TW202542138A - Compounds which bind to patatin-like phospholipase domain-containing protein3 im and their use to treat liver disease - Google Patents

Abstract

The invention relates to compounds of Formula (I), and pharmaceutically acceptable salts and isomers of such compounds, which bind to patatin-like phospholipase domain-containing protein 3 (PNPLA3) mutation PNPLA3I148M,

Description

Compounds that bind to patatin-like phospholipase domain protein 3I148M and their use in the treatment of liver disease.

This invention relates to compounds that bind to the patatin-like phospholipase domain protein 3 (PNPLA3) mutant PNPLA3I148M, and pharmaceutically acceptable salts and isomers of such compounds. Furthermore, this invention relates to pharmaceutical compositions and combinations comprising such compounds and their use in methods of treating diseases related to PNPLA3I148M.

Patatin-like phospholipase domain 2 (PNPLA2; also known as fatty triglyceride lipase, ATGL) and PNPLA3 (also known as adiponutrin) are encoded by close paralogs and appear to have opposing roles in the mobilization and storage of triglycerides (TAGs). The human PNPLA3 gene is expressed in the liver and is highly induced during feeding and may be important in lipid distribution during periods of nutritional surplus, in contrast to PNPLA2, the major triglyceride (TAG) lipase that is activated during energy demand (e.g., fasting) (Wilson et al., 2006).

Nonalcoholic fatty liver disease (NAFLD) is a group of conditions that begin as benign steatosis of the liver and progress to severe conditions in some patients, including nonalcoholic steatohepatitis (NASH), cirrhosis with liver fibrosis, and hepatocellular carcinoma (HCC). Recently, nonalcoholic fatty liver disease (NAFLD) was renamed metabolic dysfunction-associated fatty liver disease (MASLD), and subsequently, nonalcoholic steatohepatitis (NASH) was renamed metabolic dysfunction-associated fatty liver disease (MASH) (Rinella et al., 2023).

The global prevalence of NAFLD is estimated at approximately 25% and is increasing (Younossi et al., 2018; Younossi and Henry, 2021). Currently, there are no approved drugs for the treatment of NAFLD in Western markets. Gastric bypass surgery and/or weight loss of more than 10% are the most clinically beneficial treatments (Lassailly et al., 2015; Lassailly et al., 2020).

Predicting who will progress from fatty degeneration to NASH, cirrhosis, and HCC is challenging. In 2008, a genome-wide association study (GWAS) identified a nonsynonymous variant in the gene encoding PNPLA3 that is responsible for fatty degeneration and an increased risk of NASH progression (Romeo et al., 2008). This identified variant (rs738409) results in a 148-position amino acid sequence change, replacing isoleucine with methionine (I148M). Subsequent GWAS studies identified other genes and simultaneously confirmed the dominant effect of the PNPLA3I148M variant (reviewed by Trepo and Valenti, 2020). The prevalence of the PNPLA3I148M variant varies globally, with the highest allele frequency (over 50%) in Mexicans and Hispanic Americans (Younossi et al., 2018). PNPLA3I148M is also closely associated with the progression of alcoholic steatohepatitis, viral hepatitis, Wilson's disease, hereditary hemochromatosis, autoimmune hepatitis, and primary sclerosing cholangitis to severe liver disease (Dongiovanni et al., 2013; Mederacke et al., 2020). NASH caused by PNPLA3I148M is inherited in an autosomal dominant pattern, with penetrance influenced by obesity and diabetes.

Overexpression and deletion of the wild-type allele did not lead to the disease phenotype in mice. In contrast, overexpression of human PNPLA3I148M in mouse liver under the control of the albumin promoter, coupled with a high-sucrose diet, resulted in elevated liver triglyceride levels and a NAFLD-related phenotype (Li et al., 2012; Smagris et al., 2015). Reduced proteasomal degradation of PNPLA3 on lipid droplets is considered a possible pathophysiological mechanism leading to this phenotype (BasuRay et al., 2017; BasuRay et al., 2019).

The α/β-hydrolase domain 5 (ABHD5; also known as CGI-58) is an essential coactivator of PNPLA2. The accumulation of PNPLA3I148M on lipid droplets interferes with TAG hydrolysis by isolating ABHD5 (CGI-58) on the lipid droplets, and thus limits the effectiveness of cofactor activation of ATGL (PNPLA2), leading to elevated liver TG levels (Yang, W. et al., 2019).

Linden et al. first demonstrated that liver-targeted silencing with antisense oligonucleotides (ASOs) expressing the human PNPLA3I148M mutation in a mouse gene knock-in model reduced hepatic steatosis and several other NASH-related features, such as liver inflammation and fibrosis (Linden et al., 2019). However, to date, there are no descriptions of using small molecule conjugates of PNPLA3I148M to treat liver disease.

Reference: BasuRay, S., Smagris, E., Cohen, JC, and Hobbs, HH (2017). The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66 , 1111-1124.

BasuRay, S., Wang, Y., Smagris, E., Cohen, JC, and Hobbs, HH (2019). Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci USA 116 , 9521-9526.

Dongiovanni, P., Donati, B., Fares, R., Lombardi, R., Mancina, RM, Romeo, S., and Valenti, L. (2013). PNPLA3I148M polymorphism and progressive liver disease. World J Gastroenterol 19 , 6969-6978.

Lassailly, G., Caiazzo, R., Buob, D., Pigeyre, M., Verkindt, H., Labreuche, J., Raverdy, V., Leteurtre, E., Dharancy, S., Louvet, A. et al. (2015). Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology 149 , 379-388; test e315-376.

Lassailly, G., Caiazzo, R., Ntandja-Wandji, LC, Gnemmi, V., Baud, G., Verkindt, H., Ningarhari, M., Louvet, A., Leteurtre, E., Raverdy, V. et al. (2020). Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology 159 , 1290-1301 e1295.

Li, JZ, Huang, Y., Karaman, R., Ivanova, PT, Brown, HA, Roddy, T., Castro-Perez, J., Cohen, JC, and Hobbs, HH (2012). Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 122 , 4130-4144.

Linden, D., Ahnmark, A., Pingitore, P., Ciociola, E., Ahlstedt, I., Andreasson, AC, Sasidharan, K., Madeyski-Bengtson, K., Zurek, M., Mancina, RM et al. (2019). Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in PNPLA3I148M knock-in mice. Mol Metab 22 , 49-61.

Mederacke, YS, Kirstein, MM, Grosshennig, A., Marhenke, S., Metzler, F., Manns, MP, Vogel, A., and Mederacke, I. (2020). The PNPLA3 rs738409 GG genotype is associated with poorer prognosis in 239 patients with autoimmune hepatitis. Aliment Pharmacol Ther [Gastrointestinal Pharmacology and Therapeutics] 51 , 1160-1168.

Romeo, S., Kozlitina, J., Xing, C., Pertsemlidis, A., Cox, D., Pennacchio, LA, Boerwinkle, E., Cohen, JC, and Hobbs, HH (2008). Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40 , 1461-1465.

Smagris, E., BasuRay, S., Li, J., Huang, Y., Lai, KM, Gromada, J., Cohen, JC, and Hobbs, HH (2015). PNPLA3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61 , 108-118.

Trepo, E., and Valenti, L. (2020). Update on NAFLD genetics: From new variants to the clinic. J Hepatol 72 , 1196-1209.

Wilson, PA, Gardner, SD, Lambie, NM, Commans, SA, and Crowther, DJ (2006). Characterization of the human patatin-like phospholipase family. J Lipid Res 47 , 1940-1949.

Younossi, Z., Anstee, QM, Marietti, M., Hardy, T., Henry, L., Eslam, M., George, J., and Bugianesi, E. (2018). Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15 , 11-20.

Younossi, ZM, and Henry, L. (2021). Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep 3 , 100305.

Yang Wang, Nora Kory, Soumik BasuRay, Jonathan C. Cohen, and Helen H. Hobbs. (2019). PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice. Hepatology, 69(6): 2427-2441.

Renella, M.E. et al., A multisociety Delphi consensus statement on new fatty liver disease nomenclature, Hepatology, 2023, 78: 1966-1986.

Low molecular weight compounds that still bind to PNPLA3I148M are needed to normalize lipolysis and thus can be used to treat a variety of liver diseases associated with the pathophysiology of PNPLA3I148M.

This article provides compounds that bind to PNPLA3I148M, thereby normalizing lipolysis, and thus such compounds can be used to treat PNPLA3I148M-related diseases. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

Furthermore, this article provides compounds that bind to PNPLA3I148M, thereby disrupting the complex of ABHD5 and PNPLA3I148M (i.e., PNPLA3I148M-ABHD5), which normalizes lipolysis, and therefore such compounds can be used to treat PNPLA3I148M-related diseases. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the one hand, the compound that binds to PNPLA3I148M provided in this article is a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: (I), where ^RA , _L1 , X, Y, ^R5 , _Z1 , _Z2 , _Z3 , _Z4 , _Z5 , _L2 and ^R8 are as defined herein.

On the other hand, this article discloses a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

On the other hand, this article discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

On the other hand, this article discloses a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable acid addition salt thereof, and one or more pharmaceutically acceptable carriers.

On the other hand, this article discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable acid addition salt thereof, and one or more pharmaceutically acceptable carriers.

On the other hand, this article discloses a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable acid addition salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable acid addition salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a pharmaceutical combination comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a pharmaceutical combination comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, used as a drug.

In another aspect, this document discloses a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the treatment of PNPLA3I148M-related diseases. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this document discloses the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the treatment of PNPLA3I148M-related diseases. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this document discloses the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating PNPLA3I148M-related diseases. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In yet another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this article discloses a method for treating PNPLA3I148M-related diseases, comprising administering to a subject in need a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this article discloses a method for treating PNPLA3I148M-related diseases, comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article discloses a method for normalizing lipolysis by administering to a subject in need a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a method for normalizing lipolysis by administering to a subject in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a method for normalizing lipolysis by disrupting the PNPLA3I148M-ABHD5 complex, wherein the method comprises administering to a subject in need a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a method for normalizing lipolysis by disrupting the PNPLA3I148M-ABHD5 complex, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a method for treating PNPLA3I148M-related diseases by normalizing lipolysis, the method comprising administering to a subject in need a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article discloses a method for treating PNPLA3I148M-related diseases by normalizing lipolysis, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In this embodiment, PNPLA3I148M-related diseases include metabolic dysfunction-associated steatohepatitis (MASH). In this embodiment, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In this embodiment, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In this embodiment, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article discloses intermediate compounds that can be used to prepare compounds having formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

In some embodiments, compounds having formula (I) can bind to protein 3 (PNPLA3) containing patatin-like phospholipase domain.

As defined herein, the term "alkyl" refers to a saturated branched or straight-chain hydrocarbon. In some embodiments, the alkyl group is " _C1 - _C2 alkyl,"" _C1 - _C3 alkyl," or " _C1 - _C4 alkyl," wherein, as used herein, the terms " _C1 - _C2 alkyl,"" _C1 - _C3 alkyl," and " _C1 - _C4 alkyl" respectively refer to an alkyl group containing at least one and at most two, three, or four carbon atoms. " _C1 - _C2 alkyl" groups are methyl and ethyl. Non-limiting examples of " _C1 - _C3 alkyl" groups include methyl, ethyl, n-propyl, and isopropyl. Non-limiting examples of " _C1 - _C4 alkyl" groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, and tert-butyl.

