Crystal forms of imidazopyridine derivatives

Abstract

Polymorphic Forms A, B, C, D, E, and F of Compound 1, shown below, have been discovered and formulated with pharmaceutically acceptable excipients to form tablets and capsules.

Description

[0001] Patent application

[0002] Crystal forms of imidazopyridine derivatives

[0003] Inventors: Vidyasagar Reddy Gantla, Eric Brown, Nadezda V. Sokolova, Kenneth McCormack, Gregory Henkel

[0004] Entity: Small Entity

[0005] Ken McCormack

[0006] Arisan Therapeutics

[0007] 5825 Avenida Encinas, Suite 101

[0008] Carlsbad, CA 92008

[0009] 858-766-0495

[0010] kenm@arisanthera.com Cross-references to related applications

[0011] This patent application is a partial continuation of U.S. Provisional Patent Application Serial No. 63 / 612,863, filed on December 20, 2023, and claims priority to that provisional patent application, the entire contents of which are incorporated herein by reference for all purposes. Declaration of rights regarding inventions completed under federally funded research and development.

[0012] This invention was developed with funding from the National Institutes of Health (NIH) under grant number R44 AI112097. The U.S. government holds certain rights to this invention. References to the sequence listing table or computer program listing appendix submitted in CD-ROM format

[0013] not applicable Technical Field

[0014] This invention relates to crystalline forms of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine (also named 3-[4-(1,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1,2-a]pyridine or 3-(4-tert-butoxyphenyl)-7-methyl-6-(4-(propyl-2-yloxy)phenyl)imidazo[1,2-a]pyridine), methods for preparing such crystalline forms, the use of such crystalline forms in inhibiting arenavirus infection in humans, other mammals, or cell cultures, methods for treating arenavirus infections such as Lassa fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Brazilian hemorrhagic fever, Chapare hemorrhagic fever, and Luyo hemorrhagic fever, methods for inhibiting arenavirus replication, methods for reducing arenavirus load, and pharmaceutical compositions comprising such crystalline forms that can be used in such methods. The present invention also relates to pharmaceutical compositions comprising at least one crystal form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine, and to therapeutic or preventive uses relating to such crystal forms and compositions.

[0015] Furthermore, the present invention relates to methods for modulating cannabinoid receptor 1 (CB1R) in humans, other mammals, or cell cultures, and to methods for treating diseases or conditions mediated by CB1R, including metabolic diseases such as obesity, diabetes, eating disorders, weight loss and control, as well as liver diseases, fibrotic conditions, pain, neurological conditions including substance abuse / dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory conditions, gastrointestinal diseases, genetic conditions, reproductive system conditions, sleep disorders, osteoporosis, and other diseases or conditions related to or affected by CB1R. Background Technology

[0016] This invention relates to the crystal form of 3-(4-(tert-butoxyphenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine (also named 3-[4-(1,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1,2-a]pyridine or 3-(4-tert-butoxyphenyl)-7-methyl-6-(4-(propyl-2-yloxy)phenyl)imidazo[1,2-a]pyridine) (hereinafter referred to as "Compound 1").

[0017] ,

[0018] This invention relates to methods for preparing such crystalline forms, to the use of such crystalline forms in inhibiting arenavirus infection in humans, other mammals, or cell cultures, to methods for treating arenavirus infections such as Lassa fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Brazilian hemorrhagic fever, Chapare hemorrhagic fever, and Luyo hemorrhagic fever, to methods for inhibiting arenavirus replication, to methods for reducing arenavirus load, and to pharmaceutical compositions comprising such crystalline forms that can be used in such methods. The invention also relates to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine, and to the therapeutic or preventative use of such crystalline forms and compositions.

[0019] The preparation of compound 1 is described in WO 2020 / 117794 A1, the entire disclosure of which is incorporated herein by reference.

[0020] Compound 1 is a potent broad-spectrum arenavirus inhibitor that can be used to treat arenavirus infections mediated by arenavirus glycoproteins, such as Lassa fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Brazilian hemorrhagic fever, Chapare hemorrhagic fever, and Luyo hemorrhagic fever (HF).

[0021] The Arenaviridae family comprises a diverse group of 29 (and growing) negative-sense enveloped RNA viruses. Arenaviruses are divided into two groups based on serological, genetic, and geographical data: Old World viruses and New World viruses. Old World viruses are predominantly distributed throughout southern and western Africa and include proto-lymphocytic choriomeningitis virus (LCMV), as well as Lassa virus (LASV), Luyo virus (LUJV), Mopeya virus (MOPV), Ipi virus, and Mobara virus (MOBV). LASV and LUJV can cause fatal hemorrhagic fever (HF), while LCMV infection is associated with aseptic meningitis. Lassa virus (LASV) alone is estimated to cause over 300,000 cases of illness annually in western Africa, with 15–20% of hospitalized patients dying; survivors often suffer from sequelae, including permanent bilateral hearing loss. The larger New World Complex, primarily located in South America, is divided into three clades: A, B, and C. Clade B is particularly important because many viruses in this group can cause lethal HF (high-risk infection). HF viruses in clade B include Junin virus (JUNV), Machupo virus (MACV), Guanarito virus (GTOV), Sabya virus (SABV), and Chapare virus, as well as non-HF viruses such as Tacarib virus (TCRV) and Amapari virus (AMPV). Human infection occurs through contact with the excrement of infected rodents or inhalation of small particles contaminated with rodent urine or saliva (aerosol transmission). There is also evidence of human-to-human transmission, primarily occurring in healthcare settings such as hospitals. The incubation period is 1–2 weeks, followed by fever, malaise, weakness, sore throat, headache, cough, diarrhea, and vomiting. These general symptoms make differential diagnosis of arenavirus infection challenging. Poor prognosis manifests as worsening symptoms, including pleural effusion, facial edema, neurological complications, and mucosal hemorrhage. Current treatment for arenavirus is limited to ribavirin, which is only partially effective with early administration and is accompanied by significant side effects. Although a vaccine against Juninvirus has been developed, its use is primarily limited to the highest-risk population among Argentine farm workers, and there are no approved vaccines against any other arenaviruses. While highly needed, prophylactic vaccines may not always be an effective countermeasure against rapidly emerging, antigenically unique new viral strains, and existing vaccine development and production strategies are insufficient to adequately address the diverse families of current or emerging arenaviruses. Therefore, novel broad-spectrum antiviral drugs could not only provide first-line treatment and / or prevention in areas where arenavirus is prevalent but also serve as a safeguard against potential biological warfare agents.

[0022] Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope membrane. The NP contains two ambiguous RNA genomic segments, L and S, which direct the synthesis of two polypeptides. The L segment encodes an RNA-dependent RNA polymerase (RdRp) and a small RING finger protein, Z. The S segment encodes a nucleoprotein and the glycoprotein precursor GPC, which is cleaved by the host protease and undergoes post-translational modification to form a mature complex consisting of glycoprotein GP1 (which binds the host protein on the cell surface), GP2 (which directs pH-dependent membrane fusion and the release of genomic material into the cytoplasm), and a stable signal peptide (SSP1). The mature glycoprotein complex (GP, or glycoprotein) forms within the viral envelope and is responsible for mediating viral entry. Old-world arenaviruses bind to host α-anti-dystrophic glycans, while new-world arenaviruses bind to transferrin receptor 1 for entry / endocytosis into the cell. After binding to the cell surface receptor, the virus is endocytosed and guided to an acidic late endosome, where GP2 mediates pH-dependent membrane fusion and releases genomic material into the cytoplasm for viral replication and transcription. Therefore, viral entry inhibitors (e.g., small molecules) that target viral GP complexes or host factors are a potential treatment / prevention approach for patients infected with arenavirus.

[0023] Since HF arenavirus species are classified as BSL-4, alternative methods are needed to identify viral entry inhibitors. To facilitate the identification of arenavirus entry inhibitors, the arenavirus GP complex can be expressed in a non-pathogenic BSL-2 enveloped virus to generate a single-round infectious pseudovirus whose viral entry function is determined by the heterologous glycoprotein under investigation. One available viral expression system is the vesicular stomatitis virus (VSV) system, in which the envelope protein of VSV is replaced by an envelope glycoprotein from another virus (e.g., LASV) to mediate the entry of pseudovirus particles. The cell entry and infectivity characteristics of GP pseudovV have been confirmed in a variety of viruses, including HIV, hepatitis B and C viruses, Ebola virus, Lassa virus, and Hantavirus. Ogino, M ., et al. Use of vesicular stomatitis virus pseudotypesbearing hantaan or seoul virus envelope proteins in a rapid and safeneutralization test. Clin. Diagn. Lab. Immunol. (2003) 10(1):154-60; Saha, MN., et al. Formation of vesicular stomatitis virus pseudotypes bearingsurface proteins of hepatitis B virus. J. Virol. (2005) 79(19):12566-74;Takada, A., et al. A system for functional analysis of Ebola virusglycoprotein, Proc. Natl. Acad. Sci. (1997) 94:14764-69; Garbutt, M., et al. Properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses. J. Virol. (2004) 78(10):5458-65]. The above paper is incorporated herein by reference in its entirety for all purposes. To monitor pseudovirus infection, reporter genes such as green fluorescent protein (GFP) or luciferase can be engineered into the pseudovirus genome, and optical detection methods (e.g., plate readers) can be used to monitor viral infectivity in mammalian cell lines (e.g., Vero or Hek293) [Cote, M.; Misasi, J.; Ren, T.; Bruchez, A., Lee, K., Filone, CM; Hensley, L.; Li, Q.; Ory, D.; Chandran, K.; Cunningham, J., Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection, Nature (2011)477: 344-348, Elshabrawy, HA, et al. Identification of a broad-spectrum antiviral amall molecule against severe scute respiratory syndrome Coronavirus and Ebola, Hendra, and Nipah Viruses by using a novel high-throughput screening assay. J. Virol.]. (2014) 88: 4353-4365]. The aforementioned paper is incorporated herein by reference in its entirety for all purposes. Therefore, “pseudoviruses” can be used to screen chemical compound libraries to identify inhibitors of arenavirus cell entry, while avoiding the complexities of handling highly pathogenic BSL-4 reagents.

[0024] The present invention also relates to methods for modulating cannabinoid receptor 1 (CB1R) in humans, other mammals, or cell cultures, and to methods for treating diseases or conditions mediated by CB1R, including metabolic diseases such as obesity, diabetes, eating disorders, weight loss and control, as well as liver diseases, fibrotic conditions, pain, neurological conditions including substance abuse / dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory conditions, gastrointestinal diseases, genetic conditions, reproductive system conditions, sleep disorders, osteoporosis, and other diseases or conditions related to or affected by CB1R.

[0025] Cannabinoid receptor 1 (CB1R) is a G protein-coupled receptor responsible for mediating signaling of natural endocannabinoids and synthetic cannabinoid ligands, regulating physiopathology, and serving as a potential target for drug therapy. CB1R agonists regulate appetite-stimulating factors via hypothalamic CB1R [Di Marzo, V., Goparaju, SK, Wang, L., Liu, J., Batkai, S., Jarai, Z., Kunos, G. (2001). Leptin regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825], thus providing a fundamental principle for developing CB1R antagonists for the treatment of obesity and obesity-related metabolic complications. The aforementioned paper is incorporated herein by reference in its entirety for all purposes. Rimonabant is the first CB1R antagonist / inverse agonist to be clinically tested, demonstrating weight loss in obese individuals and improving several altered cardiometabolic parameters in obese patients, including waist circumference, hemoglobin A1c, high-density lipoprotein (HDL), plasma cholesterol, and triglycerides [Despres, JP, Golay, A., Sjostrom, L., & Rimonabant in Obesity-Lipids Study G (2005). Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. The New England Journal of Medicine 353, 2121–2134; Van Gaal, LF, Scheen, AJ, Rissanen, AM, Rossner, S., Hanotin, C., & Ziegler, O. (2008). Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. European Heart Journal]. [29(14), 1761–1771]. The above paper is incorporated herein by reference in its entirety for all purposes. Unfortunately, rimonaban was withdrawn from clinical use due to its neuropsychiatric side effects.

