7.74-7.81(m,3H),5.95(m,J=7.02Hz,1H),1.88(d,J=6.58Hz,3H).

[0212] Example S1-8. Synthesis of 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (Compound 1-12).

[0213] Step 1: Synthesis of 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol. To a stirred solution of 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (300 mg, 1.5 mmol, 1 eq.) in 5 mL of MeOH was added NABH in portions. 4To the 4-hydroxy-2-(4-(trifluoromethyl)-2-yl)-1-nitropropene-2-ol (5-(trifluoromethyl)-2-yl)-1-nitropropene-2-ol) was added 4-(trifluoromethyl)-2-yl)-1-nitropropene-2-ol (88.87 mg, 2.25 mmol, 1.5 eq) and allowed to stir for 1 h at RT. The reaction mixture was concentrated and extracted with ethyl acetate and water (2x25 mL). The organic layer was collected and evaporated to give 5-(trifluoromethyl)-2,3-dihydro-1H-indene-1-ol. 1 H NMR (400 MHz, DMSO-d 6 )δppm 7.49-7.60(m,3H)5.46(d,J=6.14Hz,1H)5.09(q,J=6.43Hz,1H)2.98(ddd,J=16.01,8 .55,3.51Hz,2H)2.78(dt,J=15.90,8.06Hz,1H)2.33-2.43(m,2H)1.75-1.87(m,1H).

[0214] Step 2: Synthesis of 4-nitro-1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole. 3 To the stirred solution of 4-nitro-1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazoles (583.60mg, 2.227mmol, 1.5 equivalents) and DIAD (449.95mg, 2.227mmol, 1.5 equivalents) in THF (10mL), 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol (300mg, 1.485mmol, 1 equivalent) and 4-nitro-1H-pyrazoles (167.82mg, 1.485mmol, 1 equivalent) were added and allowed to stir for 16h at RT. The reaction process was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and water (2x 25mL), the organic layer was separated and evaporated under reduced pressure to obtain a crude product, which was further purified by using Combi-flash chromatography to obtain 4-nitro-1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazoles. LCMS: 297 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δppm 9.11(s,1H)8.49(s,1H)7.68-7.74(m,2H)7.50(dd,J=5.04,1.97Hz,3H)7.38-7.41(m,1H).

[0215] Step 3: Synthesis of 1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole-4-amine. To a stirred solution of 4-nitro-1-(2,2,2-trifluoro-1-phenylethyl)-1H-pyrazole (200 mg, 0.738 mmol, 1 eq.) in 10 mL EtOH / water (1:1) was added Fe (202.95 mg, 3.69 mmol, 5 eq.) and ammonium chloride (195.57 mg, 3.69 mmol, 5 eq.) and allowed to heat at 80 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated and extracted with DCM / water (2 x 25 mL). The organic layers were collected and evaporated under reduced pressure to give 1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine. LCMS: 268 [M+H] + .

[0216] Step 4: Synthesis of 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide. To a stirred solution of 5-(pyrazin-2-yl)isoxazole-3-carboxylic acid (100 mg, 0.524 mmol, 1 eq) in DMF (4 mL) was added HATU (199.12 mg, 0.524 mmol, 1 eq) and allowed to stir at RT for 15 min. Then. A stirred solution of 1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (140 mg, 0.524 mmol, 1 eq) and DIPEA (202.72 mg, 1.572 mmol, 3 eq) was added. The reaction mixture was allowed to stir at RT for 18 h. After the reaction was complete, the reaction mixture was poured into ice-cold water; the precipitate obtained was filtered off to obtain a crude product, which was purified by using Combi flash chromatography to obtain 5-(pyrazine-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-indene-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (30 mg white solid). LCMS: 441 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6)δppm 11.12(s,1H)9.35(s,1H)8.82(s,1H)8.85(s,1H)8.18(s,1H)7.65-7.75(m,3H)7.55(d,J=7.89Hz ,1H)7.24(d,J=7.89Hz,1H)6.04(t,J=6.58Hz,1H)3.20(d,J=4.82Hz,2H)3.03(d,J=8.33Hz,2H).

[0217] Example S1-9. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide (Compound 1-13).