As used in this article, the term "alkenyl" refers to a partially saturated branched or straight hydrocarbon chain having one or more double bonds. In some embodiments, the alkenyl group is " _C2 - _C3 alkenyl", " _C2 - _C4 alkenyl", " _C2 - _C5 alkenyl", " _C2 - _C6 alkenyl", " _C2 - _C7 alkenyl", " _C2 - _C8 alkenyl", " _C2 - _C9 alkenyl" or " _C2 - _C10 alkenyl", wherein, as used herein, the terms " _C2 - _C3 alkenyl", " _C2 - _C4 alkenyl", " _C2 -C5 alkenyl", " _C2 - _C6 alkenyl", " _C2 - _C7 alkenyl", " _C2 - _{C8 alkenyl} ", " _C2 - _C9 alkenyl" and "C2- _C10 alkenyl" are used. _"10 -alkenyl" refers to an alkenyl group containing at least 2 and at most 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, dibutenyl, tributenyl, n-pentenyl, isopentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, and n-decenyl.

As used in this article, the term "alkynyl group" refers to a partially saturated branched or straight hydrocarbon chain having one or more triple bonds. In some embodiments, the alkynyl group is " _C2 - _C3 alkynyl", " _C2 - _C4 alkynyl", " _C2 - _C5 alkynyl", " _C2 - _C6 alkynyl", " _C2 - _C7 alkynyl", " _C2 - _C8 alkynyl", " _C2 - _C9 alkynyl" or " _C2 - _C10 alkynyl", wherein, as used herein, the terms " _C2 - _C3 alkynyl", " _C2 - _C4 alkynyl", " _C2 -C5 alkynyl", " _C2 - _C6 alkynyl", " _C2 - _C7 alkynyl", " _C2 - _C8 alkynyl", " _C2 - _C9 alkynyl" and "C2 _- C10 alkynyl" are _used . _"10 -alkynyl" refers to an alkynyl group containing at least 2 and at most 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, dibutynyl, n-pentynyl, isopentenynyl, n-hexynyl, n-heptynyl, n-octyynyl, n-nonynyl, and n-decynyl.

As used herein, the term "alkoxy" refers to -O-alkyl, where "alkyl" group is as defined herein. In some embodiments, the alkoxy group is " _C1 - _C2 alkoxy,"" _C1 - _C3 alkoxy," or " _C1 - _C4 alkoxy," where, as used herein, the terms " _C1 - _C2 alkoxy,"" _C1 - _C3 alkoxy," and " _C1 - _C4 alkoxy" refer to -OC1 _{- C2} alkyl, -OC1 _{- C3} alkyl, or -OC1 _{- C4} alkyl, respectively. The " _C1 - _C2 alkoxy" group is methoxy or ethoxy. Non-limiting examples of the " _C1 - _C3 alkoxy" group include methoxy, ethoxy, n-propoxy, and isopropoxy. Non-limiting examples of the " _C1 - _C4 alkoxy" group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, and tertiary butoxy.

As used herein, the term " _diC1 - _C4 alkylamino" refers to the _-NR2 group, where each R is a _C1 - _C4 alkyl group.

As used herein, the term " _C3 - _C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon system having 3 to 4 carbon atoms as ring members. Non-limiting examples of such " _C3 - _C4 cycloalkyl" groups include cyclopropyl and cyclobutyl.

As used herein, the term " _C3 - _C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon system having 3 to 6 carbon atoms as ring members. Non-limiting examples of such " _C3 - _C6 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term " _C3 - _C8 cycloalkyl" refers to a saturated monocyclic hydrocarbon system having 3 to 8 carbon atoms as ring members. Non-limiting examples of such " _C3 - _C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, the term " _C1 - _C4 fluoroalkyl" refers to the corresponding " _C1 - _C4 alkyl" as defined herein, wherein at least one of _{the hydrogen atoms in the "C1-C4 alkyl" is replaced by a fluorine atom. A C1-C4 fluoroalkyl group can be a mono-C1-C4 fluoroalkyl group having one fluorine atom . Alternatively} , a _C1 - _C4 fluoroalkyl group can be a di- _C1 - _C4 fluoroalkyl group having two fluorine atoms. Furthermore, a _C1 - _C4 fluoroalkyl group can _be a poly _{-C1 - C4 fluoroalkyl} group having two or more fluorine atoms. Such poly _(C1 - _C4) fluoroalkyl groups can be perfluoro( _C1 - _C4) fluoroalkyl groups, wherein all hydrogen atoms of the corresponding _C1 - _C4 alkyl group are replaced by fluorine atoms. Non-limiting examples of the " _C1 - _C4 fluoroalkyl" group include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, difluoropropyl, and heptafluoropropyl.

As used herein, the term " _C1 - _C4 fluoroalkoxy" refers to the corresponding " _C1 - _C4 alkoxy" as defined herein, wherein at least one of the hydrogen atoms in the " _{C1 - C4 alkyl} " group of the " _C1 - _C4 alkoxy" group is replaced by a fluorine atom. A _C1 - _C4 fluoroalkoxy group can be a mono- _C1 - _C4 fluoroalkoxy group having one fluorine atom. Alternatively, a _C1 - _C4 fluoroalkoxy group can be a di _{-C1 - C4 fluoroalkoxy} group having two fluorine atoms. Furthermore, a _C1 - _C4 fluoroalkoxy group can be a _poly - _{C1 - C4} fluoroalkoxy group having two or more fluorine atoms. Such a poly _(C1 - _C4) fluoroalkoxy group can be a perfluoro( _C1 - _C4) fluoroalkoxy group, wherein all hydrogen atoms of the corresponding _C1 - _C4 alkyl group are replaced by fluorine atoms. Non-limiting examples of the " _C1 - _C4 " fluoroalkoxy group include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, pentafluoroethoxy, difluoropropoxy, and heptafluoropropoxy.

As used herein, the term " _C1 - _C4 hydroxyalkyl" means " _C1 - _C4 alkyl" as defined herein, wherein one or more hydrogen atoms of " _C1 - _C4 alkyl" are replaced by one or more hydroxyl groups.

As used in this article, the term "carbonyl" refers to the -C(=O)- group.

As used in this article, the term "cyano" refers to the -CN group.

As used in this article, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

As used herein, the term "5- to 6-membered monocyclic heteroaryl" refers to an aromatic 5- or 6-membered monocyclic ring system in which 1, 2, 3, or 4 ring members are each independently selected from N, ^NR4 , ^NR9 , O, and S, wherein ^R4 and ^NR9 are as defined herein. Non-limiting examples of 5- to 6-membered monocyclic heteroaryl groups include furazolidone, furanyl, imidazolyl, isozolyl, isothiazolyl, acezolyl, acezolyl, acediazolyl, pyrazolyl, pyrroleyl, pyridinyl, pyridyl, pyrimidinyl, thiazolyl, thiadiazolyl, thiophene, triazolyl, triazolyl, and tetrazolyl.

As used herein, the term "partially saturated 9-, 10-, 11-, or 12-member bicyclic carbocyclic group" refers to a fused bicyclic hydrocarbon structure containing one or more double bonds and not being aromatic, having 9, 10, 11, or 12 ring members.

As used herein, the term "partially saturated 5- or 6-membered heterocyclic base" refers to a monocyclic ring structure having 5 or 6 ring members, wherein 1 or 2 ring members are each independently selected from N, ^NR9 , O, and S (where ^R9 is as defined herein), and the monocyclic ring structure contains one or more double bonds and is not aromatic.

In some implementations, as used herein, the term "partially saturated 5- or 6-membered heterocyclic basis" may also refer to a monocyclic ring structure having 5 or 6 ring members, wherein one ring member is S(=O) ₂ and 1, 2 or 3 other ring members are each independently chosen from N, ^NR9 , O and S (where ^R9 is as defined herein), and the monocyclic ring structure contains one or more double bonds and is not aromatic.

As used herein, the term "partially saturated 8-, 9-, 10-, 11-, or 12-member fused bicyclic heterocyclic base" refers to a fused bicyclic ring structure having 8, 9, 10, 11, or 12 ring members, wherein 1, 2, 3, or 4 ring members are each independently selected from N, ^NR4 , ^NR9 , O, and S (where ^R4 and ^R9 are as defined herein), and the fused bicyclic ring structure contains one or more double bonds. In particular, the partially saturated heterocyclic group is a 10-member fused bicyclic heterocyclic group containing 1, 2 or 3 ring members independently selected from N, ^NR4 , ^R9 , O and S, wherein ^R4 and ^R9 are as defined herein. Non-limiting examples of partially saturated 8-, 9-, 10-, 11-, or 12-member fused bicyclic heterocyclic groups used herein include chromyl, 3,4-dihydro-2H-benzo[b][1,4] ethoxy, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3] ethoxy, 3,4-dihydro-2H-piperano[2,3-b]pyridyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]diethoxy, 1,4,5,6-tetrahydrocyclopentadieno[c]pyrazolyl, and 4,5,6,7-tetrahydro-1H-indazoleyl. Other non-limiting examples of heterocyclic alkyl groups include dihydrobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrobenzothiophenyl, dihydrobenzoazolyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrooctyllinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroindolizinyl, dihydroindolyl, dihydroisoindolyl, and dihydroisoquinolinyl. Dihydroisoazolyl, Dihydroisothiazolyl, Dihydroisoazolyl, Dihydrooxaindolyl, Dihydroisodiazolyl, Dihydropyrazolyl, Dihydropyrroleyl, Dihydrophthaloyl, Dihydropyridyl, Dihydropyridyl, Dihydropyrimidinyl, Dihydroquinolineyl, Dihydroquinolineyl, Dihydroquinolineyl, Dihydroquinolineyl, Dihydrotetrazolyl, Dihydrothiazolyl, Dihydrothiadiazolyl, Dihydrothiophenyl, Dihydrotriazolyl, Dihydrotriazolyl, Tetrahydrobenzo[] Furanyl, tetrahydrobenzo[c]thiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzobenzoxazolyl, tetrahydrobenzothiazolyl, tetrahydrobenzoimidazolyl, tetrahydrooctyllinyl, tetrahydroindolyl, tetrahydroindolyl, tetrahydroindolyl, tetrahydroindolyl, tetrahydroisoindolyl, tetrahydroisoquinolinyl, tetrahydrooxoindolyl, tetrahydrophthaloyl, tetrahydropyridyl, tetrahydropyridyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydroquinolinyl, tetrahydroquinolinyl, tetrahydroquinazolinyl, tetrahydrotriazolinyl, hexahydrobenzofuranyl Hexahydrobenzo[c]thiophene, hexahydrobenzothiophene, hexahydrobenzozolyl, hexahydrobenzothiazolyl, hexahydrobenzoimidazolyl, hexahydrooctylindolyl, hexahydroindolyl, hexahydroindolyl, hexahydroindolyl, hexahydroisoindolyl, hexahydroisoquinolinyl, hexahydrooxoindolyl, hexahydrophthaloyl, hexahydroquinolinyl, hexahydroquinolinyl, hexahydroquinazolinyl, octahydrooctylindolyl, octahydroisoquinolinyl, octahydrophthaloyl, octahydroquinolinyl, octahydroquinolinyl and octahydroquinazolinyl.