[0026] CB1R is also expressed at low functional levels in peripheral organs, including the liver, skeletal muscle, adipose tissue, and pancreas. Interestingly, in rodent models of obesity and diabetes, selective CB-R antagonists targeting peripheral CB1R have shown similar metabolic benefits to rimonaban, but without the neuropsychiatric adverse effects. A growing body of research supports peripheral CB1R as an emerging therapeutic target for various disease conditions, with increased CB1R expression / activity in peripheral organs (liver, kidney, heart, pancreas, adipose tissue, muscle, lung) and immune cells (monocytes, macrophages) found to have pathogenic functions. Subsequent studies have shown that activation of adipocyte CB1R contributes to hyperleptinemia [Tam, J., Cinar, R., Liu, J., Godlewski, G., Wesley, D., Jourdan, T., Kunos, G. (2012). Peripheralcannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metabolism 16, 167–179] and increases lipolysis [Muller, T., Demizieux, L., Troy-Fioramonti, S., Gresti, J., Pais de Barros, JP, Berger, H., Degrace, P. (2017). Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue. American Journal of Physiology. Endocrinology and Metabolism 313, E26–E36; Sidibeh, CO,Pereira, MJ, Lau Borjesson, J., Kamble, PG, Skrtic, S., Katsogiannos,P., Eriksson, JW (2017). Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance.[Endocrine 55, 839–852]. The above paper is incorporated herein by reference in its entirety for all purposes. It was later found that selective gene deletion was sufficient to prevent diet-induced obesity (DIO) through adipose tissue reprogramming (leading to browning of white adipose tissue and increased thermogenesis). CB1R has also been identified in hepatocytes, where activation promotes de novo lipogenesis and hepatic insulin resistance [Osei-Hyiaman, D., DePetrillo, M., Pacher, P., Liu, J., Radaeva, S., Batkai, S., Kunos, G. (2005). Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. The Journal of Clinical Investigation 115, 1298–1305; Osei-Hyiaman, D., Liu, J., Zhou, L., Godlewski, G., Harvey-White, J., Jeong, WI, Kunos, G. (2008). Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. The Journal of Clinical Investigation 118, 129 ...298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, 1298, [3160–3169]. The aforementioned papers are incorporated herein by reference in their entirety for all purposes. CB1R expression and activity are increased in the liver under various pathological conditions of different etiologies, such as non-alcoholic fatty liver disease [Jourdan, T., Demizieux, L., Gresti, J., Djaouti, L., Gaba, L., Verges, B., & Degrace, P. (2012). Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from culturedexplants.]Hepatology 55, 790–799; Liu , J. , Zhou , L. , Xiong , K. , Godlewski ,G. , Mukhopadhyay , B. , Tam , J. , Kunos , G. (2012). Hepatic cannabinoidreceptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142, 1218–1228] [Choi, WM, Kim, HH, Kim, MH, Cinar, R., Yi, HS, Eun, HS, Jeong, WI (2019). Glutamate signaling in hepatic stellate cells drivesalcoholic steatosis. Cell Metabolism 30(877–889), e877; Jeong , WI , Osei-Hyiaman , D. , Park , O. , Liu , J. , Batkai , S. , Mukhopadhyay , P. , Kunos , G. (2008). Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids is mediated by alcoholic fatty liver. Cell Metabolism 7,227–235] [van der Poorten, D., Shahidi, M., Tay, E., Sesha, J.,Tran, K., McLeod, D., George, J. (2010). Hepatitis C virus induces thecannabinoid receptor 1. PLoS One 5]Introduction [Mukhopadhyay, B., Schuebel, K.,Mukhopadhyay, P., Cinar, R., Godlewski, G., Xiong, K., Kunos, G. (2015).Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms. [Hepatology 61, 1615–1626]. The above paper is incorporated herein by reference in its entirety for all purposes. Selective loss of CB1R in hepatocytes attenuates diet-induced hepatic steatosis, dyslipidemia, insulin and leptin resistance, but does not affect obesity. Therefore, CB1R antagonists have potential use in treating the aforementioned liver conditions. Activation of CB1R in skeletal muscle inhibits insulin-induced glucose uptake, leading to peripheral insulin resistance [Eckardt, K., Sell, H., Taube, A., Koenen, M., Platzbecker, B., Cramer, A., Eckel, J. (2009). Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 52, 664–674; Liu, YL, Connoley, IP, Wilson, CA, & Stock, MJ (2005). Effects of the cannabinoid CB1 receptor antagonist SR141716 onoxygen consumption and soleus muscle glucose uptake in Lep(ob) / Lep(ob) mice. International Journal of Obesity 29, 183–187]. These papers are incorporated herein by reference in their entirety for all purposes. Skeletal muscle-specific CB1R deficiency prevents diet-induced insulin resistance and increases systemic energy expenditure [Gonzalez-Mariscal, I., Montoro, RA, O'Connell, JF, Kim, Y., Gonzalez-Freire, M., Liu, QR,... Egan, JM (2019).Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism. [The FASEB Journal 33, 5850–5863]. The above paper is incorporated herein by reference in its entirety for all purposes. CB1R is expressed in pancreatic islet β cells, and its activation in pancreatic islet β cells negatively regulates insulin receptor signaling and β cell proliferation [Kim, W., Doyle, ME, Liu, Z., Lao, Q., Shin, YK, Carlson, OD, Egan, JM (2011). Cannabinoids inhibit insulin receptor signaling in pancreatic beta-cells. Diabetes 60, 1198–1209], leading to β cell death [Kim, W., Lao, Q., Shin, YK, Carlson, OD, Lee, EK, Gorospe, M., Egan, JM (2012). Cannabinoids induce pancreatic beta-cell death by directly inhibiting insulin receptor activation. Science Signaling 5, ra23. Gonzalez-Mariscal, I., Krzysik-Walker, SM, Kim, W., Rouse, M., & Egan, JM (2016). Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice. Molecular and Cellular Endocrinology 423, 1–10. The above paper is incorporated herein by reference in its entirety for all purposes. Pharmacological blockade of CB1R in β cells improves incretin-induced insulin secretion [Gonzalez-Mariscal, I., Montoro, RA, Doyle, ME, Liu, QR, Rouse, M., O'Connell, J.].F., Egan, JM (2018). Absence of cannabinoid 1 receptor in beta cells protects against high-fat / high-sugar diet-induced betacell dysfunction and inflammation in murine islets. Diabetologia 61, 1470–1483] and glucose responsiveness [Shin, H., Han, JH, Yoon, J., Sim, HJ, Park, TJ, Yang, S., Kim, W. (2018). Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. Journal of Cellular and Molecular Medicine 22, 2337–2345], while selective loss of CB1R in β cells protects against diet-induced β cell dysfunction [Gonzalez-Mariscal, I., Montoro, RA, Doyle, ME, Liu, QR, Rouse, M., O'Connell, JF, Egan, JM]. (2018). Absence of cannabinoid 1 receptor in beta cells protects against high-fat / high-sugar diet-induced beta celldysfunction and inflammation in murine islets. Diabetologia 61, 1470–1483. This paper is incorporated herein by reference in its entirety for all purposes. Therefore, peripheral CB1R antagonism has the potential to treat a variety of metabolic disorders.

[0027] Similar to many pharmaceutical compounds, compound 1 of the present invention is a CB1R modulator that can be used to treat a variety of diseases, conditions and symptoms mediated by CB1R, including metabolic diseases such as obesity, diabetes, eating disorders, weight loss and control, as well as liver diseases, fibrotic conditions, pain, neurological conditions including substance abuse / dependency disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory conditions, gastrointestinal diseases, genetic conditions, reproductive system conditions, sleep disorders, osteoporosis, and the above indications.

[0028] As those skilled in the art will understand, once a compound is selected as a clinical candidate for development, it is desirable for it to have a crystalline or amorphous form with physical properties suitable for reliable formulation and manufacture. Such properties include, for example, filterability, hygroscopicity, density and flowability, and stability.

[0029] Polymorphs are different crystal forms of the same compound with different physical properties. Polymorphs can also include solvated or hydrated products (also known as pseudopolymorphs), as described in ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidance Q6A. Such forms can have different pharmaceutically relevant properties, particularly for oral formulations, including solubility, stability, processability, hygroscopicity, density, flowability, dissolution rate, and bioavailability. It may be desirable to identify improved forms exhibiting enhanced properties, such as increased water solubility and stability, better processability, no hygroscopic tendency, enhanced dissolution rate, and improved bioavailability of orally administered compositions. By changing the form, these properties may be altered in a manner favorable to the desired therapeutic effect.

[0030] The previously known methods for preparing compound 1 (described in WO 2020 / 117794 A1) produced amorphous substances. This invention provides six polymorphs of compound 1, namely polymorphic forms A, B, C, D, E, and F, and methods for preparing these polymorphs. Polymorphic form A was found to be the most stable of the identified forms. It is anhydrous, crystalline, stable, and possesses acceptable solid-state properties for solid dosage form development.

[0031] The present invention also relates to the use of these crystal forms in therapeutic methods and in the preparation of pharmaceutical compositions comprising such crystal forms. Summary of the Invention

[0032] This invention relates to the crystal form of compound 1, as shown below, named 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine (also named 3-[4-(1,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1,2-a]pyridine or 3-(4-tert-butoxyphenyl)-7-methyl-6-(4-(propyl-2-yloxy)phenyl)imidazo[1,2-a]pyridine This invention relates to methods for preparing such crystalline forms, to the use of such crystalline forms in inhibiting arenavirus infection in humans, other mammals, or cell cultures, to methods for treating arenavirus infections such as Lassa fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Brazilian hemorrhagic fever, Chapare hemorrhagic fever, and Luyo hemorrhagic fever, to methods for inhibiting arenavirus replication, to methods for reducing arenavirus load, and to pharmaceutical compositions comprising such crystalline forms that can be used in such methods. The invention also relates to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine, and to therapeutic or preventative uses of such crystalline forms and compositions.

[0033] In one embodiment, the present invention relates to the crystal form of compound 1, wherein compound 1 is represented by the following structural formula:

[0034] .

[0035] In another embodiment, the present invention relates to the crystal form of compound 1, wherein the crystal form is selected from: polymorphic form A of compound 1, polymorphic form B of compound 1, polymorphic form C of compound 1, polymorphic form D of compound 1, polymorphic form E of compound 1 and polymorphic form F of compound 1.

[0036] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or solvent.

[0037] In another embodiment, the present invention relates to a method for treating infections associated with viruses of the Arenaviridae enveloped virus family or any virus expressing arenavir glycoproteins to mediate cell entry, the method comprising administering a pharmaceutically effective dose of a crystal form of compound 1, and a pharmaceutically acceptable carrier, diluent or solvent thereof.

[0038] The present invention also relates to a method for modulating cannabinoid receptor 1 (CB1R) in mammals, wherein the method comprises administering to the mammal in need a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or solvent thereof. Attached Figure Description

[0039] Figure 1 The XRPD diffraction pattern of polymorphic form A of compound 1 is shown.

[0040] Figure 2 The TGA / DSC overlay image of polymorphic form A of compound 1 is shown.

[0041] Figure 3 The XRPD diffraction pattern of polymorphic form B of compound 1 is shown.

[0042] Figure 4 The TGA / DSC overlay image of polymorphic form B of compound 1 is shown.

[0043] Figure 5 The XRPD diffraction pattern of the polymorphic form C of compound 1 is shown.

[0044] Figure 6 The TGA / DSC overlay image of the polymorphic form C of compound 1 is shown.

[0045] Figure 7 The XRPD diffraction pattern of polymorphic form D of compound 1 is shown.

[0046] Figure 8 The TGA / DSC overlay plot of polymorphic form D of compound 1 is shown.

[0047] Figure 9 The XRPD diffraction pattern of the polymorphic form E of compound 1 is shown.

[0048] Figure 10 The TGA / DSC overlay image of polymorphic form E of compound 1 is shown.

[0049] Figure 11 The XRPD diffraction pattern of the polymorphic form F of compound 1 is shown.

[0050] Figure 12 The TGA / DSC overlay image of the polymorphic form F of compound 1 is shown.

[0051] Figure 13 The phase diagram of crystal form AF of compound 1 is shown.

[0052] Figure 14 The DVS isotherm of polymorphic form A of compound 1 is shown.

[0053] Figure 15 The figures show A) the percentage change in average body weight and B) the average food intake in the DIO obesity study in mice.

[0054] Figure 16 The average fasting glucose level in a mouse obesity model is shown.

[0055] Figure 17 The average cholesterol measurements at the end of the 28-day GLP rat toxicity study are shown. Detailed Implementation

[0056] In one embodiment, the present invention relates to the crystal form of compound 1, wherein compound 1 is represented by the following structural formula:

[0057] .

[0058] In another embodiment, the present invention relates to the crystal form of compound 1, wherein the crystal form is selected from: polymorphic form A of compound 1, polymorphic form B of compound 1, polymorphic form C of compound 1, polymorphic form D of compound 1, polymorphic form E of compound 1 and polymorphic form F of compound 1.

[0059] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form A of compound 1, and wherein form A is characterized by having at least three characteristic peaks selected from about 7.3, 14.5 and 16.8 degrees 2θ in a powder X-ray diffraction pattern measured using Cu K-α radiation.

[0060] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form A of compound 1, and wherein the polymorph has a powder X-ray diffraction pattern containing a peak at a diffraction angle (2θ) that is similar to... Figure 1 The representation shown is essentially the same as the representation shown.

[0061] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form A of compound 1, and wherein the polymorph shows a small endothermic peak at about 70°C in DSC, followed by melting at about 120°C.

[0062] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form B of compound 1, and wherein form B is characterized by having at least three characteristic peaks selected from about 5.0, 9.9 and 14.9 degrees 2θ in its powder X-ray diffraction pattern measured using Cu K-α radiation.

[0063] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form B of compound 1, and wherein the polymorph has a powder X-ray diffraction pattern containing a peak at a diffraction angle (2θ) that is similar to... Figure 3 The representation shown is essentially the same as the representation shown.

[0064] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form B of compound 1, and wherein the crystal form shows endothermic peaks at about 67°C and 120°C in DSC.

[0065] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form C of compound 1, and wherein form C is characterized by having at least three characteristic peaks selected from about 5.0, 10.7 and 18.8 degrees 2θ in its powder X-ray diffraction pattern measured using Cu K-α radiation.

[0066] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form C of compound 1, and wherein the polymorph has a powder X-ray diffraction pattern containing peaks at a diffraction angle (2θ) that are similar to... Figure 5 The representation shown is essentially the same as the representation shown.

[0067] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form C of compound 1, and wherein the polymorph shows endothermic peaks at about 65°C, 116°C, 120°C and 137°C in DSC.