[0218] Step 1: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide. To a stirred solution of 5-(thiophen-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.256 mmol, 1.0 eq) in DMF (2 ml) was added HATU (97 mg, 0.256 mmol, 1.0 eq) and stirred at room temperature for 15 min. 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine (65 mg, 0.256 mmol, 1.0 eq) was added to the reaction mixture followed by DIPEA (0.13 mL, 0.769 mmol, 3.0 eq) and stirred again at room temperature for 1 h. The progress of the reaction was analyzed by TLC, LCMS. After the reaction was completed, the RM was poured into ice-cold water, filtered and purified using flash chromatography to obtain N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide, LCMS mass [M+1]: 433.3, 1H NMR (400 MHz, DMSO-d 6 )δppm 10.99(s,1H)8.11(s,1H)7.83(s,1H)7.90(s,1H)7.66(s,1H)7.38(d,J=8.33 Hz, 2H) 7.17 (s, 1H) 7.30 (s, 2H) 6.17 (d, J = 7.02Hz, 1H) 1.96 (d, J = 7.45Hz, 3H).

[0219] Example S1-10. Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-14 and Compound 1-15).

[0220] The racemic mixture of N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg) was purified by chiral HPLC to obtain N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide as the first eluting isomer (Compound 1-14) and the second eluting isomer (Compound 1-15). The isomers were separated by chiral SFC (Daicel Chiralpak-IA, 250x20mm, Sum). An isocratic program using analytical grade liquid carbon dioxide and HPLC grade isopropanol was used, total flow rate: 56 g / min, co-solvent percentage: 20%.

[0221] Compound 1-14: yield = 4 mg; elution time = 9.01 min. Compound 1-15: yield = 4 mg; elution time = 17.68 min.

[0222] Compound 1-14: LCMS: 401 [M+1]; 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(S,1H),8.14(S,1H),8.01(S,1H),7.64(S,1H),7.39(m,2H),7.29(m,J=3.51Hz,2H),7.14(5,1H),6.78@5.,1H),6.02(m,1H),1.92(d,J=6.58Hz,3H).Compound 1-15:LCMS:401[M+H] + ; 1 HNMR (400 Hz, DMSO-d 6 )m 11.01(5,1H),8.14(5,1H),8.00(s,1H),7.64(s,1H),7.36-7.44(m,2H),7.20 -7.30(m,2H),7.14(5,1H),6.77(m,1H),6.04(m,1H),1.92(d,J=6.14Hz,3H).

[0223] Example S1-11. Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-16 and Compound 1-17).

[0224] The racemic mixture of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg) was purified by chiral HPLC to obtain N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide as the first eluting isomer (compound 1-16) and the second eluting isomer (compound 1-17). The enantiomers were separated by chiral SFC (Daicel Chiralpak-IA, 250x20mm, sum). An isocratic program using analytical grade liquid carbon dioxide and HPLC grade methanol was used, with a total flow rate of 51 g / min and a co-solvent percentage of 15%.

[0225] Compound 1-16: Yield = 2 mg; elution time = 6.2 min. Compound 1-17: Yield = 4 mg; elution time = 7.5 min. Compound 1-16: LCMS: 385 [M+H]; 1 H NMR (400 MHz, DMSO-d 6 )δ, 11.01(s, 1H), 8.14(s, 1H), 8.00(s, 1H), 7.69(s, 1H), 7.22-7.34(m, 3H), 7.14(s, 1H), 7.08(m, 1H), 6.77(m, 1H), 5.85(m, J=7.45Hz, 1H), 1.79(d, J=7.02Hz, 3H). Compound 1-17: LCMS: 385[M+1], 1 H NMR (400 MHz, DMSO-d 6 )δ11.03(s,1H),8.13(s,1H),8.01(s,1H),7.68(s,1H),7.23 -7.35(m,3H),7.15(s,1H),7.06(m,1H),6.78(m,1H),5.84(m,J=7.45Hz,1H),1.78(d,3H). Example S1-12. Synthesis of N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide (Compounds 1-18 and 1-19)

[0226] The racemic mixture of N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide (185 mg) was purified by chiral HPLC to obtain N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide as the first eluting isomer (Compound 1-18) and the second eluting isomer (Compound 1-19). The isomers were separated by chiral SFC (Daicel -IA, 250×20 mm, 5 μm) separation. An isocratic program using analytical grade liquid carbon dioxide and HPLC grade methanol was used, with a total flow rate of 56 g / min and a co-solvent percentage of 25%.

[0227] Compound 1-18: Yield = 50 mg; elution time = 6.3 min. Compound 1-19: Yield = 50 mg; elution time = 9.3 min.