As used herein, the term 6- or 7-member fused bicyclic heterocyclic base refers to a fused bicyclic ring structure having 6 or 7 ring members, wherein one or two ring members are each independently selected from N, ^NR9 , O, and S (where ^R9 is as defined herein), and the fused bicyclic ring structure contains one or more double bonds and is not aromatic.

As used herein, the term "4-, 5-, or 6-membered heterocycloalkyl" refers to a 4-, 5-, or 6-membered saturated ring, wherein one, two, or three ring members are each independently selected from N, ^NR9 , O, and S, wherein ^R9 is as defined herein. Non-limiting examples of 4-, 5-, or 6-membered heterocycloalkyl groups as used herein include aziridine (which includes aziridine-1-yl, aziridine-2-yl, and aziridine-3-yl), pyrrolidinyl (which includes pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, and pyrrolidin-5-yl), and piperidinyl (which includes piperidin-1-yl, piperidin-4-yl, and piperidin-5-yl). 2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl and piperidin-6-yl), piperidinyl (including piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl and piperidin-6-yl) and pyrazolidine (including pyrazolidine-1-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, pyrazolidine-4-yl and pyrazolidine-5-yl).

As used herein, the term "5- or 6-membered heterocycloalkyl" refers to a 5- or 6-membered saturated ring, wherein one or two ring members are each independently selected from N, ^NR9 , O, and S, where ^R9 is as defined herein. Heterocycloalkyl groups may be attached to another group at a nitrogen or carbon atom. Non-limiting examples of 5- or 6-membered heterocyclic alkyl groups used herein include pyrrolidinyl (including pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, and pyrrolidin-5-yl), tetrahydrofuranyl (including tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, and tetrahydrofuran-5-yl), and tetrahydrothiophenyl (including tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, and tetrahydrothiophene-5-yl). (e.g., phen-4-yl and tetrahydrothiophen-5-yl), piperidinyl (including piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl and piperidin-6-yl), tetrahydropiperanyl (including tetrahydropiperan-2-yl, tetrahydropiperan-3-yl, tetrahydropiperan-4-yl, tetrahydropiperan-5-yl and tetrahydropiperan-6-yl), tetrahydrothiaranyl (including tetrahydrothiaran-2-yl, tetrahydrothiaran-3-yl, ... (e.g., 4-yl, tetrahydrothiaran-5-yl, and tetrahydrothiaran-6-yl), piperatoyl (including piperato-1-yl, piperato-2-yl, piperato-3-yl, piperato-4-yl, piperato-5-yl, and piperato-6-yl), thio- ... -yl, thiocarbamo-5-yl and thiocarbamo-6-yl), dithiazolyl (including dithiazolyl-2-yl, dithiazolyl-3-yl, dithiazolyl-5-yl and dithiazolyl-6-yl), dioxolanecycloyl (including dioxolanecyclo-2-yl, dioxolanecyclo-4-yl and dioxolanecyclo-5-yl), and pyrazolidinel (including pyrazolidine-1-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, pyrazolidine-4-yl and pyrazolidine-5-yl).

In some embodiments, as used herein, the term "4-, 5-, or 6-membered heterocycloalkyl" may also refer to a 4-, 5-, or 6-membered saturated ring, wherein one ring member is S(=O) ₂ , and one, two, or three other ring members are each independently selected from N, _NR9 , and O, wherein _R9 is as defined herein.

In some embodiments, as used herein, the term "4-membered, 5-membered or 6-membered heterocycloalkyl" may also refer to a 4-membered, 5-membered or 6-membered saturated ring, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH).

As used herein, the term "6-membered heterocycloalkyl" refers to a 6-membered saturated ring, wherein one or two ring members are each independently selected from N, ^NR9 , O, and S, wherein ^R9 is as defined herein.

As used herein, the phrase "a 6-membered heterocycloalkyl group having one or two independent ring members selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group has a _C1 - _C3 alkyl bridge or a _{-CH2OCH2 -} bridge" refers to a 6-membered heterocycloalkyl group having a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge. For example, and .

As used in this article, the term "hydroxyl" refers to the -OH group.

As used in this article, the term "lateral group" refers to the -C(=O)- group.

As used herein, the term "6-member, 7-member, 8-member, 9-member, or 10-member spirobicyclic heterocyclic alkyl" refers to a bicyclic system having "6, 7, 8, 9, or 10 ring members, wherein the bicyclic system comprises two ring systems that are screwed together, and wherein one, two, or three ring members of the bicyclic system are each independently selected from N, ^NR9 , O, and S, wherein ^R9 is as defined herein."

As used in this article, the term "screw connection" refers to the attachment of one ring system to another ring system via a single carbon atom shared by the two rings.

As used herein, the term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. Also as used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that a given compound of formula (I) can exist in, and include geometric isomers. It should be understood that substituents can be attached at the chiral center of a carbon atom. The term "chiral" refers to a molecule that is non-overlapping in its mirror pair, while the term "chiral" refers to a molecule that is overlapping in its mirror pair. Therefore, the present invention includes mirror isomers, non-mirror isomers, or racemic derivatives of compounds. A "mirror isomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of mirror isomers is a "racemic" mixture. This term is used to specify racemic mixtures where appropriate. A "non-mirror isomer" is a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure mirror isomer, the stereochemistry of each chiral carbon may be represented by R or S. Resolved compounds with unknown absolute configurations may be specified as (+) or (-) according to the direction (right-handed or left-handed) in which they cause plane-polarized light to rotate at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce mirror isomers, non-mirror isomers, and other stereoisomer forms that can be defined by absolute stereochemistry as ( R )- or ( S )-.

As used herein, the term "combination" or "drug combination" refers to a fixed combination in the form of a single dosage unit, or a combination of administrations (whereby a compound having formula (I) and a co-agent (e.g., another drug explained below, also referred to as a "treatment" or "co-agent")) can be administered independently at the same time or separately at time intervals, particularly where such time intervals allow the co-agent to exhibit synergistic (e.g., co-active) effects). Individual components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be recombinated or diluted to the desired dosage prior to administration. As used herein, the terms “co-administration” or “combination administration” are intended to cover the administration of a selected combination of agents to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or simultaneously. As used herein, the term “drug combination” means a product resulting from a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term “fixed combination” means that the therapeutic agents (e.g., a compound having formula (I) and the combination of agents) are both administered simultaneously to a patient in a single entity or dose. The term "non-fixed combination" means that therapeutic agents (e.g., compounds having formula (I) and combination partners) are administered to a patient simultaneously, concurrently, or sequentially as separate entities (without a specific time limit), wherein such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more therapeutic agents.

The terms "combination therapy," "in combination with," or "drug combination" refer to the administration of two or more therapeutic agents to treat the condition or disorder described in this disclosure. This administration encompasses the co-administration of such therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule having a fixed proportion of active ingredients. Alternatively, this administration encompasses co-administration in multiple containers or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be recombinated or diluted to the desired dosage prior to administration. Furthermore, this administration also encompasses the use of each type of therapeutic agent, administered before, simultaneously, or successively, without specific time constraints. In each case, the treatment regimen will provide the beneficial effects of the combination of drugs in treating the condition or disorder described in this article.

As used in this article, the term "co-administration" refers to the presence of two active pharmaceutical agents in an individual's blood. Co-administered active pharmaceutical agents may be administered simultaneously or sequentially.

As used herein, the term "composition" or "pharmaceutical composition" means a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

As used in this article, the term "contact" refers to bringing together the indicated parts in an external or internal system.

The terms "patient," "subject," or "individual" are used interchangeably and refer to humans or non-human animals. The term includes mammals, such as humans. Typically, the animal is a mammal. "Patient," "subject," or "individual" also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some implementations, the subject is a primate. Preferably, "patient," "subject," or "individual" refers to a human.

As used herein, the term "pharmaceutically acceptable carrier" means a substance that can be used in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delayers, salts, drug stabilizers, binders, adjuvants, disintegrants, lubricants, humectants, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington, *The Science and Practice of Pharmacy*, 22nd edition, Pharmaceutical Press, 2013). Pages 1049-1070.

The phrase "pharmaceutical acceptable" indicates that the substance, composition, or dosage form must be chemically and/or toxicologically compatible with other ingredients of the formulation and/or the mammals on which it is being treated.

The term "subjects who need this treatment" refers to subjects who will benefit biologically, medically, or in terms of quality of life from this treatment.

As used herein, the term "therapeutic effective amount" refers to the amount of a compound having formula (I) that will improve symptoms, relieve symptoms, slow or delay disease progression, or elicit a biological or medical response in a subject.

As used in this article, the term "treat, treating, or treatment" refers to the management and care of a patient in order to combat or eliminate a disease, symptom, or disability.

Furthermore, as used herein, the term “treatment” means to alleviate or improve a disease or disorder (i.e., to slow or stop the development of a disease or at least one of its clinical symptoms); or to relieve or improve at least one physical parameter or biomarker associated with a disease or disorder, including those that the patient may not be able to identify.

As used in this article, a subject is considered "needing" treatment if they will benefit biologically, medically, or in terms of quality of life from it.

Unless otherwise specified, the term "compound of the invention" means one or more compounds having formula (I) or its sub-formulas (such as formula (I-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e) and formula (I-f)), as well as illustrative compounds and their salts, and all their stereoisomers (including non-mirror isomers and mirror isomers).

Unless otherwise specified, the phrase "compound having formula (I) or a subformula thereof" as used herein means a compound having the structure of formula (I) or a subformula selected from formulas (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f), and its salts, as well as all its stereoisomers (including non-mirror isomers and mirror isomers).

As used in this article, wavy lines, as described here, are... ", is a symbol that indicates the attachment point of R to other parts of the molecule.