[0068] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form D of compound 1, and wherein form D is characterized by having at least three characteristic peaks selected from about 7.2, 14.4 and 21.7 degrees 2θ in a powder X-ray diffraction pattern measured using Cu K-α radiation.

[0069] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form D of compound 1, and wherein the polymorph has a powder X-ray diffraction pattern containing peaks at a diffraction angle (2θ) that are similar to... Figure 7 The representation shown is essentially the same as the representation shown.

[0070] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form D of compound 1, and wherein the crystal form shows endothermic peaks at about 61°C, 72°C and 118°C in DSC.

[0071] In another embodiment, the present invention relates to the crystal form of compound 1, wherein the polymorphic form is form E of compound 1, and wherein form E is characterized by having at least three characteristic peaks selected from about 5.0, 10.7 and 15.1 degrees 2θ in the powder X-ray diffraction pattern measured using Cu K-α radiation.

[0072] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form E of compound 1, and wherein the polymorph has a powder X-ray diffraction pattern containing peaks at a diffraction angle (2θ) that are similar to... Figure 9 The representation shown is essentially the same as the representation shown.

[0073] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form E of compound 1, and wherein the crystal form shows endothermic peaks at about 68°C, 118°C and 120°C in DSC.

[0074] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form F of compound 1, and wherein form F is characterized by having at least three characteristic peaks selected from about 7.3, 11.9 and 17.0 degrees 2θ in its powder X-ray diffraction pattern measured using Cu K-α radiation.

[0075] In another embodiment, the present invention relates to a polymorph of compound 1, wherein the polymorphic form is form F of compound 1, and wherein the polymorph has a powder X-ray diffraction pattern containing peaks at a diffraction angle (2θ) that are similar to... Figure 11 The representation shown is essentially the same as the representation shown.

[0076] In another embodiment, the present invention relates to a crystal form of compound 1, wherein the polymorphic form is form F of compound 1, and wherein the crystal form shows endothermic peaks at about 62°C, 73°C and 93°C in DSC.

[0077] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or solvent.

[0078] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A.

[0079] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form B.

[0080] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form C.

[0081] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form D.

[0082] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form E.

[0083] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form F.

[0084] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, carboxymethyl cellulose, povidone, sodium carboxymethyl starch, agar, carbonate. Calcium, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hexyl ester, glyceryl dis(2-2-)hexyl ester, stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

[0085] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, carboxymethyl cellulose, povidone, carboxymethyl cellulose ... Sodium methyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hexyl ester, glyceryl dis(2-2-)hexyl ester, stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

[0086] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0087] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: silicified microcrystalline cellulose, fumed silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0088] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from mannitol, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0089] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0090] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

[0091] In another embodiment, the present invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

[0092] In another embodiment, the present invention relates to a pharmaceutical composition comprising about 0.5 wt% to about 60 wt% of a polymorphic form A of compound 1, wherein the pharmaceutical composition is a tablet or capsule.

[0093] In another embodiment, the present invention relates to a pharmaceutical composition comprising about 0.5 wt% to about 60 wt% of polymorphic form A of compound 1 by weight of the composition, and wherein the composition is preferably a tablet.

[0094] In another embodiment, the present invention relates to a tablet formulation comprising about 10 mg to about 500 mg of crystalline compound 1 per tablet.

[0095] In another embodiment, the present invention relates to a tablet formulation comprising about 10 mg to about 500 mg of crystalline compound 1 per tablet, and wherein the polymorphic form of compound 1 is form A.

[0096] In another embodiment, the present invention relates to a tablet formulation comprising about 20 mg to about 350 mg of crystalline compound 1 per tablet, and wherein the polymorphic form of compound 1 is form A.

[0097] In another embodiment, the present invention relates to a tablet formulation comprising about 25 mg to about 300 mg of crystalline compound 1 per tablet, and wherein the polymorphic form of compound 1 is form A.

[0098] In another embodiment, the present invention relates to a tablet formulation comprising about 50 mg to about 250 mg of crystalline compound 1 per tablet, which may be associated with acute or severe treatment, and wherein the polymorphic form of compound 1 is form A.

[0099] In another embodiment, the present invention relates to a tablet formulation comprising about 10 mg to about 50 mg of crystalline compound 1 per tablet, which may be associated with chronic treatment, and wherein the polymorphic form of compound 1 is form A.

[0100] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0101] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate.

[0102] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, mannitol, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

[0103] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

[0104] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

[0105] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

[0106] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, and wherein the polymorphic form of compound 1 is form A.

[0107] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, silicified microcrystalline cellulose, fumed silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, and wherein the polymorphic form of compound 1 is form A.

[0108] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, mannitol, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the polymorphic form of compound 1 is form A.

[0109] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate, wherein the polymorphic form of compound 1 is form A.

[0110] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate, wherein the polymorphic form of compound 1 is form A.

[0111] In another embodiment, the present invention relates to a tablet formulation comprising crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate, wherein the polymorphic form of compound 1 is form A.

[0112] In another embodiment, the present invention relates to a capsule formulation comprising about 10 mg to about 500 mg of crystalline compound 1 per capsule.

[0113] In another embodiment, the present invention relates to a capsule formulation comprising about 10 mg to about 500 mg of crystalline compound 1 per capsule, and wherein the polymorphic form of compound 1 is form A.

[0114] In another embodiment, the present invention relates to a capsule formulation comprising about 20 mg to about 350 mg of crystalline compound 1 per capsule, and wherein the polymorphic form of compound 1 is form A.

[0115] In another embodiment, the present invention relates to a capsule formulation comprising about 25 mg to about 300 mg of crystalline compound 1 per capsule, and wherein the polymorphic form of compound 1 is form A.

[0116] In another embodiment, the present invention relates to a capsule formulation comprising about 50 mg to about 250 mg of crystalline compound 1 per capsule, and wherein the polymorphic form of compound 1 is form A.

[0117] In another embodiment, the present invention relates to a capsule formulation comprising about 10 mg to about 50 mg of crystalline compound 1 per capsule, and wherein the polymorphic form of compound 1 is form A.

[0118] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0119] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, silicified microcrystalline cellulose, fumed silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0120] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, mannitol, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0121] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0122] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0123] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

[0124] In another embodiment, the present invention relates to a capsule formulation comprising a crystalline compound 1, wherein the capsule is an HPMC capsule.

[0125] In another embodiment, the present invention relates to a capsule formulation comprising a crystalline compound 1, wherein the polymorphic form of the compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0126] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, and wherein the capsule is an HPMC capsule.

[0127] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, silicified microcrystalline cellulose, fumed silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, and wherein the capsule is an HPMC capsule.

[0128] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, mannitol, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the capsule is an HPMC capsule.

[0129] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the capsule is an HPMC capsule.

[0130] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate, wherein the capsule is an HPMC capsule.

[0131] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose and magnesium stearate, and wherein the capsule is an HPMC capsule.

[0132] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, wherein the polymorphic form of compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0133] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, silicified microcrystalline cellulose, fumed silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, wherein the polymorphic form of compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0134] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, mannitol, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose and magnesium stearate, wherein the polymorphic form of compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0135] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the polymorphic form of compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0136] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the polymorphic form of compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0137] In another embodiment, the present invention relates to a capsule formulation comprising crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose and magnesium stearate, wherein the polymorphic form of compound 1 is form A, and wherein the capsule is an HPMC capsule.

[0138] In another embodiment, the method includes administering a pharmaceutically effective amount of a pharmaceutical composition to a human, other mammal, cell culture, or biological sample, the pharmaceutical composition comprising a polymorph selected from the following: polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, and polymorph F of compound 1 as described in Examples 2 to 22, and a pharmaceutically acceptable carrier, diluent, or solvent.

[0139] In another embodiment, the method includes administering a pharmaceutically effective amount of a pharmaceutical composition to a human, other mammal, cell culture, or biological sample, the pharmaceutical composition comprising about 34.03% w / w of polymorphic form A of compound 1, 31.03% w / w of microcrystalline cellulose, 6.67% hydroxypropyl cellulose, 4.76% w / w of croscarmellose sodium, 1.49% w / w of magnesium stearate, 17.28% w / w of silanized microcrystalline cellulose, 3.78% w / w of Opadry Green, and 0.95% of Opadry Clear, as well as a pharmaceutically acceptable carrier, diluent, or solvent.

[0140] In another embodiment, the method includes administering a pharmaceutically effective amount of a pharmaceutical composition comprising a polymorphic form of compound 1 and a pharmaceutically acceptable carrier, diluent, or solvent, and an additional therapeutically effective amount of a therapeutic agent selected from: ribavirin, polymerase inhibitors, favipiravir, triazavirin, small interfering RNA (siRNA), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.

[0141] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 and a pharmaceutically acceptable carrier, diluent, or solvent, and a therapeutically effective amount of favipiravir.

[0142] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 and a pharmaceutically acceptable carrier, diluent, or solvent, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A.

[0143] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir.

[0144] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A.

[0145] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, and carboxymethyl cellulose. Povidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hes(2- ...

[0146] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose. Chloroprene, carboxymethyl cellulose, povidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hes(2-2-)hes( ...

[0147] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

[0148] In another embodiment, the method includes administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

[0149] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises about 10 mg to about 500 mg of crystalline compound 1 per tablet.

[0150] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises about 10 mg to about 500 mg of crystalline compound 1 per tablet, and wherein the polymorphic form of compound 1 is form A.

[0151] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises crystalline compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, carboxymethyl cellulose Ingredients include: polyvinylpyrrolidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hexyl ester, glyceryl dis(2-2-)hexyl ester, stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

[0152] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises crystalline compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and croscarmellose sodium carboxymethyl cellulose. Povidone, carboxymethyl cellulose, povidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hes(2- ...

[0153] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

[0154] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of compound 1 is form A.

[0155] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

[0156] In another embodiment, the method includes administering a pharmaceutically effective amount of the tablet formulation to a human, other mammal, cell culture, or biological sample, and a therapeutically effective amount of favipiravir, wherein the tablet formulation comprises crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate, and wherein the polymorphic form of compound 1 is form A.

[0157] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or solvent thereof, to a human, other mammal, cell culture, or biological sample, wherein compound 1 is represented by the following structural formula:

[0158] .

[0159] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or solvent thereof, to a human, other mammal, cell culture or biological sample, wherein the polymorphic form of compound 1 is form A, and wherein form A is characterized by a powder X-ray diffraction pattern measured using Cu K-α radiation containing at least three characteristic peaks selected from about 7.3, 14.5 and 16.8 degrees 2θ.

[0160] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or solvent thereof, and a therapeutically effective amount of favipiravir to a human, other mammal, cell culture or biological sample.

[0161] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or solvent thereof, and a therapeutically effective amount of favipiravir to a human, other mammal, cell culture or biological sample, wherein the polymorphic form of compound 1 is form A, and wherein form A is characterized by a powder X-ray diffraction pattern measured using Cu K-α radiation containing at least three characteristic peaks selected from about 7.3, 14.5 and 16.8 degrees 2θ.

[0162] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, to a human, other mammal, cell culture, or biological sample, along with at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir.

[0163] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir to a human, other mammal, cell culture, or biological sample, wherein the polymorphic form of compound 1 is form A, and wherein form A is characterized by a powder X-ray diffraction pattern measured using Cu K-α radiation containing at least three characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2θ.

[0164] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof to a human, other mammal, cell culture, or biological sample, along with at least one pharmaceutically acceptable excipient and a therapeutically effective amount of favipiravir, wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, carboxymethyl cellulose, and povidone. Sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hexyl ester, glyceryl dis(2-2-)hexyl ester, stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

[0165] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, to a human, other mammal, cell culture, or biological sample, along with at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, etc. Carboxymethyl cellulose, povidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-)hexyl ester, glyceryl dis(2-2-)hexyl ester, stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

[0166] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, to a human, other mammal, cell culture, or biological sample, along with at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

[0167] In another embodiment, the method includes administering an effective amount of at least one polymorphic form of compound 1 or a pharmaceutically acceptable solvate thereof, to a human, other mammal, cell culture, or biological sample, along with at least one pharmaceutically acceptable excipient and a therapeutically effective amount of favipiravir, wherein the polymorphic form of compound 1 is form A, and wherein the excipient is selected from: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

[0168] Unexpectedly, compound 1 of the present invention, which is being developed for the treatment of arenavirus, particularly for the treatment of Lassa fever, has been found to exhibit interesting CB1R antagonist pharmacological activities and properties.

[0169] A disease or condition in mammals or humans that is suitable for treatment by a CB1R modulator can be treated by administering a pharmaceutically effective amount of the pharmaceutical composition, said pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or solvent.

[0170] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, or tautomer form are CB1R antagonists.

[0171] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as a medicament for treating diseases and conditions that can be treated with CB1R antagonists.

[0172] In another embodiment, the compound 1 of the present invention and its therapeutically acceptable salts, esters, and tautomer forms can be used as medicines for treating metabolic diseases, fibrotic conditions, pain, neurological disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory diseases, gastrointestinal diseases, genetic diseases, reproductive system diseases, sleep disorders, and osteoporosis.

[0173] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as a medicament for treating metabolic diseases, including but not limited to obesity, diabetes, eating disorders, anorexia, bulimia, weight loss and control, and liver diseases such as nonalcoholic steatohepatitis (NASH).

[0174] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as medicaments for treating fibrotic conditions, including but not limited to liver fibrosis, pulmonary fibrosis, chronic kidney disease, and renal fibrosis.

[0175] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as a medicament for treating pain such as acute, chronic, inflammatory, and neuropathic pain.