[0228] LCMS mass [M+1]: 401.40; 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(s,1H),8.14(s,1H),8.00(d,J=1.32Hz,1H),7.64(s,1H),7.35-7.45(m,2H),7.28(d,J=3.51Hz,1H ),7.19-7.26(m,1H),7.14(s,1H),6.77(dd,J=1.75,3.51Hz,1H),5.98-6.06(m,1H),1.92(d,J=6.58Hz,3H). Example S1-13. Synthesis of 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (Compounds 1-20 and 1-21)

[0229] Step 1: Synthesis of 1-(2,4,6-trifluorophenyl) ethyl-1-ol. At 0°C, NaBH4 (0.437g, 11.49mmol, 2 equivalents) was added in batches to a stirred solution of 1-(2,4,6-trifluorophenyl) ethyl ketone (1.00g, 5.74mmol, 1.0 equivalent) in ethanol (15ml) and allowed to stir for 2h at RT, the reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was distilled and treated with water 10ml and extracted with ethyl acetate (2X 20mL) times. The organic layer was separated and evaporated under reduced pressure to obtain the product 1-(2,4,6-trifluorophenyl) ethyl-1-ol (1.00g).

[0230] Step 2: Synthesis of 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole. To a solution of 1-(2,4,6-trifluorophenyl)ethan-1-ol (1.00 g, 5.68 mmol, 1 eq.) and 4-nitro-1H-pyrazole (642 mg, 5.68 mmol, 1.0 eq.) in THF (15 ml) was added TPP (2.23 gm, 8.522 mmol, 1.5 eq.) cooled to 0°C and DIAD (1.72 ml, 8.522 mmol, 1.5 eq.) was added dropwise under inert conditions. After addition, the reaction mixture was stirred at RT and the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, treated by water 10 ml and extracted with ethyl acetate (2X 20 ml) times, the organic layer was separated and evaporated under reduced pressure to get the crude product, which was purified by combiflash chromatography to get the pure product 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole (1.2 g).

[0231] Step 3: Synthesis of 1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-amine. To a solution of 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole (1.2 g, 4.428 mmol, 1 eq.) in 10 ml of EtOH:H2O (1:1) was added NH 4 To 4-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazoles-4-amine (920mg) was added in 4-nitropropene (10mL) 4-nitropropene (20mL) 4-nitropropene (20mL) 5-nitropropene (20mL) 5-nitropropene (20mL) 4 ...

[0232] Step 4: Synthesis of 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide. To a solution of 1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-amine (900 mg, 5.027 mmol, 1 eq.) in DMF (10 ml) was added HATU (1.91 g, 5.027 mmol, 1 eq.) and DIPEA (2.62 ml, 15.08 mmol, 3 eq.) and stirred for 5 min, 5-(furan-2-yl)isoxazole-3-carboxylic acid (1.21 g, 5.027 mmol, 1 eq.) was added and the reaction mixture was stirred at RT. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, it was treated with cold water (30 ml) and extracted with ethyl acetate (2×50 mL), and the organic layer was collected and dried over sodium sulfate and concentrated to give a crude product, which was purified by combi flash chromatography using hexane:ethyl acetate to obtain the product 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (350 mg). LCMS: 403[M+H]. Example S-14. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-22)

[0233] Step 1: Synthesis of 1-(2,6-dichlorophenyl)ethan-1-ol. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-one (1.00 g, 5.29 mmol, 1 eq.) in ethanol (10 ml) was added NaBH at 0 °C. 4 (0.391g, 10.58mmol, 2 equivalents), the resulting reaction mixture was stirred at RT for 2h, and the reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with 3ml of water and all ethanol was distilled and the reaction mixture was extracted with ethyl acetate (100ml×2) and water (100mL), the organic layer was separated and evaporated under reduced pressure to obtain a crude product 1-(2,6-dichlorophenyl) ethane-1-ol (1.01g). LCMS: 191[M+H]

[0234] Step 2: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-4-nitro-1H-pyrazole. To a stirred solution of 1-(2,6-dichlorophenyl)ethane-1-ol (1.00 g, 5.23 mmol, 1 eq.) and 3-methyl-4-nitro-1H-pyrazole (0.700 g, 5.23 mmol, 1 eq.) and TPP (2.05 g, 7.85 mmol, 1.5 eq.) in THF (10 ml) was added DIAD (1.6 ml, 7.85 mmol, 1.5 eq.) dropwise at 0 °C and allowed to stir for 4 h at RT. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water (2X 500 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product, which was further purified by combi flash chromatography to 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-4-nitro-1H-pyrazole (1.32 g). LCMS: 299.9 [M+H]

[0235] Step 3: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazole-4-amine. To a solution of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-4-nitro-1H-pyrazole (1.0 g, 3.344 mmol, 1 eq.) in ethanol:water (1:1, 10 ml), NH4Cl (0.903 g, 16.722 mmol, 5 eq.) and Fe (0.936 g, 16.722 mmol, 5 eq.) were added and the resulting reaction mixture was stirred at 80 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the RM was filtered through a celite bed, ethanol was evaporated and extracted with ethyl acetate and water (2X 50 mL). The organic layers were collected and concentrated to give a crude product of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-amine (0.560 g). LCMS: 270.02 [M+H].