The present invention provides compounds that are conjugated with PNPLA3I148M and have the structure of formula (I), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, of stereoisomers thereof: (I) Wherein: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx refers to H, D, halogen, or _C1 - _C4 alkyl; ^Ry refers to H, D, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^R5 refers to H, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^RA refers to: (i) unsubstituted or substituted with 1, 2, 3, or 4 ^R1 groups; (ii) partially saturated 9-, 10-, 11-, or 12-membered bicyclic carbocyclic groups that are unsubstituted or substituted with 1 to 4 ^R1 groups; (iii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups; or (iv) a partially saturated 8, 9, 10, 11, or 12-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups; each ^R1 is independently selected from the group consisting of: halogens, _C1 - _C4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _{C1 -C4} alkoxy, _C1 - _C4 alkoxycarbonyl, _C3 -C6 cycloalkyl, C1- _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, pentafluorohydrothio, _C1 - _C4 hydroxyalkyl, _C1 - _C4 thioalkyl, azido, _diC1 - _C4 alkylamino, _diC1 - _C4 alkylaminocarbonyl, D, _CD3 , cyano, methyl, phenyl, and _5- to ₆ -membered heterocycloalkyl comprising one or two ring members independently selected from N, ^NR4 , O, and S; _L1 -linked, -( ^CR2R3 ) _p- , -( ^{CR2R3 )} _p - ^NR4- , -( ^{CR2R3 )} _p -O-, ^{-NR4 ( CR2R3 )} _q -、-(CR ² R ³ ) _q NR ⁴ -、-O-(CR ² R ³ ) _p- 、or -S-(CR ² R ³ ) _p- ; R ² is H, D, halogen, or C ₁ -C ₄ alkyl; R ³ is H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, OH, amino, or t -Boc-amino; or R ² and R ³ are connected together with the C atom to which they are attached to form an unsubstituted or substituted C 3-C ₄ cycloalkyl group, either by a single substituent selected from C _{1 -} C ₄ alkyl and an alkyl group; each R ⁴ is independently selected from the group consisting of: H and C ₁ -C ₄ alkyl; p is 1, 2, or 3; q is 0, 1, or 2; Z ₁ is N or C; Z ₂ is N or CR ^z ; Z _Z3 is N or CR ^z ; _Z4 is N or C; _Z5 is N or CR ^z ; wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl, and _C1 - _C4 fluoroalkyl; provided that at least two and no ^{more than four of Z1, Z2, Z3, Z4 and Z5 are N; L2 is a bond, -(CR6R7)n-, or -(CR6R7} _{) nO- * , where *} ^indicates _the ^attachment _point with ^R8 ; each ^R6 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; each ^R7 is independently selected from the group consisting of: H, _C1 -C4 alkyl ^, C1- _C4 fluoroalkyl, and _C1- C4 hydroxyalkyl. _4- fluoroalkyl, and _C1 - _C4 hydroxyalkyl; or ^R6 and ^R7 are connected together with the C atom to which they are attached to form _C3 - _C6 cycloalkyl, oxocyclobutyl, tetrahydrofuranyl, or tetrahydropiperanyl; n is 1, 2, or 3; ^R8 is: (i) 4-, 5-, or 6-membered heterocycloalkyl having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 -C (i) ₄ -alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 ring members independently selected from N, ^NR , O, and S, wherein the monocyclic heteroaryl is unsubstituted; (ii) 4-, 5-, or 6-membered heterocyclic alkyl, wherein one ring member is S(=O) _₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _C₁ - _C₄ alkyl, and lateral alkyl; (iii) 4-, 5-, or 6-membered heterocyclic alkyl, wherein one ring member is S(=O) _₂ or S(=O), and 1, 2, or 3 other ring members independently selected from N, NR, O, and S. (iv) A partially saturated _5- or 6-membered heterocyclic group having one or two ring members independently selected from N, ^NR9 , ^O , and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by one, two, three, or four ring members independently selected from -OH, _C1 - _C4 alkyl, and lateral oxygen; (v) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and one, _two , or three other ring members are independently selected from N, ^NR9 (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 - _C4 alkoxy, and C1-C4 alkyl; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 -C4 alkoxy, and C1- _C4 alkyl; ( ^vii ) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, C1-C4 alkoxy, and _C1 - _C4 alkyl ^. (viii) A 6- or 7-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 substituents, each independently selected from -OH, -N( ^{R10 )} , _C1 - _C4 alkyl- _NH2 , halogen, _{C1 - C4} alkyl, and lateral oxygen groups ^; _2. Substituents of _{C1- C4} alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (ix) A 6-, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted with 1, 2, 3, or 4 ring members independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (x) A 6-membered heterocyclic alkyl group having 1 to 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group has C ₁ - _C3 alkyl-bridged or _{-CH2OCH2 -} bridged; (xi) phenyl, which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from -S(=O) _2N ( ^R10 ) ₂ , -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkyl; or (xii) _C4 - _C8 cycloalkyl, which is unsubstituted or substituted with 1, ₂ , 3 or 4 substituents each independently selected from -OH, -N( ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen, C1- _C4 alkoxy, _C1 - _C4 alkyl and phenoxy; ^R9 is H, _C1 -C _4- alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In the following embodiments, additional aspects and examples of compounds having formula (I) are provided. It should be appreciated that the features specified in each embodiment may be combined with other specified features to provide additional embodiments.

In embodiments having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx refers to H, D, halogen, or _C1 - _C4 alkyl; ^Ry refers to H, D, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^R5 refers to H, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^RA refers to: (i) an unsubstituted or substituted phenyl group with 1, 2, 3, or 4 ^R1 groups; (ii) (iii) A partially saturated 9-, 10-, 11-, or 12-membered bicyclic carbocyclic group, which is unsubstituted or substituted by 1 to 4 ^R1 groups; or (iv) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups; or (iv) A partially saturated 8-, 9-, 10-, 11-, or 12-membered fused bicyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the fused bicyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups; Each ^R1 is independently selected from the group consisting of: halogens, _C1 - _C4 alkyl, _C2 - _C4 alkenyl, C2- _C4 alkoxy, _C1 - _C4 alkoxycarbonyl, _C3 -C6 cycloalkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, pentafluorohydrothio, _C1 - _C4 hydroxyalkyl, _{C1 - C4} thioalkyl, azido, _diC1 - _C4 alkylamino, _{diC1 -C4} alkylaminocarbonyl, D, _CD3 , cyano, methyl, phenyl, and _5- to ₆ -membered heterocycloalkyl containing one or two ring members independently selected from N, ^NR4 , O, and S; _{L1 -} linked, -( ^{CR2R3 ) R2 is} a ^cycloalkyl group ^consisting of: _p- , -( ^CR2R3 ) _p - ^NR4- , -( ^CR2R3 ) _p - ^O- , -NR4( ^CR2R3 ) _q- , -( ^CR2R3 )qNR4- ^{, -O-(CR2R3 ) p-} _, or -S-( ^CR2R3 ) _p- ^{; R2} is H, D, halogen, or _C1 - ^{C4 alkyl} ; _R3 is H, D, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, OH, amino, or t -Boc-amino; or ^R2 and ^R3 are connected together with the C atoms to which they are attached to form an unsubstituted or substituted _C3 - _C4 cycloalkyl group selected from _C1 - _{C4 alkyl} and lateral oxygen groups; each R ^4. Independently selected from the following groups: H and _C1 - _C4 alkyl; p is 1, 2 or 3; q is 0, 1 or 2; _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C, and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; or _Z1 is _N , Z2 is CR ^z , _Z3 is CR ^z , _Z4 is C, and _Z5 is N; each R ^z is independently selected from the following groups: H, halogen, C ₁ - _C4 alkyl, ^and _C1 - _C4 fluoroalkyl; _L2 series bond, - ^{( CR6R7} ) _n- , or -( ^CR6R7 ) _nO- *, where * indicates the attachment point with ^R8 ; Each ^R6 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; Each ^R7 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; or ^R6 and ^R7 are linked together with the C atom to which they are attached to form _C3 - _C6 cycloalkyl, oxocyclobutyl, tetrahydrofuranyl, or tetrahydropiperanyl; n is 1, 2, or 3; ^R8 series: (i) A 4-, 5-, or 6-membered heterocycloalkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _2. (iii) A _4- , 5-, or ₆ -membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O), and one, two, or three other ring members are independently selected from N, ^NR9 , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted by one, two, three, or four substituents independently selected from _C1 - _C4 alkyl and lateral alkyl groups; (iv) Having one or two independently selected from N, ^NR9 (v) A partially saturated 5- or 6-membered heterocyclic group of ring members of O and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, _C1 - _C4 alkyl and lateral oxygen groups; (vi) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and 1, 2 or 3 other ring members are independently selected from N, ^NR9 , O ^and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, _C1 - _C4 alkyl and lateral oxygen groups; (vii) A 5- or 6-membered monocyclic heteroaryl group having one or two ring members selected independently of -OH, -N(R10)2, _C1 - _C4 alkyl-NH2, halogen, _C1 - _C4 alkyl, and alkyl groups; (viii) A 6- or 7-membered fused-bicyclic heterocyclic group having one or two ring members selected independently of -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl ^, and alkyl groups; Partially saturated 8-, 9-, 10-, 11-, or 12-membered fused bicyclic heterocyclic groups having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (ix) Having 1, 2, or 3 ring members independently selected from N, ^NR9 (x) A 6-membered, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having one or two ring members independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxy groups; (x) A 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge; (xi) A phenyl group having one or two ring members independently selected from -S(=O) _2. N( ^R10 ) ₂ , -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, and _C1 - _C4 alkyl substituents; or (xii) _C4 - _C8 cycloalkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( ^R10 ) ₂ , ^-S(=O)2R10 _{, C1} - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkoxy, _C1 - _C4 alkyl, and thyloxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 , or -C(=O) ^R10 , and ^R10 is H, or _C1 -C... _4- alkyl group.