[0176] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salts, esters, and tautomer forms can be used as medicaments for treating neurological disorders, including but not limited to seizures, epilepsy, migraines, anxiety, depression, bipolar disorder, psychosis, schizophrenia, cognitive impairments such as learning and memory impairment, withdrawal syndromes, neurodegenerative diseases such as Alzheimer's and Huntington's diseases, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, spasticity in multiple sclerosis, and substance abuse / dependency disorders such as opioid addiction, stimulant addiction, alcohol addiction, and nicotine addiction.

[0177] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as a medicament for treating cardiovascular diseases, including but not limited to hypertension and atherosclerosis.

[0178] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as medicaments for treating various types of cancer, including but not limited to breast cancer, prostate cancer, and colon cancer.

[0179] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salts, esters, and tautomer forms can be used as medicaments for treating inflammatory and autoimmune diseases, including but not limited to systemic sclerosis and rheumatoid arthritis.

[0180] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salts, esters, and tautomer forms can be used as medicaments for treating respiratory conditions, including but not limited to asthma.

[0181] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as a medicament for treating gastrointestinal diseases, including but not limited to inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), constipation, vomiting, and nausea.

[0182] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as medicaments for treating hereditary diseases, including but not limited to Duchenne muscular dystrophy and Down syndrome.

[0183] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, and tautomer forms can be used as a medicament for treating reproductive system disorders, including but not limited to endometriosis and erectile dysfunction.

[0184] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, or tautomer forms can be used as a medicament for treating sleep disorders, including but not limited to narcolepsy and insomnia.

[0185] In another embodiment, compound 1 of the present invention and its therapeutically acceptable salt, ester, or tautomer forms can be used as a medicament for treating osteoporosis.

[0186] definition

[0187] As used herein, the terms “comprising” and “including” are used in their open, non-restrictive sense.

[0188] The term "crystallization" refers to any solid substance that exhibits three-dimensional order, as opposed to amorphous solid substances, and gives a unique XRPD spectrum with sharp defining peaks.

[0189] The term “polymorph” refers to different crystal forms of the same compound, and includes, but is not limited to, other solid molecular forms of the same compound, including hydrates (e.g., bound water present in a crystalline structure) and solvates (e.g., bound solvents other than water).

[0190] The term "amorphous" refers to any solid, oily, or liquid substance that (i) lacks order in three dimensions, or (ii) exhibits order in fewer than three dimensions, with order only over short distances (e.g., less than 10 Å), or both. Therefore, amorphous substances include partially crystalline materials and crystalline intermediate phases, such as materials exhibiting one-dimensional or two-dimensional translational order (liquid crystals), orientation disorder (orientation-disordered crystals), or conformational disorder (conformation-disordered crystals).

[0191] The term "solvent" is used to describe molecular complexes between compounds of the present invention and solvent molecules. Examples of solvates include, but are not limited to, combinations of compounds of the present invention with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. When the solvent is water, the term "hydrate" may be used. Specifically, in the present invention, it is contemplated that one solvent molecule may associate with one molecule of a compound of the present invention, such as a hydrate. Furthermore, it is contemplated that more than one solvent molecule may associate with one molecule of a compound of the present invention, such as a dihydrate. Additionally, it is contemplated that fewer than one solvent molecule may associate with one molecule of a compound of the present invention, such as a hemihydrate. Moreover, the solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the bioavailability of the non-hydrated form of the compound.

[0192] The terms "powder X-ray diffraction pattern," "XRPD pattern," or "PXRD pattern" refer to an experimentally observed diffraction pattern or parameters derived from it. Powder X-ray diffraction patterns are characterized by peak positions (x-axis) and peak intensities (y-axis).

[0193] The terms "2θ value," "2-theta," or "2θ" refer to the peak position in degrees in the experimental setup of X-ray diffraction experiments, and are a commonly used unit of horizontal axis in diffraction patterns.

[0194] As used in this article, “cannabinoid receptor 1” or “CB1 receptor” or “CB1R” or “CB1” refers to the G protein-coupled type 1 cannabinoid receptor encoded by the CNR1 gene in humans.

[0195] As used herein, the term "pharmaceutically acceptable formulation" refers to a combination of the compound of the present invention or its solvation with one or more excipients that are compatible with the compound of the present invention and harmless to the recipient. Pharmaceutical formulations can be prepared by methods known to those skilled in the art. For example, the compounds of the present invention can be formulated and formed into tablets, capsules, etc., using common excipients. Examples of excipients suitable for such formulations include: fillers and extenders such as starch, sugars, mannitol, and silicon derivatives; binders such as carboxymethyl cellulose and other cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone; humectants such as glycerin; disintegrants such as povidone, sodium glycolate, sodium carboxymethyl cellulose, agar, calcium carbonate, and sodium bicarbonate; delayed dissolution agents such as paraffin; reabsorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol and glyceryl monostearate; adsorbents such as kaolin and bentonite; and lubricants such as talc, calcium stearate and magnesium stearate, solid polyethylene glycol, and sodium dodecyl sulfate. The final drug form may be pills, tablets, powders, lozenges, sachets, capsules, sugar-coated pills, or aseptically packaged powders, depending on the type of excipients used. Furthermore, it is specifically envisioned that pharmaceutically acceptable formulations of the present invention may contain more than one active ingredient. For example, such formulations may contain one compound of the present invention and one or more other agents that inhibit arenavirus. Alternatively, such formulations may contain compound 1 of the present invention and one or more other agents that modulate CB1R activity.

[0196] The terms “pharmaceutically acceptable formulation” and “pharmaceutical composition” are synonyms and can be used interchangeably.

[0197] The term "excipient" is defined as: any ingredient or substance that is intentionally added to a drug rather than as part of the active pharmaceutical ingredient.

[0198] The term "active pharmaceutical substance" is defined as: any substance intended to be incorporated into a final medicine and intended to provide pharmacological activity or to produce other direct effects in the diagnosis, cure, relief, treatment or prevention of a disease, or to affect the structure or any function of the body.

[0199] Examples of excipient types include, but are not limited to, compatibilizers, fillers, carriers, diluents, disintegrants, lubricants, solubility enhancers, gliding agents, sweeteners, coating agents, and colorants.

[0200] A "composite agent" is defined as a pharmaceutical agent that provides a matrix to carry the active pharmaceutical ingredient when it is at a low concentration. Compatibilizers include, but are not limited to, mannitol, lactose, sucrose, dextran, trehalose, and glycine.

[0201] "Filler" is defined as a non-active substance used to make the active pharmaceutical ingredient more easily measurable in tablet or capsule formation. Fillers increase the volume of a formulation while imparting mechanical properties that increase flowability and compressibility, which is beneficial for manufacturing and improving the robustness and content uniformity of the final formulation. Examples of fillers include, but are not limited to, lactose, mannitol, microcrystalline cellulose, dicalcium phosphate, and dicalcium phosphate dihydrate.

[0202] A “binder” is defined as a substance used to bind ingredients together in a formulation. Binders are used in tablets and granules to hold the active pharmaceutical ingredient (API) and excipients together. Adding binders improves the mechanical properties of tablets and can also improve flowability and API distribution. Examples of binders include, but are not limited to, povidone, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, gelatin, starch, carbomer, and sodium carboxymethyl cellulose.

[0203] "Carrier" is defined as: a drug carrier or drug solvent is a matrix used in the drug delivery process to improve the selectivity, efficacy, and / or safety of the active pharmaceutical ingredient. Carrier types include, but are not limited to, liposomes, polymeric micelles, microspheres, and dextran.

[0204] "Diluent" is defined as a filler used in pharmaceutical tablets to increase weight and improve content uniformity. Diluents include, but are not limited to, natural diluents such as starch, hydrolyzed starch, and partially pregelatinized starch. Commonly used diluents include anhydrous lactose, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol, and mannitol. Diluents provide better tablet properties, such as improving cohesiveness or promoting flow during tablet or capsule formation.

[0205] "Disintegrant" is defined as: a pharmaceutical agent added to tablet formulations to promote the breakdown of tablets into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a faster release of the active pharmaceutical ingredient. Disintegrants include, but are not limited to, alginate, bentonite, microcrystalline cellulose, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium low-substituted carboxymethyl cellulose, sodium low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.

[0206] "Lubricant" is defined as: a pharmaceutical agent added in small amounts to tablet and capsule formulations to improve the powder processing properties of the formulation. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-3 ...

[0207] "Gliders" are defined as substances that enhance powder flowability by reducing interparticle friction, surface charge, and cohesive forces, which in turn reduces the angle of repose. They are typically incorporated in dry powder form before direct tableting. Gliders include, but are not limited to, ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, colloidal silica, starch, and talc.

[0208] "Solubility enhancer" or "solubility-enhancing excipient" is defined as a substance used to enhance the solubility of an active pharmaceutical ingredient (API) and increase its bioavailability. Solubility enhancers include, but are not limited to, meglumine, cyclodextrin, polymers such as polyacrylic acid and polyamino acids, copolymers such as copolymers derived from methacrylic acid / ethyl acrylate, liposomes, and polymeric micelles.

[0209] A "sweetener" is defined as someone who masks the taste of a medication to make it palatable to the patient. For example, a spoonful of sugar helps the medication be swallowed. Sweeteners include sugar, sorbitol, xylitol, and artificial sweeteners.

[0210] "Coating" is defined as a film formed by a coating process. For example, coating is defined as a process in which a desired dosage form, such as granules or tablets, is coated with an external dry film to achieve a specific purpose, such as masking flavor or protecting against environmental conditions. Coating materials can consist of coloring agents, flavoring agents, gums, resins, waxes, plasticizers, and polyols. In modern times, polymers and polysaccharides are primarily used as coating materials, along with other materials such as plasticizers and pigments. Many precautions must be taken into account during the coating process to ensure the coating's durability and stability.

[0211] "Coloring agent" is defined as any dye, pigment, or substance that imparts color when added to food, medicine, or cosmetics or to the human body.

[0212] Examples of excipient types also include surfactants, emulsifiers, solubilizers, dispersants, and in vivo absorption enhancers, such as poloxamer.

[0213] As used herein, the term "arenavirus GP inhibition amount" refers to the amount of the compound of the present invention or its solvate required to inhibit the entry of arenavirus into cells in vivo (e.g., in mammals, birds) or in vitro. The amount of such compound required to induce such inhibition can be determined without excessive experimentation using the methods described herein and methods known to those skilled in the art.

[0214] As used herein, the term "therapeutic effective amount" refers to the amount of the compound of the invention sufficient to achieve the treatment as defined herein when administered to a mammal requiring such treatment. Therefore, the therapeutic effective amount of the compound of the invention is sufficient to modulate or inhibit the activity of the isopyrvirus GP protein, thereby reducing or mitigating the amount of isopyrvirus cell entry and replication mediated by the isopyrvirus GP protein activity.

[0215] Regarding arenavirus infection, the term "treatment" in mammals, particularly humans, includes: (i) preventing the occurrence of a disease or condition in individuals who may be susceptible to it, such that the treatment constitutes a preventive treatment of the pathological condition; (ii) regulating or suppressing a disease or condition, i.e., preventing its development; (iii) alleviating a disease or condition, i.e. causing the remission of the disease or condition; or (iv) alleviating and / or reducing the disease or condition or the symptoms caused by the disease or condition.

[0216] The term “regulation” used in this article for CB1R refers to the inhibition or enhancement of CB1R activity by a measurable amount. Inhibition means a decrease in CB1R activity, and enhancement means an increase in CB1R activity. Such enhancement or inhibition may depend on the occurrence of specific events, such as the activation of signal transduction pathways, and / or may only be observed in specific cell types.

[0217] As used herein, the term "modifier" in relation to CB1R refers to the use of the compounds of this invention or their salts or solvates as CB1R antagonists.

[0218] As used in this article, the term "antagonist" for CB1R refers to a compound that has no intrinsic regulatory activity and exerts its effect by interfering with the binding of agonists (e.g., endogenous cannabinoid ligands arachidonic acid ethanolamine (N-arachidonic ethanolamine) and 2-AG (2-arachidonic glycerol)) or inhibiting the action of agonists, or by reducing basal activity in the absence of agonists.

[0219] As used herein with respect to CB1R, the term "regulatory amount" refers to the amount of the compound of the present invention or its salt or solvation required to inhibit or enhance CB1R activity in vivo (e.g., in mammals) or in vitro. The amount of such compound required to induce such regulation can be determined without excessive experimentation using the methods described herein and methods known to those skilled in the art.

[0220] As used herein with respect to CB1R, the term "inhibitory amount" refers to the amount of the compound of the present invention or its salt or solvation required to inhibit or enhance CB1R activity in vivo (e.g., in mammals) or in vitro. The amount of such compound required to induce such inhibition or enhancement can be determined without excessive experimentation using the methods described herein and methods known to those skilled in the art.

[0221] As used herein with respect to CB1R, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention, or a salt or solvation thereof, sufficient to achieve the treatment as defined herein when administered to a mammal requiring such treatment. Therefore, a therapeutically effective amount of the compound of the present invention, or a salt or solvation thereof, is an amount sufficient to inhibit or enhance CB1R activity, thereby reducing or alleviating conditions that may be affected by CB1R activity.