[0236] Step 4: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. A solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (0.365 g, 2.044 mmol, 1 eq.) and HATU (0.776 gm, 2.044 mmol, 1 eq.) in DMF (5 mL) was stirred for 5 min and DIPEA (1 ml, 6.133 mmol, 3 eq.) and 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-amine (0.550 g, 2.044 mmol, 1 eq.) were added thereto. The resulting reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water (2X 25 mL). The organic layer was collected and concentrated to give a crude product, which was purified by combi flash chromatography to give N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (80 mg). LCMS: 431.0 [M+H], 1 H NMR (400 MHz, DMSO-d 6 )10.19(s,1H),7.99(s,1H),7.64(s,1H),7.49 -7.13(s,5H),6.76(d,J=3.5Hz,1H),6.26(m,1H),1.92(d,J=7.0Hz,3H),1.80(s,3H). Example S1-15. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compounds 1-23 and 1-24)

[0237] Step 1: Synthesis of 1-(2,6-dichlorophenyl)ethan-1-ol. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-one (1.00 g, 5.29 mmol, 1 eq.) in ethanol (10 ml) was added NaBH4 (0.391 g, 10.58 mmol, 2 eq.) at 0°C, the resulting reaction mixture was stirred at RT for 2 h, the reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (3 ml) was added and all ethanol was distilled and the reaction mixture was extracted with ethyl acetate (100 ml X 2) and water (100 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product 1-(2,6-dichlorophenyl)ethan-1-ol (1.01 g). LCMS: 191 (M+H)+ .

[0238] Step 2: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-4-nitro-1H-pyrazole. To a stirred solution of 1-(2,6-dichlorophenyl)ethane-1-ol (1.00 g, 5.23 mmol, 1 eq.) and 3-methyl-4-nitro-1H-pyrazole (0.700 g, 5.23 mmol, 1 eq.) and TPP (2.05 g, 7.85 mmol, 1.5 eq.) in THF (10 ml) was added dropwise DIAD (1.6 ml, 7.85 mmol, 1.5 eq.) at 0 ° C. and allowed to stir for 4 h at RT. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (100 ml x 2) and water (100 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product, which was further purified by combi flash chromatography to give 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-4-nitro-1H-pyrazole (1.32 g). LCMS: 299.9 [M+H].

[0239] Step 3: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-amine. To a solution of 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-4-nitro-1H-pyrazole (1.0 g, 3 344.mmol, 1 eq.) in ethanol:water (1:1, 10 ml) was added NH4Cl (0.903 g, 16.722 mmol, 5 eq.) and Fe (0.936 g, 16.722 mmol, 5 eq.) and the resulting reaction mixture was stirred at 80°C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was filtered through a celite bed, ethanol was evaporated and extracted with ethyl acetate and water (2X 50 mL), the organic layers were collected and concentrated to give the crude product 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-amine (0.560 g). LCMS: 270.02 [M+H].

[0240] Step 4: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. A solution of 5-(Furan-2-yl)isoxazole-3-carboxylic acid (0.332 gm, 1.858 mmol, 1 eq.) and HATU (0.7063 gm, 1.858 mmol, 1 eq.) in DMF (5 mL) was stirred for 5 min and DIPEA (1 ml, 5.576 mmol, 3 eq.) and 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-amine (0.500 g, 1.858 mmol, 1 eq.) were added thereto. The resulting reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water (2 X 25 mL). The organic layer was collected and concentrated to give a crude product, which was purified by combi flash chromatography to obtain N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (200 mg). LCMS: 431.0 [M+H], 1 H NMR (400 MHz, DMSO-d 6 )10.28(s,1H),7.91-8.14(m,2H),7.43-7.51(m,2H),7.37(d,J=7.89Hz,1H),7.27(d,J=3.51Hz,1 H), 7.16 (s, 1H), 6.77 (dd, J = 1.75, 3.51Hz, 1H), 3.33 (s, 6H), 2.12 (s, 3H), 1.92 (d, J = 7.02Hz, 3H).