In embodiments of a compound having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- is -CRx= ^CRy- , ^-CRx =N-, or -N= ^{CRy- ; Rx} is H, D, or a halogen; ^Ry is H, D, a halogen, or -CN; ^R5 is a halogen or -CN; ^RA is: (i) a phenyl group substituted with one or two ^R1 groups; (ii) a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and ^NR4 , wherein the monocyclic heteroaryl group is substituted with one or two ^R1 groups; or (iii) having one, two, or three ring members independently selected from N, NR4, ... Partially saturated 8-, 9-, or 10-membered fused bicyclic heterocyclic groups of ^{the 4} and O ring members, wherein the fused bicyclic heterocyclic group is substituted by 1, 2, or 3 ^R1 groups; each ^R1 is independently selected from the group consisting of: halogen, D, _CD3 , _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, _C3 - _C6 cycloalkyl, and pentafluorohydrothioyl; _L1 is bonded, -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) ^q- , or -O-( ^{CR2R3 )} _p- ; ^R2 is H, D, or halogen; ^R3 is H, D, _halogen , OH, or ^C1 _{-C4 alkyl} ; or R ^R2 and ^R3 are linked together with the C atoms to form _C3 - _C4 cycloalkyl groups, which are unsubstituted ^R4 -H or _C1 - _C4 alkyl groups; p-1; q-0; _Z1 -N, _Z2 - ^CRz , _Z3 -N, _Z4 -C, and _Z5 -N; or _Z1-N , _Z2 -CRz, Z3-N, _Z4 -C, and Z5- ^CRz ; or Z1-C, _Z2 - ^CRz , _Z3 -N, _Z4 -N, and Z5-CRz; or _Z1 -C, _Z2 - ^CRz , _Z3 -N, _Z4 -N, and Z5- ^CRz ; or _Z1 -C, _Z2 -N, _Z3 - _N , Z4-N, and _Z5 - ^CRz ; each ^Rz -H; _L2 - ^bonded , -( ^CR6R7 ) _n- , or -( ^CR6R7 ₎ ⁿ O-*, where * indicates the attachment site with R ⁸ ; each R ⁶ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; each R ⁷ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; or R ⁶ and R ⁷ are connected together with the C atom to which they are attached to to form a tetrahydropiperanyl group; n is 1 or 2; R ⁸ is: (i) having 1 or 2 independently selected from N, NR ⁹ (i) A 4-, 5-, or 6-membered heterocyclic alkyl group having a ring member of O and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1 or 2 ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 5-membered heterocyclic alkyl group having a ring member of S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by -OH and _C10. (iii) A ₆ -membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S(=O), and the other ring member is selected from N, ^NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR₉ , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , and the other ring member is selected from N, NR₉, and S. (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, ² , 3 or 4 ring members independently selected from N, NR ⁹ and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy and _C1 -C4 alkyl; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from N and NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a substituent; (viii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, ₃ or 4 ring members independently selected from N, NR 9 and O. A partially saturated 10-membered fused bicyclic heterocyclic group having a ring member of N, NR ⁹ , or O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) a 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from N, NR ⁹ , or O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) a 6-membered heterocyclic alkyl group having one or two independently selected ring members selected from N, NR ⁹ , or O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge; (xi) a phenyl group substituted with -S(=O) _2N ( ^R10 ) ₂ ; or (xii) a C4 _-C10 ... _8- cycloalkyl group, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N ₍ ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formula (I), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof: -X=Y- are -CRx= ^CRy- , ^-CRx = ^N- , or -N= ^CRy- ; ^Rx is H or F; Ry is H, F, or ^CN ; ^R5 is F, Cl, or CN; ^RA is: (i) phenyl, substituted with 1 to 2 ^R1 groups; (ii) pyrazolyl or pyridinyl, substituted with 1 or 2 ^R1 groups; or (iii) Chromyl, 3,4-dihydro-2H-piperano[2,3-b]pyridyl, 3,4-dihydro-2H-benzo[b][1,4]carboxyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]carboxyl, 5,6-dihydrocyclopentadienano[c]pyrazol-1(4H)-yl), 2,3-dihydrobenzo[b][1,4]dicarboxyl, 4,5,6,7-tetrahydro-1H-indazolyl, 1H-benzo[d]imidazolyl, or 2,3-dihydrobenzofuranyl, each of which is unsubstituted or substituted with one or two ^R1 groups; each R ^1. Independently selected from the group consisting of: F, Cl, Br, methyl, isopropyl, tributyl, cyclopropyl, _-CF3 , _CHF2 , _CF2CF3 , _OCF3 , and _SF5 ; _L1 is a bond _, -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) _q- , or ^-O- ( ^CR2R3 ) _p- ; ^R2 is H or ^F ; ^R3 is H, OH, F, or methyl; or ^R2 and ^R3 are linked together with the C atom to which they are attached to form a cyclopropyl group, which is unsubstituted; ^R4 is H, methyl, or ethyl; p is 1; q is 0; _Z1 is _N , _Z2 is ^CR2 , ^Z3 is N, _Z4 is C, and _Z5 is N; or _Z1 is N, _Z2 is ^CR2 _Z3 is N, _Z4 is C, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N, and _Z5 is ^{CR z} ; each R ^z is H; _L2 is a bond, -( ^CR6R7 ) _n- , or - ^{( CR6R7} ) _nO- *, where * indicates the attachment point with ^R8 ; each ^R6 is independently selected from the group consisting of: H, methyl, isopropyl, _-CH2OH , and _{CH2CF3 ;} each ^R7 is independently selected from the group consisting of: H, methyl, isopropyl, _-CH2OH , and _CH2CF3 ; or ^R6 and _R ^7. They are attached together with the C atoms to form a tetrahydropiperanyl group; n is 1 or 2; ^R8 is: (i) a 4-, 5-, or 6-membered heterocyclic alkyl group having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, _NH2 , F, _CF3 , methyl, methoxy, sideoxy, and a 5- or 6-membered monocyclic heteroaryl group having 1 or 2 ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted; (ii) a 5-membered heterocyclic alkyl group, wherein one ring member is S(=O) _2. (iii) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S(=O), and the other ring member is selected from N, ^NR₉ , and O, and the heterocyclic alkyl group is unsubstituted or substituted with a methyl group; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR₉ , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂. (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, NR ^{9 or} O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy or methyl; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from N or NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy or methyl; (viii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, NR 9 or O. A partially saturated 10-membered fused bicyclic heterocyclic group having a ring member of N, NR ⁹ , or O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) a 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from N, NR ⁹ , or O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) a 6-membered heterocyclic alkyl group having one or two independently selected ring members selected from N, NR ⁹ , or O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge; (xi) a phenyl group substituted with -S(=O) _2NH2 ; _or (xii) Cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted by one _, two, or three substituents independently selected from -OH, _-NH2 , _{-S(=O)2CH3 , -CH2NH2} , F, and methoxy _; and ^R9 is H, methyl, benzyl, -C(=O)CH3, _{-C (} = _{O)O(CH3)3 , CH2CH2OH ,} or _CH2CH2OCH3 .

In embodiments of a compound having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- is ^-CRx = ^CRy- , or ^-CRx =N-; ^Rx is H; ^Ry is H, F, or CN; ^R5 is F or CN; ^RA is: (i) phenyl, which is substituted with 1 to 2 ^R1 groups; (ii) pyrazolyl or pyridinyl, which is substituted with 1 or 2 ^R1 groups; or (iii) chromyl or 3,4-dihydro-2H-piperano[2,3-b]pyridinyl, which is unsubstituted or substituted with ^R1 groups; each ^R1 is independently selected from the group consisting of: F, Cl, methyl, _-CF3 , and _SF5 ; _L1 is bond, -( ^{CR2R3 )} ) _p -、-NR ⁴ (CR ² R ³ ) _q -、or -O-(CR ² R ³ ) _p -； R ² is H； R ³ is H, OH or methyl； R ⁴ is H, methyl or ethyl； p is 1； q is 0； Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N； or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is N, and Z ₅ is CR ^z ； or Z ₁ is C, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is N, and Z ₅ is CR ^z ； or Z ₁ is C, Z 2 is N, Z ₃ is N, Z ₄ is N, and Z ₅ is CR ^z ； each R ^z is H； L ₂ is a bond、- ₍ CR ⁶ R ⁷ ) _n - or -( ^CR6R7 ) _nO- *, where * ^indicates the attachment site with ^R8 ; each ^R6 is independently selected from the group consisting of: H, methyl, and _-CH2OH ; each ^R7 is independently selected from the group consisting of: H, methyl, and _-CH2OH ; n is 1 or 2; ^R8 is: (i) a 4-, 5-, or 6-membered heterocycloalkyl group having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, _NH2 , F, _CF3 , methyl, methoxy, sideoxy, and having 1 or 2 substituents independently selected from N and NR9. (ii) a 5- or 6-membered monocyclic heteroaryl group of a ring member of ⁹ , wherein the monocyclic heteroaryl group is unsubstituted; (iii) a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from OH and methyl; (iv) a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O), and one other ring member is selected from N, ^NR₉ and ^O , and wherein the heterocycloalkyl group is unsubstituted or substituted with a methyl group; (v) A partially saturated 6-membered heterocyclic group having one ring member selected from N, NR, and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vi) A partially saturated 6-membered heterocyclic group having one ring member selected from S(=O) ₂ and another ring member selected from N, ^NR4 , and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy, and methyl; (vii) A group having one ring member selected from N and NR (viii) A ⁶ -membered fused bicyclic heterocyclic group having 1, 2, or 3 independently selected ring members from N, NR ⁹ , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) A 7-membered spirobicyclic heterocyclic alkyl group having 1 independently selected ring member from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) A group having 1 to 2 independently selected ring members from N, NR 9, and O. A 6-membered heterocycloalkyl group of ring members ⁹ and O, wherein the heterocycloalkyl group has a _C1 - _{C3 alkyl} bridge or a _-CH2OCH2 -bridge; (xi) phenyl, which is substituted with -S(=O) _2NH2 ; or ( _xii ) cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with 1, ₂ , or 3 substituents independently selected from -OH, -NH2, -S(=O) _{2CH3 , -CH2NH2 , F ,} and methoxy; and ^R9 is H, methyl, benzyl, -C(=O) _CH3 , _-C (=O)O( _CH3 ) ₃ , _CH2CH2OH , or _CH2CH2OCH3 .