[0222] Regarding CB1R activity, the term "treat / treating / treatment" in mammals, particularly humans, includes: (i) preventing the occurrence of a disease or condition in a potentially susceptible subject, such that the treatment constitutes a preventive treatment of the pathological condition; (ii) regulating or inhibiting a disease or condition, i.e., preventing its development; (iii) alleviating a disease or condition, i.e. causing the remission of the disease or condition; or (iv) alleviating and / or reducing a disease or condition or the symptoms caused by a disease or condition.

[0223] To treat or prevent diseases or conditions mediated in part or in whole by CB1R activity, the pharmaceutical composition of the present invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an amount of CB1R that is regulated, modulated, or inhibited to achieve therapeutic efficacy) of compound 1 of the present invention (as the active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients, and adjuvants that facilitate the processing of the active compound into a final pharmaceutical formulation.

[0224] The polymorphs of the present invention can be formulated into pharmaceutical compositions as described below, in any pharmaceutical form that is deemed suitable by those skilled in the art.

[0225] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one polymorph of the present invention and an inert, pharmaceutically acceptable excipient.

[0226] To treat or prevent diseases or conditions mediated by viruses, either partially or wholly caused by arenavirus infection or expressing arenavirus glycoproteins, the pharmaceutical compositions of the present invention are administered in a suitable formulation prepared by combining at least one compound of the present invention (as the active ingredient) in a therapeutically effective amount (i.e., an amount of arenavirus GP that is regulated, modulated, or inhibited to achieve therapeutic efficacy) with one or more pharmaceutically suitable excipients, such as diluents, carriers, and adjuvants that facilitate the processing of the active compound into a final pharmaceutical formulation.

[0227] The drug carrier used can be solid or liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Exemplary liquid carriers include syrup, peanut oil, olive oil, water, etc. Similarly, the compositions of the present invention may include time-delayed or sustained-release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with wax, ethyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate, etc. Other additives or excipients may be added to achieve the desired formulation properties. For example, bioavailability enhancers such as Labrasol, Gelucire, etc., or formulations such as CMC (carboxymethyl cellulose), PG (propylene glycol), or PEG (polyethylene glycol) may be added. Gelucire® (a semi-solid solvent that protects the active ingredient from light, moisture, and oxidation) may be added, for example, in the preparation of capsule formulations.

[0228] If a solid carrier is used, the formulation can be compressed into tablets, powder, or pellets and placed in hard gelatin capsules, or formulated as tablets or lozenges. The amount of solid carrier can vary, but is typically from about 25 mg to about 1 g. If a liquid carrier is used, the formulation can be in the form of a sterile injectable solution or suspension or non-aqueous liquid suspension in syrup, emulsion, soft gelatin capsules, ampoules, or vials. If a semi-solid carrier is used, the formulation can be in the form of both hard and soft gelatin capsule formulations. The compositions of the present invention are prepared in unit dosage forms suitable for administration, such as parenteral or oral administration.

[0229] The pharmaceutical agent can be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, etc., with a concentration ranging from 0% to 60% of the total volume. The composition can also be in the form of a salt of the active ingredient in a suitable aqueous solvent such as water or isotonic saline or glucose solution.

[0230] For oral administration, compounds can be formulated by combining at least one polymorph with a pharmaceutically acceptable carrier known in the art. Such carriers enable the polymorphs of the present invention to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a patient. Orally administered pharmaceutical formulations may use solid excipients mixed with the active ingredient (pharmaceutical), optionally milling the resulting mixture, and processing the granular mixture after adding suitable excipients (if desired) to obtain tablets or sugar-coated pill cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrants such as croscarmellose, agar, or alginate or its salts such as sodium alginate may be added. Sugar-coated pill cores are provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or sugar coatings to identify or characterize different combinations of active agents.

[0231] Orally applicable pharmaceutical formulations include push-in capsules made of gelatin and soft-seal capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Stabilizers may also be added. All formulations intended for oral administration should be administered in appropriate amounts for such administration. For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0232] Pharmaceutical compositions may also contain suitable solid or gel phase carriers. These carriers can significantly improve the bioavailability of poorly soluble drugs. Examples of such carriers include calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Additionally, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol®, Transcutol®, etc., may be used.

[0233] It should be understood that the actual dosage of the pharmaceutical agent of the present invention will vary depending on the specific agent used, the specific composition formulated, the method of administration, and the specific site, host, and disease treated. Those skilled in the art can determine the optimal dosage for a given set of conditions using conventional dosage determination experiments based on experimental data. For oral administration, the typically used exemplary daily dose will be from about 0.001 to about 1000 mg / kg body weight, with treatment courses repeated at appropriate intervals.

[0234] Furthermore, pharmaceutically acceptable formulations of the present invention may contain an amount of the polymorph of the present invention or a solvate thereof in the amounts of about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 10 mg to about 50 mg, or about 25 mg to about 500 mg, or about 50 mg to about 500 mg, or about 50 mg to about 250 mg, or about 100 mg to about 500 mg, or about 25 mg to about 300 mg, or about 50 mg to about 300 mg, or about 100 mg to about 300 mg.

[0235] Furthermore, pharmaceutically acceptable formulations of the present invention may contain an amount of the polymorph of the present invention or a solvate thereof of about 0.5 w / w% to about 95 w / w%, or about 1 w / w% to about 95 w / w%, or about 1 w / w% to about 75 w / w%, or about 5 w / w% to about 75 w / w%, or about 10 w / w% to about 75 w / w%, or about 10 w / w% to about 50 w / w%.

[0236] The polymorphs of the present invention or their solvates can be administered to mammals, such as humans, suffering from conditions or diseases mediated by isopyrvirus or any virus expressing isopyrvirus glycoproteins. They can be administered alone or in combination with one or more compounds selected from ribavirin, polymerase inhibitors, favipiravir, triazole, small interfering RNA (siRNA), vaccines, monoclonal antibodies, immunomodulators, and other isopyrvirus inhibitors, as part of a pharmaceutically acceptable formulation, once daily, twice daily, three times daily, four times daily, or even more frequently.

[0237] The polymorphs of the present invention or their solvates can be combined with at least one other agent for treating arenavirus and administered to mammals, such as humans, suffering from arenavirus-mediated conditions or diseases, said agent being selected from: ribavirin, viral RNA-dependent RNA polymerase inhibitors such as those shown in Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol Immunol, 2008; 320: 137-156 (which is incorporated herein by reference in its entirety), favipiravir (a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase), triazolelin (a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase), and those shown in Carthew RW and Sontheimer EJ, Origins and Mechanisms of miRNAs and siRNAs, Nature, 2009; 136: Small interfering RNAs (siRNAs) and microRNAs as shown in 642-655 (which are incorporated herein by reference in their entirety), vaccines as shown in Nablel GJ, Designing Tomorrow's Vaccines, NEJM, 2013; 368:551-560 (which are incorporated herein by reference in their entirety), and immunomodulators as shown in Patil US, Jaydeokar AV and Bandawane DD, Immunomodulators: A Pharmacological Review, Internatl J Pharmacy and Pharmaceutical Sci, 2012; 4: 30-36 (which are incorporated herein by reference in their entirety), may be administered once daily, twice daily, three times daily, four times daily, or even more frequently, alone or as part of a pharmaceutically acceptable formulation containing other arenavirus inhibitors.

[0238] Those skilled in the art will understand that, with respect to the polymorphs of the present invention, the specific pharmaceutical formulation, dosage, and frequency of administration to mammals requiring such treatment per day are all choices within the knowledge of those skilled in the art and can be determined without excessive experimentation.

[0239] The polymorphs of the present invention can be used to regulate or inhibit isoplasmic virus glycoprotein (GP) in vitro and in vivo.

[0240] Therefore, these polymorphs can be used to prevent and / or treat disease states associated with arenavirus infection or to treat viruses expressing arenavirus glycoproteins.

[0241] The present invention also relates to a method for treating arenavirus infection in mammals, including humans, comprising administering to the mammal an amount of a polymorph of compound 1 as defined above or a solvate thereof that is effective in treating a disease state associated with arenavirus infection or a virus expressing arenavirus glycoproteins.

[0242] The compounds of the present invention, or their salts or solvates, may be administered to mammals, such as humans, suffering from conditions or diseases mediated by CB1R activity, alone or as part of a pharmaceutically acceptable formulation, once daily, twice daily, three times daily, four times daily, or even more frequently.

[0243] The compounds of the present invention, or their salts or solvates, may be administered, together with at least one other agent for treating / preventing / inhibiting or improving CB1R-mediated diseases or conditions, to mammals such as humans suffering from CB1R-mediated diseases or conditions, said agent being selected from, but not limited to: anti-obesity agents, antidiabetic agents, lipid-lowering agents, antihypertensive agents, appetite suppressants, antiepileptic agents, anxiolytic agents, antidepressants, anti-inflammatory agents, anti-asthmatic agents, anti-migraine agents, cognitive enhancers, antipsychotic agents, nicotinic receptor partial agonists, opioid receptor antagonists, dopamine receptor agonists, alone or as part of a pharmaceutically acceptable formulation, once daily, twice daily, three times daily, four times daily, or even more frequently.

[0244] Those skilled in the art will understand that, with respect to the compounds of the present invention, the specific pharmaceutical formulation, dosage, and frequency of administration to mammals requiring such treatment per day are all choices within the knowledge of those skilled in the art and can be determined without excessive experimentation.

[0245] The compounds of this invention can be used to regulate CB1R.

[0246] Therefore, this compound can be used to prevent and / or treat CB1R-mediated diseases or conditions.

[0247] The present invention also relates to a method of treating CB1R-mediated diseases or conditions, comprising administering to the mammal an amount of compound 1 as defined above or a salt or solvate thereof that is effective in treating CB1R-mediated diseases or conditions.

[0248] In the following preparation examples and embodiments, "Ac" refers to acetyl, "Me" refers to methyl, "Et" refers to ethyl, "DCM" (CH2Cl2) refers to dichloromethane or methylene chloride, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "IPA" refers to isopropanol, "EtOAc" refers to ethyl acetate, "Na2SO4" refers to sodium sulfate, "MeOH" refers to methanol, "EtOH" refers to ethanol, "H2O" refers to water, "K2CO3" refers to potassium carbonate, "THF" refers to tetrahydrofuran, "TBME" or "MTBE" refers to tert-butyl methyl ether, "dppf" refers to 1,1'-bis(diphenylphosphine)ferrocene, "ACN" refers to acetonitrile, "MIBK" refers to methyl isobutyl ketone, "IPAc" refers to isopropyl acetate, "CPME" refers to cyclopentyl methyl ether, "MEK" refers to methyl ethyl ketone, and "2-MeTHF" refers to 2-methyltetrahydrofuran. "N" refers to equivalent, "M" refers to molar concentration, "mL" refers to milliliters, "mmol" refers to millimoles, "μmol" refers to micromoles, "eq." refers to equivalent, "℃" refers to degrees Celsius, "RT" refers to room temperature, "RH" refers to relative humidity, "XRPD" refers to X-ray powder diffraction, "DSC" refers to differential scanning calorimetry, "TGA" refers to thermogravimetric analysis, "DVS" refers to dynamic vapor adsorption, "HPLC" refers to high performance liquid chromatography, "HPMC" refers to hydroxypropyl methylcellulose, "MCC" refers to microcrystalline cellulose, "HPC" refers to hydroxypropyl cellulose, "PVP" refers to polyvinylpyrrolidone, "Mann" refers to mannitol, "Lact" refers to lactose, "CPV" refers to cross-linked carboxymethyl cellulose, "CCS" refers to sodium carboxymethyl cellulose, "SLS" refers to sodium dodecyl sulfate, "FS" refers to fumed silica, "SSF" refers to sodium stearoyl fumarate, and "MS" refers to magnesium stearate.

[0249] Experimental methods

[0250] X-ray powder diffraction (XRPD)

[0251] XRPD analysis was performed using Panalytical X'Pert. 3 Powder XRPD was performed on a Si zero-background support. The 2θ position was calibrated using a Panalytical Si reference disk. The parameters used are listed in Table 1.

[0252] Table 1. XRPD Test Parameters

[0253]

[0254] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0255] TGA data were collected using a TA Instruments TA Discovery 550 TGA. DSC analysis was performed using a TA Instruments TA Q2000 DSC. The DSC was calibrated using an indium reference standard, and the TGA was calibrated using a nickel reference standard. Detailed parameters used are listed in Table 2.

[0256] Table 2. Test parameters for TGA and DSC

[0257]

[0258] Example

[0259] The amorphous compound 1 used to prepare the polymorphs of the present invention can be synthesized using the method described in the WO 2020 / 117794 A1 patent application.

[0260] Example 1: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine (amorphous compound 1)

[0261] Step 1: 6-Bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1,2-a]pyridine

[0262]

[0263] To a solution of 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine (0.033 g, 0.1 mmol) in dioxane (1 mL) and water (0.5 mL), 4-(tert-butoxy)phenylboronic acid (0.020 g, 0.1 mmol) and sodium carbonate (0.032 g, 0.3 mmol) were added. The reaction mixture was purged with nitrogen, and then Pd(dppf)Cl2 (0.05 g, 0.06 mmol) was added. The resulting reaction mixture was heated to 90 °C for 12 hours, cooled to room temperature, and extracted with ethyl acetate. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by SiO2 column chromatography (hexane / EtOAc, from 4:1 to 1:2) to give 0.026 g of the title compound. Yield: 72%. LC / MS m / z: C 18 H 19 Calculated value of BrN2O [M+H] + 359.08, measured value 359.22.