[0241] Step 5: Separation of isomers of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. A racemic mixture of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (90 mg) was purified by chiral HPLC to obtain the first eluting isomer (Compound 1-23; 30 mg) and the second eluting isomer (Compound 1-24; 30 mg).

[0242] Compound 1-23: LCMS: 431 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6) 10.28 (s, 1H), 8.05-8.01 (d, J = 0.88 Hz, 2H), 7.48 (d, J = 8.33 Hz, 2H), 7.32-7.16 (s, 3H), 6.77 (dd, J = 2.19, 3.51 Hz, 1H), 6.02-6.17 (m, 1H), 2.04-2.15 (m, 3H), 1.92 (d, J = 7.02 Hz, 3H). Compound 1-24: LCMS: 431 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )10.28(s,1H),8.05-8.01(d,J=0.88Hz,2H),7.48(d,J=8.33Hz,2H),7.32-7.16(s,3H),6. 77(dd,J=2.19,3.51Hz,1H),6.02-6.17(m,1H),2.04-2.15(m,3H),1.92(d,J=7.02Hz,3H). Example S1-16. Synthesis of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (Compound 1-25 and Compound 1-26).

[0243] The racemic mixture of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (130 mg) was purified by chiral HPLC to obtain the first eluting isomer (Compound 1-25) and the second isomer (Compound 1-26). The enantiomers were separated by chiral SFC (Daicel -IC, 250×21 mm, 5 μm) separation. An isocratic program using analytical grade liquid carbon dioxide and HPLC grade methanol was used, with a total flow rate of 56 g / min and a co-solvent percentage of 33%.

[0244] Compound 1-25: Yield = 29 mg; elution time = 3.0 min. Compound 1-26: Yield = 32 mg; elution time = 4.2 min.

[0245] Compound 1-25: LCMS: 497.11 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δppm11.24(s,1H)9.32(s,1H)8.75-8.94(m,2H)8.21(s,1H)8.02-8.16(m,2H)7.70-7.86(m,3H)5.95(d,J=7.02Hz,1H)1.88(d,J=7.02Hz,3H). Compound 1-26: LCMS:497.11[M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δppm 11.22(s,1H)9.30(s,1H)8.73-8.94(m,2H)8.21(s,1H)8.01-8.16(m,2H)7.74-7.86(m,3H)5.92(d,J=7.02Hz,1H)1.84(d,J=7.02Hz,3H). Biological Examples Example B1. ERSE ATF6-luciferase assay

[0246] To understand how exemplary compounds of the invention modulate the activity of ATF6 in the absence or presence of endoplasmic reticulum (ER) stress, a human bone osteosarcoma (U2-OS) based TRE-luciferase reporter stable cell line was generated to determine the regulation of transcription of ATF6 target genes.

[0247] U2-OS cells were obtained from the American Type Culture Collection (ATCC HTB-96, ATCC, Manassas, VA) and cultured with growth medium containing Dulbecco's modified Eagle's medium (DMEM) (Catalog No.: SH30023.02, HyClone) supplemented with fetal bovine serum (FBS) 10% (Catalog No.: 16000044, Gibco) and 1% penicillin-streptomycin antibiotic mixture (Catalog No.: SV30010, Hyclone).

[0248] Cignal Lenti ATF6 luc reporter (Qiagen #CLS-6031L) was used to generate a stable cell line in U2-OS cells (U2-OS ATF6 TRE-luciferase reporter). The lenti ATF6 reporter is a preparation of replication-incompetent VSV-g pseudotyped lentiviral particles expressing the firefly luciferase gene under the control of tandem repeats of the minimal (m) CMV promoter and the ATF6 transcriptional response element (TRE). The number of response elements and the intermediate sequences between the response elements have been experimentally optimized to maximize the signal-to-noise ratio.

[0249] Exemplary compounds of the invention and reference compounds were prepared from powder as 10 mM stock solutions in dimethyl sulfoxide (DMSO; catalog # D2650, Sigma Aldrich) and incubated at N 2 Store at -80 °C under neutral atmosphere.

[0250] For the primary screen, 40,000 U2-OS ATF6TRE-luciferase reporter cells were plated in poly-D-lysine (Cat. No.: P2636, Sigma) pre-coated white 96-well plates (ThermoScientific Nunc #136101) with 100 μL of growth medium. The cells were incubated in a humidified chamber for 24 h.