In embodiments of compounds having formula (I), the compounds provided herein are compounds having formula (Ia) or formula (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, of stereoisomers thereof: (Ia) (Ib) Wherein: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx refers to H, D, halogen, or _C1 - _C4 alkyl; ^Ry refers to H, D, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^R5 refers to H, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; Each ^R1 is independently selected from the group consisting of: halogen, _C1 - _C4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _C1 - _C4 alkoxy, C1- _C4 alkoxycarbonyl, _{C3 - C6} cycloalkyl, _C1 - _C4 fluoroalkyl, C ₁ - _C4 fluoroalkoxy, pentafluorohydrothio, C1-C4 hydroxyalkyl, _C1 - _C4 thioalkyl, azido, _diC1 - _C4 alkylamino, _{diC1 - C4} alkylaminocarbonyl, D, _CD3 , cyano, methyl, phenyl, and 5- to ₆ -membered heterocycloalkyl groups comprising one or two ring members independently selected from N, ^NR4 , O ^, and S; _L1 series -( ^CR2R3 ) _p- , -( ^CR2R3 ) _p - ^{NR4- ,} -( ^{CR2R3 )} _p -O-, ^-NR4 ( ^CR2R3 ) _q- , -( ^CR2R3 )qNR4- ^{, -O- ( CR2R3} _{) p-} , or ^-S- ( ^{CR2R3 )} _p -; ^R2 is H, D, halogen, or _C1 - _C4 alkyl; ^R3 is H, D, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, OH, amino, or t -Boc-amino; or ^R2 and ^R3 are connected together with the C atom to which they are attached to form an unsubstituted or substituted C3- _C4 cycloalkyl group, individually selected from _C1 - _C4 alkyl and _lateral alkyl groups; each ^R4 is independently selected from the group consisting of: H and _C1 - _C4 alkyl; p is 1, 2, or 3; q is 0, ₁ , or 2; Z1 is N or C; _Z2 is N or ^CRz ; _Z3 is N or ^CRz ; _Z4 is N or C; _Z5 is N or ^CRz ; wherein each R ^Z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl, and _C1 - _C4 fluoroalkyl; provided that at least two and no ^more than four of _Z1 , _Z2 , _Z3 , _Z4 , and _Z5 are N; _L2 bond, -( ^CR6R7 ) _n- , or - ^{( CR6R7} ) _nO- *, where * indicates the attachment point with ^R8 ; each ^R6 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; each ^R7 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; or ^R6 and R ^7. Linked together with the C atoms to which they are attached to form _C3 - _C6 cycloalkyl, oxocyclobutyl, tetrahydrofuranyl, or tetrahydropiperanyl; n is 1, 2, or 3; ^R8 is: (i) 4-, 5-, or 6-membered heterocycloalkyl having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral oxy, and having 1, 2, 3, or 4 substituents independently selected from N, ^NR9 (i) a 5- or 6-membered monocyclic heteroaryl group of ring members of O and S, wherein the monocyclic heteroaryl group is unsubstituted; (ii) a 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents each independently selected from -OH, _C1 - _C4 alkyl and lateral oxygen groups; (iii) a 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and 1, 2 or 3 other ring members are independently selected from N, NR (iv) A partially saturated _5- or 6-membered heterocyclic group having one or two ring members independently selected from N, ^NR9 , ^O , and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by one, two, three, or four ring members independently selected from -OH, _C1 - _C4 alkyl, and lateral oxygen; (v) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and one, _two , or three other ring members are independently selected from N, ^NR9 (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 - _C4 alkoxy, and C1-C4 alkyl; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 -C4 alkoxy, and C1- _C4 alkyl; ( ^vii ) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, C1-C4 alkoxy, and _C1 - _C4 alkyl ^. (viii) A 6- or 7-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 substituents, each independently selected from -OH, -N( ^{R10 )} , _{C1 - C4} alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups ^; _2. Substituents of _{C1- C4} alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (ix) A 6-, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted with 1, 2, 3, or 4 ring members independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (x) A 6-membered heterocyclic alkyl group having 1 to 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group has C ₁ - _C3 alkyl-bridged or _{-CH2OCH2 -} bridged; (xi) phenyl, which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from -S(=O) _2N ( ^R10 ) ₂ , -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkyl; or (xii) _C4 - _C8 cycloalkyl, which is unsubstituted or substituted with 1, ₂ , 3 or 4 substituents each independently selected from -OH, -N( ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkoxy, _C1 - _C4 alkyl and phenoxy; ^R9 is H, _C1 -C _4- alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, of stereoisomers thereof: -X=Y- is -CRx= CRy- , -CRx =N-, or -N= CRy- ; Rx is H, D, halogen, or C1 - C4 alkyl; Ry is H, D, halogen, -CN, C1-C4 alkyl, C1 - C4 fluoroalkyl, or C1- C4 alkoxy; R5 is H, halogen, -CN, C1 - C4 alkyl, C1 -C4 fluoroalkyl, or C1 - C4 alkoxy; each R1 is independently selected from the group consisting of: halogen, C1 - C4 alkyl, C2- C4 alkenyl, C2 - C4 alkenyl, C2-C4 alkyl, C1 - C4 alkyl, C1 -C4 alkoxy. 4- alkynyl, C1 - C4 alkoxy, C1 - C4 alkoxycarbonyl, C3 - C6 cycloalkyl, C1- C4 fluoroalkyl, C1 - C4 fluoroalkoxy, pentafluorohydrothioyl, C1 -C4 hydroxyalkyl, C1 - C4 thioalkyl, azidoyl, diC1 - C4 alkylamino, diC1 - C4 alkylaminocarbonyl, D, CD3 , cyano, methyl, phenyl, and 5- to 6 -membered heterocycloalkyl groups comprising one or two ring members independently selected from N, NR4 , O , and S; L1 - system -( CR2R3 ) p- , -( CR2R3 ) p - NR4- , -( CR2R3 ) p -O-, -NR4 ( CR2R3 ) q- , -( CR2R3 ) qNR4- , -O-( CR2R3 ) p- , or -S-( CR2R3 ) p- ; R2 is H , D, halogen, or C1 - C4 alkyl; R3 is H, D, halogen, C1 - C4 alkyl, C1 - C4 alkoxy, OH, amino, or t - Boc -amino; or R2 and R3 are connected together with the C atom to which they are attached to form an unsubstituted or substituted C3- C4 cycloalkyl group, either by a single substituent selected from C1 - C4 alkyl and lateral alkyl groups; each R4 is independently selected from the group consisting of: H and C1 - C4 alkyl; p is 1 , 2, or 3; q is 0, 1, or 2; Z1 is N, Z2 is CR2 , Z3 ... Z 3 N, Z 4 C, and Z 5 N; or Z 1  N , Z 2  CRz, Z 3 N, Z 4 C, and Z 5 CRz  ; or Z 1  C , Z 2 N, Z 3  N , Z 4 N, and Z 5  CRz; or Z 1 N, Z 2 CR z , Z  3 CR z , Z 4  C, and Z 5 N; each R  z is independently selected from the following groups: H, halogens, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;L 2  bonds, -( CR 6 R 7 ) n -, or -(CR 6 R 7 )n O-*, where * indicates the attachment site to R 8 ; each R 6 is independently selected from the group consisting of: H, C1 - C4 alkyl, C1 - C4 fluoroalkyl, and C1 - C4 hydroxyalkyl; each R 7 is independently selected from the group consisting of: H, C1 - C4 alkyl, C1 - C4 fluoroalkyl, and C1 - C4 hydroxyalkyl; or R 6 and R 7 are connected together with the C atoms to which they are attached to form C3 - C6 cycloalkyl, oxocyclobutyl, tetrahydrofuranyl, or tetrahydropiperanyl; n is 1, 2, or 3; R 8 is: (i) having 1, 2, or 3 independently selected from N, NR 9 ( ii) A 4-, 5-, or 6-membered heterocyclic alkyl group having one ring member of O and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N(R10 ) 2 , halogen, C1 - C4 fluoroalkyl, C1 - C4 alkyl, C1 - C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, NR9 , O, and S , wherein the monocyclic heteroaryl group is unsubstituted; (iii) A 4- , 5-, or 6 -membered heterocyclic alkyl group, wherein one ring member is S(=O) 2 or S(=O), and one, two, or three other ring members are independently selected from N, NR9 , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted by one, two, three, or four substituents independently selected from C1 - C4 alkyl and lateral alkyl groups; (iv) Having one or two independently selected from N, NR9 (v) A partially saturated 5- or 6-membered heterocyclic group of ring members of O and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, C1 - C4 alkyl and lateral oxygen groups; (vi) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) 2 and 1, 2 or 3 other ring members are independently selected from N, NR9 , O and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, C1 - C4 alkyl and lateral oxygen groups; (vii) A 5- or 6-membered monocyclic heteroaryl group having one or two ring members selected independently of -OH, -N(R10)2, C1 - C4 alkyl-NH2, halogen, C1 - C4 alkyl, and alkyl groups; (viii) A 6- or 7-membered fused-bicyclic heterocyclic group having one or two ring members selected independently of -OH, -N( R10 ) 2 , C1 - C4 alkyl- NH2 , halogen, C1 - C4 alkyl , and alkyl groups; Partially saturated 8-, 9-, 10-, 11-, or 12-membered fused bicyclic heterocyclic groups having 1, 2, 3, or 4 ring members independently selected from N, NR9 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( R10 ) 2 , C1 - C4 alkyl- NH2 , halogen, C1 - C4 alkyl, and lateral oxygen groups; (ix) Having 1, 2, or 3 ring members independently selected from N, NR9 (x) A 6-membered, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having one or two ring members independently selected from -OH, -N( R10 ) 2 , C1 - C4 alkyl- NH2 , halogen, C1 - C4 alkyl, and lateral oxy groups; (x) A 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, NR9 , O, and S, wherein the heterocyclic alkyl group has a C1 - C3 alkyl bridge or a -CH2OCH2 -bridge; (xi) A phenyl group having one or two ring members independently selected from -S(=O) 2. N( R10 ) 2 , -OH, -N( R10 ) 2 , C1 - C4 alkyl- NH2 , halogen, and C1 - C4 alkyl substituents; or (xii) C4 - C8 cycloalkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( R10 ) 2 , -S(=O)2R10 , C1 - C4 alkyl- NH2 , halogen, C1 - C4 alkoxy, C1 - C4 alkyl, and thyloxy; R9 is H, C1 - C4 alkyl, benzyl, C1 - C4 alkyl- OR10 , -C(=O) OR10 , or -C(=O) R10 , and R10 is H, or C1 -C... 4- alkyl group.

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, of their stereoisomers: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx refers to H, D, or a halogen; ^Ry refers to H, D, a halogen, or -CN; ^R5 refers to a halogen or -CN; each ^R1 is independently selected from the group consisting of: halogen, D, _CD3 , _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, _{C1 - C4} fluoroalkoxy, _C3 ^- _C6 cycloalkyl, and pentafluorohydrothio; _L1 refers to -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) ^q - or -O-( ^CR2R3 ) _p- ; ^R2 is H, D ^, or halogen; ^R3 is H, D, halogen, OH, or _C1 - _C4 alkyl; or ^R2 and ^R3 are connected together with the C atoms to which they are attached to form a _C3 - _C4 cycloalkyl group, wherein ^R4 is unsubstituted H or _C1 - _C4 alkyl; p is 1; q is 0; _Z1 is N, Z2 is CRz, _Z3 is N, _Z4 is ^C , and _Z5 is N; or _Z1 is N, _Z2 is CRz, Z3 is N, _Z4 is ^C , and Z5 is CRz; or _Z1 is C, _Z2 is CRz, Z3 is N, _Z4 is N, and _Z5 is ^CRz ; or _Z1 is ^C , _Z2 is N, Z3 is N, _Z4 is N, and _Z5 is ^CRz ; or _Z1 is C, _Z2 is N, Z ₃ -series N, Z ₄ -series N, and Z ₅ -series CR ^z ; each R ^z is H; L ₂ -series bond, -(CR ⁶ R ⁷ ) _n -, or -(CR ⁶ R ⁷ ) _n O-*, where * indicates the attachment point with R ⁸ ; each R ⁶ is independently selected from the group consisting of: H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, and C ₁ -C ₄ hydroxyalkyl; each R ⁷ is independently selected from the group consisting of: H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, and C ₁ -C ₄ hydroxyalkyl; or R ⁶ and R ⁷ are linked together with the C atom to which they are attached to to form a tetrahydropiperanyl group; n is 1 or 2; R ^8- series: (i) having 1 or 2 independently selected from N, NR ⁹ (i) A 4-, 5-, or 6-membered heterocyclic alkyl group having a ring member of O and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1 or 2 ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 5-membered heterocyclic alkyl group having a ring member of S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by -OH and _C10. (iii) A ₆ -membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S(=O), and the other ring member is selected from N, ^NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR₉ , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , and the other ring member is selected from N, NR₉, and S. (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, ² , 3 or 4 ring members independently selected from N, NR ⁹ and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy and _C1 -C4 alkyl; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from N and NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a substituent; (viii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, ₃ or 4 ring members independently selected from N, NR 9 and O. A partially saturated 10-membered fused bicyclic heterocyclic group having a ring member of N, NR ⁹ , or O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) a 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from N, NR ⁹ , or O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) a 6-membered heterocyclic alkyl group having one or two independently selected ring members selected from N, NR ⁹ , or O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge; (xi) a phenyl group substituted with -S(=O) _2N ( ^R10 ) ₂ ; or (xii) a C4 _-C10 ... _8- cycloalkyl group, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N ₍ ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments of compounds having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, having stereoisomers thereof: -X=Y- is -CRx= ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx is H or ^F ; ^Ry is H, F, or CN; ^R5 is F, Cl, or CN; each ^R1 is independently selected from the group consisting of: F, Cl, Br, methyl, isopropyl, _tributyl ^, cyclopropyl, _-CF3 , _CHF2 , _CF2CF3 , _OCF3 , and _SF5 ; _L1 is -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) _q- , or ^-O- ( ^{CR2R3 )} _p- ; R ² is H or F; ^R3 is H, OH, F or methyl; or ^R2 and ^R3 are linked together with the C atom to which they are attached to form a cyclopropyl group, which is unsubstituted; ^R4 is H, methyl or ethyl; p is 1; q is 0; _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C, and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; each R ^z is H; _L2 is a bond, -( ^{CR6R7 )} _n - or -( ^CR6R7 ) _nO- *, where * ^indicates the attachment site with ^R8 ; each ^R6 is independently selected from the group consisting of: H, methyl, isopropyl, _-CH2OH , and _CH2CF3 ; each R7 is independently selected from the group consisting of: H _, methyl, isopropyl, _-CH2OH , and _CH2CF3 ; or ^R6 and ^R7 are connected together with the C atom to which they are attached to form a tetrahydropiperanyl group; n _is 1 or ² ; ^R8 is: (i) a 4-, 5-, or 6-membered heterocycloalkyl group having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, NH _2. F, CF _3. Methyl, methoxy, phenoxy, and a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and NR ⁹ , wherein the monocyclic heteroaryl group is unsubstituted; (ii) a 5-membered heterocycloalkyl group having one ring member as S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from OH and methyl; (iii) a 6-membered heterocycloalkyl group having one ring member as S(=O) ₂ or S(=O), and one other ring member selected from N, NR ⁹ and O, and wherein the heterocycloalkyl group is unsubstituted or substituted with methyl; (iv) having one or two ring members independently selected from N, NR ⁹ (v) A partially saturated 6-membered heterocyclic group having one ring member selected from N, NR9, and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vi) A partially saturated 6-membered heterocyclic group having one ring member selected from S(=O) ₂ and another ring member selected from N, ^NR9 , and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy, and methyl; (vii) A group having one ring member selected from N and NR9. (viii) A ⁶ -membered fused bicyclic heterocyclic group having 1, 2, or 3 independently selected ring members from N, NR ⁹ , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) A 7-membered spirobicyclic heterocyclic alkyl group having 1 independently selected ring member from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) A group having 1 to 2 independently selected ring members from N, NR 9, and O. A 6-membered heterocycloalkyl group of ring members ⁹ and O, wherein the heterocycloalkyl group has a _C1 - _{C3 alkyl} bridge or a _-CH2OCH2 -bridge; (xi) phenyl, which is substituted with -S(=O) _2NH2 ; or ( _xii ) cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with 1, ₂ , or 3 substituents independently selected from -OH, -NH2, -S(=O) _{2CH3 , -CH2NH2 , F ,} and methoxy; and ^R9 is H, methyl, benzyl, -C(=O) _CH3 , _-C (=O)O( _CH3 ) ₃ , _CH2CH2OH , or _CH2CH2OCH3 .