[0264] Step 2: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine (amorphous compound 1)

[0265]

[0266] To a solution of 6-bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1,2-a]pyridine (0.026 g, 0.072 mmol) in dioxane (1 mL) and water (0.5 mL), 4-(isopropoxy)phenylboronic acid (0.015 g, 0.083 mmol) and sodium carbonate (0.022 g, 0.216 mmol) were added. The reaction mixture was purged with nitrogen, and then Pd(dppf)Cl2 (0.025 g, 0.03 mmol) was added. The resulting reaction mixture was heated to 90 °C for 12 hours, cooled to room temperature, and extracted with ethyl acetate. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by SiO2 column chromatography (hexane / EtOAc, from 4:1 to 1:2) to give 0.009 g of the title compound as an amorphous solid. Yield: 31%. LC / MS m / z: C 27 H 30 Calculated N₂O₂ value [M+H] + 415.24, measured value 415.36. 1 H NMR (500 MHz, DMSO-d6) δ 8.13 (s,1H), 7.65 (s, 1H), 7.57 (d, 2H), 7.54 (s, 1H), 7.33 (d, 2H), 7.11 (d, 2H),6.97 (d, 2H), 4.62- 4.67 (m, 1H), 2.24 (s, 3H), 1.33 (s, 9H), 1.28 (d, 6H). 13 C NMR: (300 MHz, CDCl3) δ 157.56, 155.34, 145.81, 134.59, 132.26, 130.72,129.57, 128.71, 129.54, 124.93, 124.55, 124.31, 121.83, 116.88, 115.49,78.93, 69.91, 28.8, 22.05, 20.68.

[0267] Furthermore, the amorphous compound 1 of the present invention can be prepared by standard operating methods known to those skilled in the art.

[0268] Polymorphic form A can be prepared by recrystallizing compound 1 from hot ethanol, then grinding the resulting solid into a powder and drying it under vacuum at 60°C, using the following method:

[0269] Example 2: Polymorphic form A of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0270] Amorphous compound 1 was dissolved in a minimum volume (approximately 2.8 times its volume) of hot (near-boiling) ethanol to form a homogeneous solution. The hot solution was cooled to room temperature and then placed in a freezer. Precipitation occurred during the freezing of the ethanol solution at approximately -20°C. The precipitate was filtered under vacuum, and the solid material was collected in polymorphic form F. The obtained solid material was ground into powder using a mortar and pestle and dried under vacuum at 60°C for approximately 2 days to obtain a white solid in polymorphic form A.

[0271] Alternatively, form A can be prepared by crystallizing amorphous compound 1 from hexane using the following method:

[0272] Example 3: Polymorphic form A of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0273] Amorphous compound 1, a colorless oily substance separated from a mixture of hexane and ethyl acetate by rotary evaporation, was treated with a small amount of hexane. After shaking, the resulting mixture began to solidify. The mixture was placed in a freezer until all the oily substance crystallized into a hard solid. The hexane was then decanted, and the residue was dried on a rotary evaporator at about 50°C to give a white solid in polycrystalline form A.

[0274] Alternatively, polymorphic form A can be prepared by recrystallization of compound 1 from a heptane solution.

[0275] The XRPD and TGA / DSC overlay plots of form A are shown in the figure below. Figure 1 and Figure 2 The XRPD patterns of Form A (expressed in degrees (2θ) and relative intensities, measured on a diffractometer with Cu K-α radiation) are shown in Table 3.

[0276] Table 3. List of XRPD peaks in Form A.

[0277]

[0278]

[0279] *Relative strength may vary depending on the morphology and particle size of the sample.

[0280] Example 4: Polymorphic form B of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0281] Polymorphic form B can be prepared by pulping polymorphic form A in a mixture of DMF:H2O (3:7) at room temperature.

[0282] The XRPD and TGA / DSC overlay plots of form B are shown in the figure. Figure 3 and Figure 4 The XRPD patterns of Form B (expressed in degrees (2θ) and relative intensities, measured on a diffractometer with Cu K-α radiation) are shown in Table 4.

[0283] Table 4. List of XRPD peaks in Form B.

[0284]

[0285]

[0286] Example 5: Polymorphic form of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine C

[0287] Polymorphic form C can be prepared by pulping polymorphic form A in a mixture of EtOH: n-heptane (2:8) at room temperature.

[0288] The XRPD and TGA / DSC overlay plots of form C are shown in the figure. Figure 5 and Figure 6 The XRPD patterns of form C (expressed in degrees (2θ) and relative intensities, measured on a diffractometer with Cu K-α radiation) are shown in Table 5.

[0289] Table 5. List of C-type XRPD peaks.

[0290]

[0291]

[0292] Example 6: Polymorphic form D of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0293] Polymorphic form D can be prepared by pulping polymorphic form A in a mixture of MTBE: n-heptane (3:7) at room temperature.

[0294] The XRPD and TGA / DSC overlay plots of form D are shown in the figure. Figure 7 and Figure 8 The XRPD patterns of form D (expressed in degrees (2θ) and relative intensities, measured on a diffractometer with Cu K-α radiation) are shown in Table 6.

[0295] Table 6. List of Form D XRPD peaks.

[0296]

[0297]

[0298] Example 7: Polymorphic form E of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0299] Polymorphic form E can be prepared by pulping polymorphic form A in a mixture of EtOH:H2O (1:1) at 50°C.

[0300] The XRPD and TGA / DSC overlay plots of form E are shown below. Figure 9 and Figure 10 The XRPD patterns of form E (expressed in degrees (2θ) and relative intensities, measured on a diffractometer with Cu K-α radiation) are shown in Table 7.

[0301] Table 7. List of EXRPD peaks in the form of EXRPD.

[0302]

[0303]

[0304] Example 8: Polymorphic form F of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0305] The polymorphic form F can be prepared by recrystallization of the amorphous compound 1 from hot ethanol. Compound 1 is dissolved in a minimum volume (approximately 2.8 times its volume) of boiling ethanol to form a homogeneous solution. The hot solution is slowly cooled. The formed crystals are filtered from the solution, washed with cold ethanol and hexane, and dried under high vacuum to give form F as a white solid.

[0306] The XRPD and TGA / DSC overlay plots of form F are shown in the figure. Figure 11 and Figure 12 The XRPD patterns of form F (expressed in degrees (2θ) and relative intensities, measured on a diffractometer with Cu K-α radiation) are shown in Table 8.

[0307] Table 8. List of Form F XRPD peaks.

[0308]

[0309]

[0310] Alternatively, polymorphic form F can be obtained by solid vapor diffusion of polymorphic form A in ethanol vapor.

[0311] Alternatively, polymorphic form A can be prepared by conversion from polymorphic form F using the following methods:

[0312] Example 9: Polymorphic form A of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

[0313] The polymorphic form F of compound 1 was dissolved in a minimum volume (approximately 2.8 times its volume) of hot (near-boiling) ethanol to form a homogeneous solution. The hot solution was cooled to room temperature and then placed in a freezer. Precipitation occurred during the freezing of the ethanol solution at approximately -20°C. The precipitate was filtered under vacuum, and the solid material, which was polymorphic form F, was collected. The obtained solid material was ground into powder using a mortar and pestle and dried under vacuum at 60°C for approximately 2 days. The obtained solid was analyzed by XRPD. The XRPD spectrum was consistent with that of form A.

[0314] The characterization of the polymorphic form AF of compound 1 is listed in Table 9.

[0315] Table 9. Characterization of the polymorphic forms of compound 1.

[0316]

[0317] *Form A after vacuum drying or heating shows no peaks (very small peaks) at approximately 7.5° 2θ and / or approximately 21° 2θ.

[0318] The relationship between the polymorphic forms AF of compound 1 is shown in Figure 13 The interconversion diagram.

[0319] The hygroscopic and adsorption properties of polymorphic form A of compound 1 were evaluated using DVS. Isotherms obtained at 25 °C showed that form A of compound 1 exhibits slight hygroscopicity, with a weight increase of approximately 0.28% at 80% RH and less than 0.5% at 95% RH. Figure 14 ).

[0320] Water activity experiments were performed on polymorphic form A of compound 1 using the IPA / H2O system at different water concentrations to identify possible hydrates, as shown in Table 10.

[0321] Table 10. Concentrations of water and isopropanol (IPA) used in water activity screening.

[0322]

[0323] To investigate the stability relationship between the anhydrous polymorphs A and E and the ethanol solvate polymorph F, a pulping competition experiment was conducted in ACN at room temperature and 60 °C. The results showed that all polymorphs were converted to form A, indicating that form A is the most stable anhydrous form of compound 1 currently known (Table 11).

[0324] Table 11. Summary of studies on the tautomerization of anhydrous substances and solvates.

[0325]

[0326] The approximate solubility of polymorphic form A of compound 1 in various solvents shown in Table 12 at room temperature was determined.

[0327] Table 12. Approximate solubility (S) of polymorphic form A of compound 1 at room temperature.

[0328]

[0329] The solubility properties of polymorphic form A of compound 1 in water and three biologically relevant media were evaluated at room temperature for 24 hours. The results are summarized in Table 13.

[0330] Table 13. Solubility of polymorphic form A of compound 1 in water and biologically relevant media.

[0331]

[0332] Polymorph screening experiments were conducted using polymorph form A of compound 1 to evaluate the formation of different polymorphs using various solvents and multiple formation processes, including room temperature pulping, 50°C pulping, solid vapor diffusion, liquid vapor diffusion, antisolvent addition, cooling crystallization, polymer-induced crystallization, and slow evaporation.

[0333] Room temperature pulping

[0334] Slurry experiments were conducted at room temperature in various solvent systems. Approximately 11 mg of polymorphic form A of compound 1 was suspended in approximately 0.2–0.5 mL of solvent in a 1.5 mL glass vial. After magnetically stirring the suspension at room temperature for three days, the remaining solids were separated for XRPD analysis (Table 14).

[0335] Table 14. Summary of room temperature pulping experiment.

[0336]

[0337] Pulping at 50℃

[0338] Slurry experiments were conducted at 50°C in various solvent systems. Approximately 10 mg of polymorphic form A of compound 1 was suspended in approximately 0.2–0.4 mL of solvent in a 1.5 mL glass vial. After magnetically stirring the suspension at 50°C for two days, the remaining solids were separated for XRPD analysis (Table 15).

[0339] Table 15. Summary of pulping experiment at 50℃.

[0340]

[0341] Solid vapor diffusion

[0342] Solid vapor diffusion experiments were conducted using various solvents. Approximately 11 mg of polymorphic form A of compound 1 was weighed into a 3 mL vial, which was then placed into a 20 mL vial containing 4 mL of volatile solvent. The 20 mL vial was then sealed and left at room temperature for seven days to allow the solvent vapor to interact with the sample. The remaining solid was separated and analyzed by XRPD (Table 16).

[0343] Table 16. Summary of solid vapor diffusion experiments.

[0344]

[0345] Liquid vapor diffusion

[0346] Liquid vapor diffusion experiments were performed using various solvents. Approximately 11 mg of polymorphic form A of compound 1 was dissolved in approximately 0.2–0.5 mL of a suitable solvent in a 1.5 mL vial to obtain a clear solution. This solution was then transferred to a 20 mL vial containing 4 mL of volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature to allow the organic vapor to interact with the solution. The precipitate was separated and analyzed by XRPD (Table 17).

[0347] Table 17. Summary of liquid vapor diffusion experiments.

[0348]

[0349] Antisolvent addition

[0350] Antisolvent addition experiments were conducted using various solvents. Approximately 10 mg of polymorphic form A of compound 1 was dissolved in approximately 0.3–0.6 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and then approximately 0.5–0.8 mL of antisolvent was added gradually until precipitation occurred or the total amount of antisolvent reached 15.0 mL. The separated precipitates were analyzed by XRPD (Table 18).

[0351] Table 18. Summary of antisolvent addition experiments.

[0352]

[0353] Slow evaporation

[0354] Slow evaporation experiments were conducted using various solvents. Approximately 10 mg of polymorphic form A of compound 1 was dissolved in approximately 1–1.5 mL of solvent in a 3 mL glass vial. The vial was then covered with a sealing film, allowing the solution to evaporate through pinhole-sized pores punched in the film at room temperature. The solid was then separated for XRPD analysis (Table 19).

[0355] Table 19. Summary of the slow evaporation experiment.

[0356]

[0357] Polymer-induced crystallization

[0358] Polymer-induced crystallization experiments were conducted in various solvent systems. Approximately 15 mg of polymorphic form A of compound 1 was suspended in 0.4 mL of solvent in 3 mL glass vials at room temperature. Approximately 4 mg of the polymer mixture was added to each vial, and the mixture was stirred at 800 RPM at room temperature to induce precipitation. The solids were then separated for XRPD analysis (Table 20).

[0359] Table 20. Summary of polymer-induced crystallization experiments.

[0360]

[0361] *A: Polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC) (mass ratio 1:1:1:1:1).

[0362] **B: Polymethyl methacrylate (PMMA), sodium alginate (SA), and hydroxyethyl cellulose (HEC) (mass ratio 1:1:1).

[0363] Cooling crystallization

[0364] Data from the cooling crystallization experiment are shown in Table 21. Approximately 30 mg of polymorphic form A of compound 1 was dissolved in the corresponding solvent in a 1.5 mL glass vial at 50 °C. The suspension was then filtered at 50 °C, and the vial was immediately capped after filtration. The sample was then heated to 50 °C and held for 30 minutes, followed by cooling from 50 °C to 5 °C over 8 hours. The sample was then held at 5 °C until removal. The solid was then separated and analyzed by XRPD (Table 21).