[0251] To test exemplary compounds in the presence of ER stress, cells were pretreated with 50 μL of growth medium containing vehicle (DMSO), 1 μM or 10 μM test compounds for 30 min. After this pre-incubation, 50 μL of a solution containing 0.2 μM of the ER stress inducer thapsigargin (Tg) was added to the appropriate wells. The Tg solution also contained vehicle or 1 μM or 10 μM test compounds as indicated. The final concentration of DMSO in each well was maintained at 0.3%. The plate was incubated in a humidified chamber for 8 h.

[0252] After 8h incubation, the plate was cooled down to room temperature for 10min and then luciferase assay was performed. Luciferase reaction was performed using luciferase assay system (Catalog No.: E4550, Promega). In brief, each well was washed with 100μl of PBS1X, and then, 20μl of lysis reagent was added to each well. The plate was shaken for 10min, and then, 50μl of luciferase assay reagent was added to each well. Luminescence was determined by integration of 1s and gain of 110 in Synergy 4 microplate reader. All measurements were performed in triplicate.

[0253] The average activity determined from the wells containing only vehicle (DMSO, 0% ATF6 activity) is used as blank, and is subtracted from the remaining measurements. The average activity determined from the wells containing only Tg is used as 100% ATF6 activity. The adjustment percentage of exemplary compounds is calculated by normalizing the value relative to the potential maximum activation using Tg. In this assay, the exemplary compounds showing ATF6 activity higher than 100% (positive regulation) indicate activator activity to these molecules, while the compounds showing ATF6 activity less than 100% (negative regulation) indicate inhibitory regulation.

[0254] ATF6 activity of exemplary compounds tested in U2-OS ATF6 TRE-luciferase reporter cells at 1 μM and 10 μM in the presence of Tg-induced ER stress was determined and is shown in Table 2. Table 2: ATF6 activity in the presence of ER stress in the ATF6-luc cell reporter Ceapin-A4, Ceapin-A7, and Ceapin-A8 refer to compounds described in Gallagher et al. eLife 2016;5:e11878; For ATF6 % activity: --- refers to <50% at 1 μM or 10 μM test compound; -- refers to 50% < % activity <75% at 1 μM or 10 μM test compound; - refers to 75% < % activity <100% at 1 μM or 10 μM; + refers to 100% < % activity <125% at 1 μM or 10 μM; ++ refers to 125% < % activity <150% at 1 μM or 10 μM test compound; +++ refers to >150% at 1 μM or 10 μM test compound; NT: not tested.

[0255] To test exemplary compounds in the absence of ER stress, cells were treated with 100 μL growth medium containing vehicle (DMSO), 1 μM or 10 μM test compound, or 0.1 μM Tg for 8 h. The final concentration of DMSO in each well was maintained at 0.3%. The plates were incubated in a humidified chamber.

[0256] After 8h incubation, the plate was cooled down to room temperature for 10min and then luciferase assay was performed. Luciferase reaction was performed as above. Luminescence was read in Synergy 4 microplate reader by integration of 1s and gain of 110. All measurements were performed in triplicate.

[0257] The average activity determined from wells containing vehicle only (DMSO, 0% ATF6 activity) was used as blank and subtracted from the rest of the measurements. The percent modulation of exemplary compounds was calculated by normalizing the values ​​to the potential maximal activation using Tg.

[0258] ATF6 activity of exemplary compounds at 1 μM and 10 μM in the absence of Tg-induced ER stress was determined in U2-OS ATF6 TRE-luciferase reporter cells and is shown in Table 3. Table 3: ATF6 activity in the absence of ER stress in the ATF6-luc cell reporter For ATF6 activity %: + means 0% < activity % < 25% at 1 μM or 10 μM test compound; ++ means 25% < activity % < 50% at 1 μM or 10 μM test compound; +++ means activity % > 50% at 1 μM or 10 μM test compound; NT: not tested.

[0259] All references cited throughout the text, such as publications, patents, patent applications, and published patent applications, are incorporated herein by reference in their entirety.

[0260] Although the foregoing invention has been described in detail by way of illustration and example for purposes of clarity of understanding, it is obvious to one skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and example should not be construed as limiting the scope of the invention.