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, having stereoisomers thereof: -X=Y- is -CRx= ^CRy- , or ^-CRx =N-; ^Rx is H; ^Ry is H, D, halogen, or -CN; ^R5 is halogen or -CN; ^{each R1} is independently selected from the group consisting of ^: halogen, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and pentafluorohydrothioyl; _L1 is - ^{( CR2R3} ) _p- , ^-NR4 ( ^CR2R3 ) _q- , or ^-O- ( ^CR2R3 ) _p- ; ^R2 is H; ^R3 is H, OH, or _C1 - _C4 alkyl; ^R4 is H, or C ₁ - _C4 alkyl; p-type 1; q-type 0; _Z1 -type N, _Z2 -type _CR ^z , _Z3 -type N, Z4-type C, and _Z5 -type N; or _Z1 -type N, _Z2 -type CR ^z , _Z3 -type N, _Z4 -type C, and _Z5 -type CR ^z ; or _Z1 -type C, _Z2 -type CR ^z , _Z3 -type N, _Z4 -type N, and _Z5 -type CR ^z ; or _Z1 -type C, _{Z2 -} type N, _Z3 -type N, Z4-type N, and _Z5 -type CR ^z ; each R ^z is H; _L2 -type bond, -( ^CR6R7 ) _n- , or - ^{(CR6R7 ) nO-} _* , where * indicates the attachment point with ^R8 ; each ^R6 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, and C ₁ - _C4 hydroxyalkyl; each ^R7 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, and _C1 - _C4 hydroxyalkyl; n is 1 or 2; ^R8 is: (i) a 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 -C4 alkyl, _{C1 - C4} alkoxy, lateral oxy, and having 1 or 2 substituents independently selected from N and NR (ii) A 5- or 6-membered monocyclic heteroaryl group of ^a ring member, wherein the monocyclic heteroaryl group is unsubstituted; (iii) A 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from -OH and _C1 - _C4 alkyl groups; (iv) A 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and one other ring member is selected from N, ^{NR9 and} O, and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from _C1 - _C4 alkyl groups; (v) A partially saturated 6-membered heterocyclic group having one ring member selected from N, NR, and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted with an oxy group; (vi) A partially saturated 6-membered heterocyclic group having one ring member selected from S(=O) ₂ and another ring member selected from N, ^NR4 , and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with an oxy group; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy, and _C1 - _C4 alkyl; (vii) A group having one ring member selected from N and NR (viii) A ⁶ -membered fused bicyclic heterocyclic group having 1, 2, or 3 independently selected ring members from N, NR ⁹ , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) A 7-membered spirobicyclic heterocyclic alkyl group having 1 independently selected ring member from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) A group having 1 to 2 independently selected ring members from N, NR 9, and O. A 6-membered heterocycloalkyl group of ring members ⁹ and O, wherein the heterocycloalkyl group has a _C1 - _C3 alkyl bridge or a _{-CH2OCH2 -} bridge; (xi) phenyl, which is substituted with -S(=O) _2N ( ^R10 ) ₂ ; or (xii) _C4 - _C8 cycloalkyl, which is substituted with 1, 2 or 3 substituents independently selected from -OH, -N( ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _{C1 -C4 alkyl} - ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and R ¹⁰ -series H, or _C1 - _C4 alkyl.

In embodiments having formulas (Ia) and (Ib), or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts: -X=Y- is -CRx= ^CRy- , or ^-CRx =N-; ^Rx is H; ^Ry is H, ^F , or CN; ^R5 is F or CN; each ^R1 is independently selected from the group consisting of: F, Cl, methyl ^{, -CF3, and SF5; L1 is -(CR2R3)p-, -NR4(CR2R3)q-, or -O-(CR2R3} _{) p- ;} ^R2 _is ^{H ;} _R3 ^is _H ^{, OH ,} or methyl; ^R4 is H, methyl ^, or ethyl; p is 1; q is 0; _Z1 is N, _Z2 is ^CRz , _Z3 is N, Z ₄ is C, and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N, and _Z5 is CR ^z ; each R ^z is H; _L2 is a bond, -( ^CR6R7 ) _n- , or - ^{( CR6R7} ) _nO- *, where * indicates the attachment point with ^R8 ; ^{each R6} is independently selected from the group consisting of: H, methyl, and _-CH2OH ; each ^R7 is independently selected from the group consisting of: H, methyl, and _-CH2OH ; n is 1 or 2; R ⁸ -membered heterocycloalkyl: (i) a 4-, 5-, or 6-membered heterocycloalkyl having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by one, two, or three substituents independently selected from -OH, -CN, _NH2 , F, _CF3 , methyl, methoxy, sideoxy, and a 5- or 6-membered monocyclic heteroaryl having one or two ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl is unsubstituted; (ii) a 5-membered heterocycloalkyl having one ring member as S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocycloalkyl is unsubstituted or substituted by substituents selected from OH and methyl; (iii) (iv) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S( ⁼ O), and the other ring member is selected from N, ^NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted with a methyl group; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , and the other ring member is selected from N, ^NR₉ , and O, and wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (vi) (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, NR ⁹ , and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy, and methyl; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from N and NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a side-oxy group; (viii) A partially saturated 10-membered fused bicyclic heteroaryl group having 1, 2, or 3 ring members independently selected from N, NR ⁹ , and O, wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a side-oxy group; (ix) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members selected from N, NR 9, and O. (x) A 7-membered spirobicyclic heterocyclic alkyl group having one or two ring members independently selected from N, ^{NR, 9 ,} and O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or a _-CH2OCH2 -bridge; (xi) A phenyl group substituted with -S(=O) _2NH2 ; or (xii) A cyclobutyl, cyclopentyl, or cyclohexyl group substituted with _{one ,} two, or _three substituents independently selected from -OH, _-NH2 , _-S (=O) _2CH3 , _-CH2NH2 , F, and methoxy; and ^R9 is H, methyl, benzyl, -C(=O)CH _3. -C(=O)O(CH ₃ ) ₃ , CH ₂ CH ₂ OH, or CH ₂ CH ₂ OCH ₃ .

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, having stereoisomers thereof: -X=Y---CR ^x =N-; R ^x --H; R ⁵ --halogen; each R ¹ independently selected from the group consisting of: halogens, C ₁ -C ₄ alkyl, and C ₁ -C ₄ fluoroalkyl; L ₁ --(CR ² R ³ ) _p- ; R ² --H; R ³ --H, or C ₁ -C ₄ alkyl; p---1; Z ₁ --N, Z ₂ --CR ^z , Z ₃ --N, Z ₄ --C, and Z ₅ --N; or Z ₁ --N, Z ₂ --CR ^z , Z ₃ --N, Z ₄ --C, and Z ₅ --CR ^z ; or Z ₁ -series C, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series N, and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N, and _Z5 -series CR ^z ; each R ^z is H; _L2 -series bond or -(CR ⁶ R ⁷ ) _n -; each R ⁶ is independently selected from the group consisting of H and _C1 - _C4 alkyl; each R ⁷ is independently selected from the group consisting of H and _C1 - _C4 alkyl; n is 1 or 2; R8 ^- series: (i) having 1 or 2 independently selected from N, NR ⁹ (i) A 4-, 5-, or 6-membered heterocyclic cycloalkyl group of the ring members of O and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, and lateral oxy; (ii) A 5-membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by substituents selected from _C1 - _C4 alkyl; (iii) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O), and one other ring member is selected from N, ^NR9 , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted by substituents selected from _C1 -C4 alkyl. (iv) A partially saturated _6- membered heterocyclic group having one or two ring members independently selected from O and S, wherein the partially saturated heterocyclic group is unsubstituted; (v) A partially saturated 6-membered heterocyclic group having one ring member S(=O) ₂ and the other ring member O, wherein the partially saturated heterocyclic group is unsubstituted; (vi) A 5-membered monocyclic heteroaryl group having three ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered heterocyclic group having one ring member selected from N and O. (viii) A ⁶ -membered fused and bicyclic heterocyclic group having one ring member selected from N, NR ^{9, and O, wherein the fused and bicyclic heterocyclic group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having one ring member selected from N, NR 9} , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; or (x) A C 4-C 8 cycloalkyl group having one ring member selected from NR ⁹ , wherein the heterocyclic alkyl group has a C ₁ -C ₃ alkyl bridge; or (x) A C ₄ -C ₈ cycloalkyl group substituted by one, two, or three substituents independently selected from -OH, -N(R ¹⁰ ) ₂ , C ₁ -C ₄ alkyl-NH ₂ , and halogen; R ⁹ is H, C ₁ -C _4- alkyl, or -C(=O) ^R10 , and ^R10 is H, or _C1 - _C4 alkyl.