[0365] Table 21. Summary of cooling crystallization experiments.

[0366]

[0367] Excipient compatibility study

[0368] Polymorphic form A of compound 1 was screened with various excipients to evaluate compatibility (Table 22). The mixture was stored in an open container at 50°C and 75% relative humidity (RH) for 4 weeks. The compound was compatible with all excipients and blends in Table 22 and maintained its polymorphic form and thermal stability as a pure powder.

[0369] Table 22. Compatibility study of polymorph A of compound 1 with various excipients.

[0370]

[0371]

[0372] Example 10: Prototype-1 tablet formulation (100 mg dose tablet)

[0373] Using the amounts of ingredients described in Table 23, a batch of elliptical tablets were prepared according to the following procedure, each containing approximately 100 mg of polymorphic form A of compound 1.

[0374] Polymorphic form A of compound 1 (40.0% w / w), silicified microcrystalline cellulose (40.0% w / w), colloidal silica (1.0% w / w), and croscarmellose sodium (2.5% w / w) were mixed for 10 minutes, and then mixed with magnesium stearate (1.0% w / w) for 2 minutes to obtain an intragranular blend. The intragranular blend was dry-granulated using a roller press to obtain intact tablets with an average thickness of 1.59-1.94 mm. The tablets were granulated using a 20-mesh sieve. The dry-granulated blend was further mixed with silicified microcrystalline cellulose (12.0% w / w) and croscarmellose sodium (2.5% w / w) for 10 minutes, and then mixed with magnesium stearate (1.0% w / w) for 2 minutes to obtain a tablet blend. The tablet blend was compressed using a manual tablet press to obtain 100 mg tablets. The weight, thickness, hardness and disintegration time of the core were characterized (Table 24).

[0375] The tablets were analyzed using USP apparatus 2 (paddle method) at a paddle speed of 75 rpm in 900 mL of 0.1N HCl dissolution medium. The dissolution data are shown in Table 25.

[0376] Table 23. Prototype-1 tablet formulation for producing 100 mg dose tablets.

[0377]

[0378] *Adjusted based on the purity value of compound 1, which is 97.7%.

[0379] Table 24. Compressed tablets of prototype-1 formulation (100 mg dose tablets).

[0380]

[0381] Table 25. Dissolution of prototype-1 tablets (100 mg dose) in 0.1 N HCl.

[0382]

[0383] Example 11: Prototype-1 capsule formulation (100 mg dose capsule)

[0384] HPMC capsules (size 1) were manually filled with approximately 250 mg of the tablet blend described in Example 10, at a dosage of 100 mg of polymorph A of compound 1 per capsule. The capsules were analyzed using a USP apparatus 2 (paddle method) with a spiral capsule settler at a paddle speed of 75 rpm in 900 mL of 0.1N HCl dissolution medium. Dissolution data are shown in Table 26.

[0385] Table 26. Dissolution of prototype-1 capsules (100 mg dose) in 0.1 N HCl.

[0386]

[0387] Example 12: Prototype-1 tablet formulation (300 mg dose tablet)

[0388] Following the same procedure as in Example 10, a batch of elliptical tablet cores were prepared using the amounts of ingredients described in Table 27, each containing approximately 300 mg of polymorphic form A of compound 1. The tablet cores were characterized for weight, thickness, hardness, disintegration time, and friability (Table 28). The tablet cores were coated with Opadry White, which was prepared by dispersing a film coating in treated water (375 g (25% w / w) Opadry White and 1125 g (75% w / w) water). A tablet core (750 mg / tablet, 96.2% w / w) coated with this suspension (30 mg / tablet) showed a weight gain of 3.8%.

[0389] Table 27. Prototype-1 tablet formulation for producing 300 mg dose tablets.

[0390]

[0391] *Adjusted based on the purity value of compound 1, which is 99.42%.

[0392] Table 28. Compressed tablets of prototype-1 formulation (300 mg dose tablets).

[0393]

[0394] Example 13: Prototype-1 tablet formulation (25 mg and 300 mg dose tablets)

[0395] A batch of tablet blends was formulated according to the following procedure for preparing elliptical tablet cores, each containing 25 mg and 300 mg of polymorphic form A of compound 1. The composition of the prototype-1 tablet formulation for the 25 mg and 300 mg doses is shown in Table 29.

[0396] Polymorphic form A of compound 1 (40.2% w / w), silicified microcrystalline cellulose (39.8% w / w), fumed silica (1.0% w / w), and croscarmellose sodium (2.5% w / w) were mixed for 10 minutes, and then mixed with magnesium stearate (1.0% w / w) for 2 minutes to obtain an intragranular blend. The intragranular blend was dry-granulated using a roller press to obtain intact tablets with an average thickness of 1.59-1.94 mm. The tablets were granulated using a 20-mesh sieve. The dry-granulated blend was further mixed with silicified microcrystalline cellulose (12.0% w / w) and croscarmellose sodium (2.5% w / w) for 10 minutes, and then mixed with magnesium stearate (1.0% w / w) for 2 minutes to obtain a tablet blend. The obtained tablet blend was fractionated, and a portion was compressed using a tablet press to obtain 25 mg dose tablet cores. The weight, thickness, hardness and friability of the core were characterized (Table 30).

[0397] A portion of the tablet blend was mixed with additional magnesium stearate (1.0% w / w) for 2 minutes. The resulting tablet blend was then compressed using a tablet press to obtain 300 mg tablet cores. The tablet cores were characterized for weight, thickness, and hardness (Table 31).

[0398] Table 29. Prototype-1 tablet formulation composition for 25 mg and 300 mg dose tablets.

[0399]

[0400] *Adjusted based on the purity value of compound 1, which is 99.42%.

[0401] **Only applicable to 300 mg dose tablet cores.

[0402] Table 30. Compressed tablets of prototype-1 formulation (25 mg dose tablets).

[0403]

[0404] Table 31. Compressed tablets of prototype-1 formulation (with an additional 1% magnesium stearate) (300 mg dose tablets).

[0405]

[0406] Example 14: Prototype-2 tablet formulation (100 mg dose tablet)

[0407] Using the amounts of ingredients described in Table 32, a batch of elliptical tablets were prepared according to the following procedure, each containing approximately 100 mg of polymorphic form A of compound 1.

[0408] Polymorphic form A of compound 1 (40.0% w / w), dicalcium phosphate (10.0% w / w), microcrystalline cellulose (30.0% w / w), colloidal silica (1.0% w / w), and croscarmellose sodium (2.5% w / w) were mixed for 10 minutes, followed by mixing with magnesium stearate (1.0% w / w) for 2 minutes to obtain an in-granule blend. The in-granule blend was dry-granulated using a roller press to obtain intact tablets with an average thickness of 1.80-1.86 mm. The tablets were granulated using a 20-mesh sieve. The dry-granulated blend was further mixed with silicified microcrystalline cellulose (12.0% w / w) and croscarmellose sodium (2.5% w / w) for 10 minutes, followed by mixing with magnesium stearate (1.0% w / w) for 2 minutes to obtain a tablet blend. The tablet blend was compressed using a manual tablet press to obtain 100 mg tablets. The weight, thickness, hardness and disintegration time of the core were characterized (Table 33).

[0409] Table 32. Prototype-2 tablet formulations used to produce 100 mg dose tablets.

[0410]

[0411] *Adjusted based on the purity value of compound 1, which is 97.7%.

[0412] Table 33. Compressed tablets of prototype-2 formulation (100 mg dose tablets).

[0413]

[0414] Example 15: Prototype-3 tablet formulation (100 mg dose tablet)

[0415] Using the amounts of ingredients described in Table 34, a batch of elliptical tablets were prepared according to the following procedure, each containing approximately 100 mg of polymorphic form A of compound 1.

[0416] Polymorphic form A of compound 1 (40.9% w / w), mannitol (16.0% w / w), silicified microcrystalline cellulose (23.1% w / w), colloidal silica (1.0% w / w), and croscarmellose sodium (2.5% w / w) were mixed for 10 minutes, followed by mixing with magnesium stearate (1.0% w / w) for 2 minutes to obtain an in-granule blend. The in-granule blend was dry-granulated using a roller press to obtain intact tablets with an average thickness of 1.63–1.86 mm. The tablets were granulated using a 20-mesh sieve. The dry-granulated blend was further mixed with silicified microcrystalline cellulose (12.0% w / w) and croscarmellose sodium (2.5% w / w) for 10 minutes, followed by mixing with magnesium stearate (1.0% w / w) for 2 minutes to obtain a tablet blend. The tablet blend was compressed using a manual tablet press to obtain 100 mg tablets. The weight, thickness, hardness and disintegration time of the core were characterized (Table 35).

[0417] The tablets were analyzed using USP apparatus 2 (paddle method) at a paddle speed of 75 rpm in 900 mL of 0.1N HCl dissolution medium. The dissolution data are shown in Table 36.

[0418] Table 34. Prototype-3 tablet formulations used to produce 100 mg dose tablets.

[0419]

[0420] *Adjusted based on the purity value of compound 1, which is 97.7%.

[0421] Table 35. Compressed tablets of prototype-3 formulation (100 mg dose tablets).

[0422]

[0423] Table 36. Dissolution of prototype-3 tablets (100 mg dose) in 0.1 N HCl.

[0424]

[0425] Example 16: Prototype-3 capsule formulation (100 mg dose capsule)

[0426] HPMC capsules (size 1) were manually filled with approximately 250 mg of the tablet blend described in Example 15, at a dosage of 100 mg of polymorph A of compound 1 per capsule. The capsules were analyzed using a USP apparatus 2 (paddle method) with a spiral capsule settler at a paddle speed of 75 rpm in 900 mL of 0.1N HCl dissolution medium. Dissolution data are shown in Table 37.

[0427] Table 37. Dissolution of prototype-3 capsules (100 mg dose) in 0.1 N HCl.

[0428]

[0429] Example 17: Prototype-4 tablet formulation (100 mg dose tablet)

[0430] Using the amounts of ingredients described in Table 38, a batch of elliptical tablets were prepared according to the following procedure, each containing approximately 100 mg of polymorphic form A of compound 1.

[0431] Polymorphic form A of compound 1 (40.9% w / w), mannitol (16.0% w / w), microcrystalline cellulose (23.1% w / w), colloidal silica (1.0% w / w), and croscarmellose sodium (2.5% w / w) were mixed for 10 minutes, followed by mixing with magnesium stearate (1.0% w / w) for 2 minutes to obtain an in-granule blend. The in-granule blend was dry-granulated using a roller press to obtain intact tablets with an average thickness of 1.65-1.86 mm. The tablets were granulated using a 20-mesh sieve. The dry-granulated blend was further mixed with silicified microcrystalline cellulose (12.0% w / w) and croscarmellose sodium (2.5% w / w) for 10 minutes, followed by mixing with magnesium stearate (1.0% w / w) for 2 minutes to obtain a tablet blend. The tablet blend was compressed using a manual tablet press to obtain 100 mg tablets. The weight, thickness, hardness and disintegration time of the core were characterized (Table 39).

[0432] Table 38. Prototype-4 tablet formulation for producing 100 mg dose tablets.

[0433]

[0434] *Adjusted based on the purity value of compound 1, which is 97.7%.

[0435] Table 39. Compressed tablets of prototype-4 formulation (100 mg dose tablets).

[0436]

[0437] Example 18: Prototype-5 tablet formulation (300 mg dose tablet)

[0438] Following the procedure described below, a batch of elliptical tablets were prepared using the amounts of ingredients described in Table 40, each containing approximately 300 mg of polymorphic form A of compound 1.

[0439] Polymorphic form A of compound 1 (35.4% w / w), silicified microcrystalline cellulose (35.2% w / w), colloidal silica (1.0% w / w), and croscarmellose sodium (2.5% w / w) were mixed for 10 minutes, and then mixed with magnesium stearate (1.0% w / w) for 2 minutes to obtain an intragranular blend. The intragranular blend was dry-granulated using a roller press to obtain complete tablets. The tablets were granulated using a 20-mesh sieve. The dry-granulated blend was further mixed with silicified microcrystalline cellulose (20.4% w / w) and croscarmellose sodium (2.5% w / w) for 10 minutes, and then mixed with magnesium stearate (2.0% w / w) for 2 minutes to obtain a tablet blend. The obtained tablet blend was compressed using a tablet press to obtain 300 mg dose tablet cores. The weight, thickness, and hardness of the tablet cores were characterized (Table 41). The tablet cores were coated with Opadry Green, prepared by dispersing the film coating in treated water (250 g (20% w / w) Opadry Green and 1000 g (80% w / w) water). The cores (850 mg / tablet, 96.2% w / w) were coated with this suspension (34 mg / tablet), resulting in a 3.8% weight gain. A second coating was performed with Opadry II Clear, prepared by dispersing the film coating in treated water (160 g / batch (8% w / w) Opadry II Clear and 1840 g / batch (92% w / w) water). The tablets (884 mg / tablet, 99% w / w) were coated with this suspension (8.84 mg / tablet), resulting in a 1% weight gain.

[0440] The tablets were analyzed using USP apparatus 2 (paddle method) at a paddle speed of 75 rpm in 900 mL of 0.1N HCl dissolution medium. The dissolution data are shown in Table 42.

[0441] Table 40. Composition of the prototype-5 tablet formulation for the 300 mg dose tablet.

[0442]

[0443] *Adjusted based on the purity value of compound 1, which is 99.6%.

[0444] Table 41. Compressed tablets of prototype-5 (300 mg dose tablets).