[0261] The present disclosure relates to the following embodiments. 1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R d Is H or C 1 -C 6 alkyl; R 1 It is C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl or C 1 -C 6 Haloalkyl; L is -CH 2 - or does not exist; -- is a key or does not exist; R 2 , R 3 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group, wherein R 2 , R 3 , R 4 , R 5 and R 6 At least two of them are halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl, and / or wherein R2 , R 3 , R 4 , R 5 and R 6 One of them is CN; or R 2 , R 4 , R 5 and R 6 are independently H, halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl and -- is a bond such that R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, wherein the 5- or 6-membered carbocyclic ring is unsubstituted or substituted by one to three groups selected from the group consisting of halogen, CN, -OH, C 1 -C 6 alkyl Base and C 1 -C 6 Haloalkyl; A is R a is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy, The condition is that when A is And R a is 2-furyl or 2-thiofuryl, at least one of (i.) to (vi.) One applies: (i.) L does not exist, and R 1 It is C 1 -C 6 alkyl; (ii.)--is the bond that makes R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, provided that when forming said 5-membered carbocyclic ring, R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Haloalkyl; (iii.) R2 , R 3 , R 4 , R 5 and R 6 One of them is CN; (iv.) R 4 and R 5 are independently Cl, Br, I, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Haloalkyl; (v.) R 2 and R 3 Each is Cl; and (vi.) R 2 , R 3 , R 4 , R 5 and R 6 At least one of them is F, Br, I, CN, or C 1 -C 6 haloalkyl and R a is 2-thiofuranyl; and R 7 It is H, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl, The condition is that when R d It is C 1 -C 6 When alkyl, R 7 is H, and when R 7 It is C 1 -C 6 When alkyl, R d It's H. 2. The compound according to item 1, wherein R a The 5- or 6-membered heteroaryl is selected from 2-furyl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl and 2-pyrazinyl. 3. A compound according to item 1 or 2, wherein A is And R a It is 2-furyl. 4. A compound according to item 1 or 2, wherein A is And R a It is 2-pyridyl. 5. A compound according to item 1 or 2, wherein A is And R a It is 2-pyrimidinyl. 6. A compound according to item 1 or 2, wherein A is And R a It is 4-pyrimidinyl. 7. A compound according to item 1 or 2, wherein A is And R a It is 2-pyrazinyl. 8. A compound according to item 1 or 2, wherein A is And R a It is 2-furyl. 9. A compound according to item 1 or 2, wherein A is And R a It is 2-pyridyl. 10. A compound according to item 1 or 2, wherein A is And R a It is 2-pyrimidinyl. 11. A compound according to item 1 or 2, wherein A is And R a It is 4-pyrimidinyl. 12. A compound according to item 1 or 2, wherein A is And R a It is 2-pyrazinyl. 13. A compound according to item 1 or 2, wherein A is And R a It is 2-furyl. 14. A compound according to item 1 or 2, wherein A is And R a It is 2-pyridyl. 15. A compound according to item 1 or 2, wherein A is And R a It is 2-pyrimidinyl. 16. A compound according to item 1 or 2, wherein A is And R a It is 4-pyrimidinyl. 17. A compound according to item 1 or 2, wherein A is And R a It is 2-pyrazinyl. 18. A compound according to any one of items 1-17, wherein -- is a bond such that R 3 With R 1 Together with the atoms to which they are attached they form a 5-membered carbocyclic ring. 19. A compound according to any one of items 1-17, wherein - is a bond such that R 3 With R 1 Together with the atoms to which they are attached they form a 6-membered carbon ring. 20. A compound according to any one of items 1-3, wherein A is R a is 2-furyl, L is absent and R 1 It is C 1 -C 6 alkyl. 21. A compound according to any one of items 1-3, wherein A is R a is 2-furyl, -- is a bond, making R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, provided that when forming said 5-membered carbocyclic ring, R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Halogenated alkyl. 22. The compound according to item 21, wherein L is absent, R 3 With R 1 Together with the atoms to which they are attached, they form the 5-membered carbon ring, and R 2 , R 4 , R 5 and R 6 At least one of them is halogen, CN, C 1 -C 6 Alkyl, or C 1 -C 6 Halogenated alkyl. 23. The compound according to item 21, wherein L is absent, R 3 With R 1 Together with the atoms to which they are attached, they form the 6-membered carbon ring, and R 2 , R 4 , R 5 and R 6 Each of them is hydrogen. 24. A compound selected from: or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition comprising the compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 26. A method for treating a disease or disorder mediated by activating transcription factor 6 (ATF6) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound according to any one of items 1-24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 27. A method of treating a disease or disorder characterized by activation of ATF6 in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound according to any one of items 1-24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 28. The method according to item 26 or 27, wherein ATF6 is ATF6α. 29. A method according to any one of items 26-28, wherein the disease or disorder is cancer, a neurodegenerative disease, or a vascular disease. 30. A method according to any one of items 26-28, wherein the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, or Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. 31. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 32. A method for treating a disease or disorder associated with angiogenesis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 33. A method for treating a metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 34. A method for regulating ATF6 in an individual, the method comprising administering to the individual a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 35. A method for regulating ATF6 in a cell, the method comprising administering or delivering to the cell a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25, or a metabolite thereof. 36. A method for activating ATF6 in an individual, the method comprising administering to the individual a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 37. A method for activating ATF6 in a cell, the method comprising administering or delivering to the cell a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25, or a metabolite thereof. 38. A method of inhibiting ATF6 in an individual, the method comprising administering to the individual a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25. 39. A method for inhibiting ATF6 in a cell, the method comprising administering or delivering to the cell a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 25, or a metabolite thereof. 40. Use of the compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 25, in the manufacture of a medicament for preventing and / or treating a disorder or disease mediated by ATF6. 41. A compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, for use in therapy. 42. A compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder mediated by activating transcription factor 6 (ATF6) in a subject in need thereof. 43. A compound according to any one of items 1 to 24 for use in a method of treating a disease or disorder characterized by activation of ATF6 in a subject in need thereof. 44. The compound for use according to item 42 or 43, or a pharmaceutically acceptable salt thereof, wherein ATF6 is ATF6α. 45. The compound for use according to any one of items 42 to 44, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is cancer, a neurodegenerative disease, or a vascular disease. 46. ​​A compound for use according to any one of items 42 to 44, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, or Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. 47. A compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with angiogenesis in a subject in need thereof. 48. A compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method of treating a metabolic disorder in a subject in need thereof.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R d is H or C1-C6 alkyl; R 1 is C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 haloalkyl; L is -CH2- or absent; -- is a key or does not exist; R 2 , R 3 , R 4 , R 5 and R 6 are each independently H, halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl, wherein R 2 , R 3 , R 4 , R 5 and R 6 At least two of are halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl, and / or where R 2 , R 3 , R 4 , R 5 and R 6 One of them is CN; or R 2 , R 4 , R 5 and R 6 are each independently H, halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl and -- is a bond such that R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, wherein the 5- or 6-membered carbocyclic ring is unsubstituted or substituted with one to three groups selected from the group consisting of halo, CN, -OH, C1-C6 alkyl and C1-C6 haloalkyl; A is R a is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one to four groups selected from the group consisting of OH, halo, C1-C6 alkyl and C1-C6 alkoxy, The condition is that when A is And R a When it is 2-furyl or 2-thiofuryl, at least one of (i.) to (vi.) applies: (i.) L does not exist, and R 1 is a C1-C6 alkyl group; (ii.)--is the bond that makes R 3 With R 1 Together with the atoms to which they are attached, they form a 5- or 6-membered carbocyclic ring, provided that when forming said 5-membered carbocyclic ring, R 2 , R 4 , R 5 and R 6 At least one of them is halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl; (iii.) R 2 , R 3 , R 4 , R 5 and R 6 One of them is CN; (iv.) R 4 and R 5 Each is independently Cl, Br, I, CN, C1-C6 alkyl, or C1-C6 haloalkyl; (v.) R 2 and R 3 Each is Cl; and (vi.) R 2 , R 3 , R 4 , R 5 and R 6 At least one of is F, Br, I, CN, or C1-C6 haloalkyl and R a is 2-thiofuranyl; and R 7 is H, C1-C6 alkyl or C1-C6 haloalkyl, The condition is that when R d When it is C1-C6 alkyl, R 7 is H, and when R 7 When it is C1-C6 alkyl, R d It's H.

2. The compound according to claim 1, wherein R a The 5- or 6-membered heteroaryl is selected from 2-furyl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl and 2-pyrazinyl.

3. The compound according to claim 1 or 2, wherein A is And R a It is 2-furyl.

4. The compound according to claim 1 or 2, wherein A is And R a It is 2-pyridyl.

5. The compound according to claim 1 or 2, wherein A is And R a It is 2-pyrimidinyl.

6. The compound according to claim 1 or 2, wherein A is And R a It is 4-pyrimidinyl.

7. The compound according to claim 1 or 2, wherein A is And R a It is 2-pyrazinyl.

8. The compound according to claim 1 or 2, wherein A is And R a It is 2-furyl.

9. The compound according to claim 1 or 2, wherein A is And R a It is 2-pyridyl.

10. The compound according to claim 1 or 2, wherein A is And R a It is 2-pyrimidinyl.

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