[0445]

[0446] Table 42. Dissolution of prototype-5 tablets (300 mg dose) in 0.1 N HCl.

[0447]

[0448] *Average of 6 containers.

[0449] Example 19: Prototype-5 tablet formulation (25 mg and 150 mg dose tablets)

[0450] Following the same procedure as in Example 18, a batch of tablet blends was prepared using the amounts of ingredients described in Table 43 to prepare elliptical tablet cores, each containing 25 mg and 150 mg of polymorphic form A of compound 1. The tablet cores were characterized for weight, thickness, hardness, disintegration time, and friability (Tables 44 and 45). The tablet cores were coated with a 20% solids Opadry Green aqueous suspension, followed by a second coating with an 8% solids Opadry II Clear aqueous suspension, using the amounts of ingredients described in Table 43.

[0451] Each tablet containing 25 mg of polymorphic form A of compound 1 was analyzed in 900 mL of 0.1 N HCl dissolution medium using a USP apparatus 2 (paddle method) at a paddle speed of 75 rpm. The dissolution data are shown in Table 46.

[0452] Table 43. Prototype-5 tablet formulation composition for 25 mg and 150 mg dose tablets.

[0453]

[0454] *Adjusted based on the purity value of compound 1, which is 99.6%.

[0455] Table 44. Compressed tablets of prototype-5 (25 mg dose tablets).

[0456]

[0457] Table 45. Compressed tablets of prototype-5 formulation (150 mg dose tablets).

[0458]

[0459] Table 46. Dissolution of prototype-5 tablets (25 mg dose) in 0.1 N HCl.

[0460]

[0461] *Average of 6 containers.

[0462] Example 19: Prototype-5 tablet formulation (100 mg dose tablet)

[0463] Following the same procedure as in Example 18, a batch of elliptical tablets containing approximately 100 mg of polymorphic form A of compound 1 was prepared using the amounts of ingredients described in Table 47. The tablets were characterized for weight, thickness, hardness, and friability (Table 48). The tablets were coated with Opadry Green and then with Opadry II Clear, using the amounts of ingredients described in Table 47.

[0464] The tablets were analyzed using USP apparatus 2 (paddle method) at a paddle speed of 75 rpm in 900 mL of 0.1N HCl dissolution medium. The dissolution data are shown in Table 49.

[0465] Table 47. Composition of the prototype-5 tablet formulation for 100 mg dose tablets.

[0466]

[0467] a. Thin-film coated suspensions are prepared in quantities exceeding theoretical requirements.

[0468] b. Water is removed during processing and is not present in the final product.

[0469] Table 48. Compressed tablets of prototype-5 formulation (100 mg dose tablets).

[0470]

[0471] *Average value of 10 pieces

[0472] Table 49. Dissolution of prototype-5 tablets (100 mg dose) in 0.1 N HCl.

[0473]

[0474] *Average of 6 containers.

[0475] Example 20: Prototype-6 tablet formulation (300 mg dose tablet)

[0476] Following the same procedure as in Example 18, a batch of elliptical tablets containing approximately 300 mg of polymorphic form A of compound 1 was prepared using the amounts of ingredients described in Table 50. The tablets were characterized for weight, thickness, and hardness (Table 51). The tablets were coated with Opadry Green, prepared by dispersing a film coating in treated water (250 g (20% w / w) Opadry Green and 1000 g (80% w / w) water). A tablet (850 mg / tablet, 96.2% w / w) coated with this suspension (34 mg / tablet) showed a 3.8% weight gain. A second coating was performed with Opadry II Clear, prepared by dispersing a film coating in treated water (160 g / batch (8% w / w) Opadry II Clear and 1840 g / batch (92% w / w) water). The tablets (884 mg / tablet, 99% w / w) were coated with this suspension (8.84 mg / tablet), resulting in a 1% weight gain.

[0477] Table 50. Prototype-6 tablet formulation for producing 300 mg dose tablets.

[0478]

[0479] *Adjusted based on the purity value of compound 1, which is 99.6%.

[0480] Table 51. Compressed tablets of prototype-6 (300 mg dose tablets).

[0481]

[0482] Example 21: Prototype-7 tablet formulation (300 mg dose tablet)

[0483] Following the same procedure as in Example 18, a batch of elliptical cores were prepared using the amounts of components described in Table 52, each containing approximately 300 mg of polymorphic form A of compound 1. The cores were characterized for weight, thickness, hardness, friability, and disintegration (Table 53).

[0484] Table 52. Prototype-7 tablet formulation for producing 300 mg dose tablets.

[0485]

[0486] Table 53. Compressed tablets of prototype-7 (300 mg dose tablets).

[0487]

[0488] Example 22: Prototype-8 tablet formulation (300 mg dose tablet)

[0489] Following the same procedure as in Example 18, a batch of elliptical cores were prepared using the amounts of components described in Table 54, each containing approximately 300 mg of polymorphic form A of compound 1. The cores were characterized for weight, thickness, hardness, friability, and disintegration (Table 55).

[0490] Table 54. Prototype-8 tablet formulation for producing 300 mg dose tablets.

[0491]

[0492] Table 55. Compressed tablets of prototype-8 (300 mg dose tablets).

[0493]

[0494] The following tablets can be prepared using the amounts of ingredients described in Table 56, following the procedure described in Example 18.

[0495] Table 56. Exemplary tablet formulations for producing 25, 100, 150 and 300 mg dose tablets.

[0496]

[0497] CB1R human cannabinoid GPCR cell-based antagonist cAMP assay

[0498] The potency of compound 1 against human CB1R in stably transfected CHO-K1 cells was evaluated using HTRF assay in cAMP cell-based assay. 50 Cells were seeded at a total volume of 20 μL in white-walled 384-well microplates and incubated overnight at 37°C before testing. Before testing, the cell-coating medium was replaced with 10 μL of assay buffer (HBSS + 10 mM HEPES). In short, the sample stock solution was intermediately diluted in assay buffer to prepare the final test concentration of 4X. 5 μL of the 4X sample was added to the cells and incubated at 37°C for 30 minutes. 5 μL of CP55940 (for the final EC) was added. 80 The concentration of 4X was dissolved in 4X laryngin reagent (80 μM), and the cells were incubated at 37°C for 30 minutes. The final concentration of laryngin in the assay was 20 μM. The final solvent concentration was 1%. The results are expressed as the percentage of inhibition against CP55940 in antagonist mode.

[0499] Compound 1 was screened for CB1R functional activity, IC50 50 It is 3.8 μM.

[0500] Mouse DIO Obesity Study

[0501] To determine whether compound 1 possesses anti-obesity activity through CB1R antagonism, a four-week in vivo study was initiated in obese C57BL / 6J DIO mice to investigate weight gain, food intake, and fasting blood glucose levels (experimental design shown in Table 57). Different doses of GMP-compliant batches of compound 1 were evaluated and compared with DIO mice administered the solvent only. The compound was formulated as a homogeneous suspension containing vitamin E-TPGS, PEG400, glycerol, methylcellulose, 10 mM sodium citrate buffer (pH 6), and water. Animals were administered the test compound or the solvent orally once daily by gavage for four weeks.

[0502] Table 57. Experimental design for evaluating compound 1 in a DIO mouse obesity model.

[0503]

[0504] Compared with obese mice treated with the solvent, the percentage of weight gain in obese mice in groups 4 and 5 treated with compound 1 showed a significant dose-dependent decrease. In group 5, the percentage of weight loss was significantly correlated with a reduction in food intake. Figure 15 On the other hand, compared with obese mice treated with the solvent, the fasting blood glucose levels of obese mice treated with compound 1 were not significantly affected. Figure 16 ).

[0505] In addition to the ob DIO mouse obesity model, in the 28-day GLP toxicity study, a significant dose-dependent decrease in mean cholesterol was observed in rats administered compound 1 compared to rats administered the solvent. Figure 17 The same suspension formulation used in the mouse obesity model was also used in rat GLP toxicity studies.

[0506] In summary, mice administered compound 1 at both 10 and 30 mg / kg / day showed significant weight loss relative to obese mice administered the solvent. Furthermore, food intake was significantly reduced in the 30 mg / kg / day group compared to obese mice administered the solvent. Finally, in a 28-day GLP toxicity study in rats, cholesterol levels were significantly reduced at all tested doses (including 10, 30, and 50 mg / kg / day). In the same rat toxicity study, no evidence of CNS effects was found by combined measurements of functional observations. Therefore, compound 1 demonstrates potential for therapeutic treatment of metabolic disorders and other therapeutic applications through peripheral CB1R antagonism.

Claims

1. The crystal form of compound 1, wherein compound 1 is represented by the following structural formula: 。 2. The crystal form according to claim 1, wherein the crystal form is selected from the following polymorphs: polymorph A of compound 1, polymorph B of compound 1, polymorph C of compound 1, polymorph D of compound 1, polymorph E of compound 1, and polymorph F of compound 1.

3. The polymorphic form according to claim 2, wherein the polymorphic form is form A of compound 1, and wherein form A is characterized by having a powder X-ray diffraction pattern measured using Cu K-α radiation containing at least three characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2θ.

4. A pharmaceutical composition comprising a crystal form of compound 1 and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, comprising polymorphic form A and at least one pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 4, wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, carboxymethyl cellulose, povidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerin, stearin Magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-hedrin), glyceryl dis(2-2-hedrin), stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

7. The pharmaceutical composition according to claim 5, wherein the excipient is selected from: mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, dicalcium phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginate, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium carboxymethyl cellulose, crospovidone, carboxymethyl cellulose, povidone, sodium carboxymethyl starch, agar, calcium carbonate, sodium bicarbonate, alginate, gelatin, polyvinylpyrrolidone, glycerin, stearin Magnesium stearate, calcium stearate, polyethylene glycol, colloidal silica, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tris(2-2-3-hedrin), glyceryl dis(2-2-hedrin), stearic acid, hydrogenated vegetable oil, sodium stearoyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrin, polymers, polyacrylic acid, polyamino acids, copolymers, methacrylic acid / ethyl acrylate copolymers, liposomes, polymer micelles, microspheres, paraffin wax, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycol, sodium lauryl sulfate, coloring materials, flavoring agents, gums, resins, waxes, plasticizers, polyols, pigments, polysaccharides, dyes, poloxamer, and film coatings.

8. The pharmaceutical composition according to claim 7, wherein the excipient is selected from: silicified microcrystalline cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

9. The pharmaceutical composition according to claim 7, wherein the excipient is selected from: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

10. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises about 0.5 wt% to about 60 wt% of polymorphic form A of compound 1 based on the weight of the composition, wherein the pharmaceutical composition is a tablet or capsule.

11. The pharmaceutical composition according to claim 10, wherein the preferred composition is a tablet.

12. A tablet formulation comprising about 10 mg to about 500 mg of crystalline compound 1 per tablet.

13. The tablet formulation according to claim 12, wherein the crystalline compound 1 is in polymorphic form A.

14. The tablet formulation of claim 13, wherein each tablet comprises about 50 mg to about 250 mg of crystalline compound 1, which may be associated with acute or severe treatment.

15. The tablet formulation of claim 13, wherein each tablet comprises about 10 mg to about 50 mg of crystalline compound 1, which may be associated with chronic treatment.

16. The tablet formulation of claim 13, wherein the tablet comprises crystalline compound 1, silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and magnesium stearate.

17. The tablet formulation according to claim 13, wherein the tablet comprises crystalline compound 1, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.

18. The crystal form according to claim 1, wherein a therapeutically effective amount of the crystal form according to claim 1 is administered together with a therapeutically effective amount of at least one compound selected from the group consisting of: ribavirin, polymerase inhibitors, favipiravir, triazole, small interfering RNA (siRNA), vaccines, monoclonal antibodies, and immunomodulators.

19. The pharmaceutical composition of claim 4, wherein a pharmaceutically effective amount of the pharmaceutical composition comprising crystalline compound 1 is administered together with a therapeutically effective amount of at least one compound selected from the group consisting of: ribavirin, polymerase inhibitors, favipiravir, triazole, small interfering RNA (siRNA), vaccines, monoclonal antibodies, and immunomodulators.

20. A method for treating infection associated with a virus of the Arenaviridae enveloped virus family or any virus expressing an arenavir glycoprotein to mediate cell entry, the method comprising administering a pharmaceutically effective dose of a crystal form of compound 1, and a pharmaceutically acceptable carrier, diluent, or solvent thereof, wherein compound 1 is represented by the following structural formula: 。 21. The method of claim 20, wherein a pharmaceutically acceptable dose of the crystal form of compound 1 of claim 20 is administered together with a pharmaceutically acceptable dose of at least one compound selected from: ribavirin, polymerase inhibitors, favipiravir, triazole, small interfering RNA (siRNA), vaccines, monoclonal antibodies, and immunomodulators.

22. A method for modulating cannabinoid receptor 1 (CB1R) in a mammal, wherein the method comprises administering to the desired mammal a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or solvent thereof, wherein compound 1 is represented by the following structural formula: 。 23. A method of treating a disease state in mammals suitable for treatment by a cannabinoid receptor 1 (CB1R) modulator, comprising administering a therapeutically effective amount of the compound according to claim 22.

24. The method of claim 23, wherein the disease state is selected from metabolic diseases, fibrotic disorders, pain, neurological disorders, substance abuse / dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory diseases, gastrointestinal diseases, hereditary diseases, reproductive disorders, sleep disorders, and osteoporosis.

Images