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, of which: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and -CF ₃ ; L ₁ is -(CR ² R ³ ) _p- , R ² is H; R ³ is H or methyl; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is CR ^z ; or Z ₁ is C, Z ₂ is CR ^z , Z ₃ is N, Z ₄ -series N, and Z ₅ -series CR ^z ; or Z ₁ -series C, Z ₂ -series N, Z _{3 -} series N, Z 4-series N, and Z ₅ -series CR ^z ; each R ^z is H; L ₂ -series bond or -(CR ⁶ R ⁷ ) _n -; each R ⁶ is independently selected from the group consisting of H and methyl; each R ⁷ is independently selected from the group consisting of H and methyl; n is 1 or 2; R ^8- series: (i) a 4-, 5-, or 6-membered cyclohexaalkyl group having 1 or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, F, CF ₃ , methyl, and lateral oxygen; (ii) (iii) A 5-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a methyl group; (iv) A 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O), and one other ring member is selected from N, ^NR₉ , and O, and wherein the heterocycloalkyl group is unsubstituted or substituted with a methyl group; (v) A partially saturated 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂. (vi) A 5-membered monocyclic heteroaryl group having three independent ring members selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered fused-bicyclic heteroaryl group having one ring member selected from NR ⁹ , wherein the fused-bicyclic heteroaryl group is unsubstituted; (viii) A 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from NR ⁹ and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having one ring member selected from NR ⁹ , wherein the heterocyclic alkyl group has a C ₁ -C ₃ -alkyl bridged; or (x) cyclobutyl, cyclopentyl, or cyclohexyl, which _is substituted by 1, 2, or 3 substituents independently selected from -OH, _-NH2 , _-CH2NH2 , and F; and ^R9 is H, methyl, or -C(=O) _CH3 .

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or stereoisomers thereof: -X=Y---CR ^x =N-; R ^x --H; R ⁵ --halogen; each R ¹ independently selected from the group consisting of: halogens, C ₁ -C ₄ alkyl, and C ₁ -C ₄ fluoroalkyl; L ₁ --(CR ² R ³ ) _p- ; R ² --H; R ³ --H, or C ₁ -C ₄ alkyl; p---I; Z ₁ --N, Z ₂ --CR ^z , Z ₃ --N, Z ₄ --C, and Z ₅ --N; or Z ₁ --N, Z ₂ --CR ^z , Z ₃ --N, Z ₄ --C, and Z ₅ --CR ^z ; each R ^z --H; _{L2 series} ^: bond or -( ^CR6R7 ) _n- ; each ^R6 is independently selected from the group consisting of H and _C1 - _C4 alkyl; each ^R7 is independently selected from the group consisting of H and _C1 - _C4 alkyl; n is 1 or 2; ^R8 series: (i) a 4-, 5-, or 6-membered cyclohexaalkyl group having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, and lateral oxygen; (ii) a 5-membered heterocycloalkyl group, wherein one ring member is S (=O). (iii) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O), and the other ring member is selected from N, _NR9 ^, and O, and the heterocyclic alkyl group is unsubstituted or substituted from _C1 - _C4 alkyl groups; (iv) A partially saturated ₆ -membered heterocyclic alkyl group having _one or two ring members independently selected from O and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _2. (vi) A 5-membered monocyclic heteroaryl group having 3 ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted; (viii) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from N, NR ⁹ and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (ix) A 5-membered monocyclic heteroaryl group having 3 ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; A 6-membered heterocycloalkyl group of ring member ⁹ , wherein the heterocycloalkyl group has _C1 - _C3 alkyl bridging; or (x) _C4 - _C8 cycloalkyl group, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 and halogen; ^R9 is H, _C1 - _C4 alkyl, or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, of which: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and -CF ₃ ; L ₁ is -(CR ² R ³ ) _p- , R ² is H; R ³ is H or methyl; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is CR ^z ; each R ^z is H; L ₂ is bonded or -(CR ⁶ R ⁷ ) _n- ; Each R ⁶ is independently selected from the group consisting of H and methyl; each R ⁷ is independently selected from the group consisting of H and methyl; n is 1 or 2; R ⁸ is: (i) a 4-, 5-, or 6-membered cyclohexaalkyl group having 1 or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, F, CF ₃ , methyl, and lateral oxygen; (ii) a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by methyl; (iii) a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) (iv) A partially saturated 6-membered heterocyclic group having _one or two ring members independently selected from O and ^S , wherein the partially saturated heterocyclic group is unsubstituted; (v) A partially saturated 6-membered heterocyclic group having one ring member S(=O) ₂ and one other ring member O, wherein the partially saturated heterocyclic group is unsubstituted; (vi) A 5-membered monocyclic heteroaryl group having three ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A heteroaryl group having one ring member selected from NR (viii) A ⁶ -membered fused and bicyclic heterocyclic group having one ring member selected from NR ⁹ and O, wherein the fused and bicyclic heterocyclic group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having one ring member selected from NR ⁹ , wherein the heterocyclic alkyl group is _C1 - _C3 alkyl-bridged; or (x) A cyclobutyl, cyclopentyl, or cyclohexyl group substituted by one, two, or three substituents independently selected from -OH, _-NH₂ , _-CH₂NH₂ , and F; and ^R₉ is H, methyl, or -C ₍ =O) _CH₃ .

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or stereoisomers thereof: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is a halogen; each R ¹ is independently selected from the group consisting of: halogens, C ₁ -C ₄ alkyl groups, and C ₁ -C ₄ fluoroalkyl groups; L ₁ is -(CR ² R ³ ) _p- ; R ² is H; R ³ is H; p is 1; Z ₁ is N, Z 2 is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; each R ^z is H; L ₂ is a bond; R ₈ is a pyrrolidyl group, which is substituted by one or two substituted groups ^, each independently selected from a halogen and a C ₁ -C ₄ fluoroalkyl group.

In embodiments having formulas (Ia) and (Ib), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and CF ₃ ; L ₁ is -(CR ² R ³ ) _p- ; R ² is H; R ³ is H; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; each R ^z is H; L ₂ is a bond; R ⁸ is a pyrrolidyl group, which is substituted by one or two of which are independently selected from F and CF ₃ .

In any of the above embodiments, the compound having formula (I) is a compound having formula (Ia), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (Ia.)

In any of the above embodiments, the compound having formula (I) is a compound having formula (Ib), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (Ib).

In embodiments of compounds having formula (I), the compounds provided herein are compounds having formula (Ic), formula (Id), formula (Ie) or formula (If), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof: (Ic) (Id) (Ie) (If) Where: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx refers to H, D, halogen, or _C1 - _C4 alkyl; ^Ry refers to H, D, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^R5 refers to H, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; Each ^R1 is independently selected from the group consisting of: halogen, _C1 - _C4 alkyl, C2-C4 alkenyl, _C2 - _C4 alkynyl, _C1 - _C4 alkoxy, C1-C4 alkoxycarbonyl, _C3 - _C6 cycloalkyl, _C1 -C4 fluoroalkyl, C1- _C6 cycloalkyl, _C1 - _C4 fluoroalkyl, _C1 -C6 cycloalkyl, C1- _C4 fluoroalkyl, C1 _-C4 cyclo ... _4- fluoroalkoxy, pentafluorohydrothio, _C1 -C4 hydroxyalkyl, _C1 - _C4 thioalkyl, azido, _diC1 - _C4 alkylamino, _diC1 - _C4 alkylaminocarbonyl, D, _CD3 , cyano, methyl, phenyl, and 5- to 6 _- membered heterocycloalkyl groups comprising one or two ring members independently selected from N, ^NR4 , O, and S; _L1 ^series -( ^CR2R3 ) _p- , -( ^CR2R3 ) _p - ^NR4- , -( ^CR2R3 ) _p -O-, ^-NR4 ( ^{CR2R3 )} _q- ^, -( ^{CR2R3 ) qNR4- , -O-} ( ^CR2R3 ) _{p- ,} or -S-( ^{CR2R3 )} _p- ; R ^R2 is H, D, halogen, or _C1 - _C4 alkyl; ^R3 is H, D, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, OH, amino, or t -Boc-amino; or ^R2 and ^R3 are connected together with the C atom to which they are attached to form a _C3 - _C4 cycloalkyl group, which is unsubstituted or substituted by a single substituent selected from _C1 - _C4 alkyl and lateral alkyl groups; each ^R4 is independently selected from the group consisting of: H and _C1 - _C4 alkyl; p is 1, 2, or 3; q is 0, 1, or 2; _Z1 is N or C; _Z2 is N or ^CRz ; _Z3 is N or ^CRz ; _Z4 is N or C; _Z5 is N or ^CRz ; wherein each ^Rz is independently selected from the group consisting of: H, halogen, C ₁ - _C4 alkyl and _C1 - _C4 fluoroalkyl; and the condition is that at least two and no more than four of _Z1 , _Z2 , _Z3 , _Z4 and _Z5 are N; each ^R6 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl and _C1 - _C4 hydroxyalkyl; each ^R7 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl and _C1 - _C4 hydroxyalkyl; or ^R6 and ^R7 are connected together with the C atoms to which they are attached to form _C3 - _C6 cycloalkyl, oxocyclobutyl, tetrahydrofuranyl or tetrahydropiperanyl; n is 1, 2 or 3; ^R8 is: (i) (i) A 4-, 5-, or 6-membered heterocycloalkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _2. (iii) A _4- , 5-, or ₆ -membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O), and one, two, or three other ring members are independently selected from N, ^NR9 , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted by one, two, three, or four substituents independently selected from _C1 - _C4 alkyl and lateral alkyl groups; (iv) Having one or two independently selected from N, ^NR9 (v) A partially saturated 5- or 6-membered heterocyclic group of ring members of O and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, _C1 - _C4 alkyl and lateral oxygen; (vi) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and 1, 2 or 3 other ring members are independently selected from N, ^NR9 , O ^and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, _C1 - _C4 alkyl and lateral oxygen; (vii) A 5- or 6-membered monocyclic heteroaryl group having one or two ring members selected independently of -OH, _C1 - _C4 alkoxy, and _C1 - _C4 alkyl; (vii) A 6- or 7-membered fused bicyclic heterocyclic group having one or two ring members selected independently of -OH, -N( ^R10 )2, C1-C4 alkyl-NH2, halogen, C1-C4 alkyl, and lateral oxy; (viii) A 5- or 6-membered monocyclic heterocyclic group having one or two ring members selected independently of -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxy. A partially saturated fused bicyclic heterocyclic group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen; (ix) Having 1, 2, or 3 ring members independently selected from N, ^NR9 (x) A 6-membered, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having one or more ring members selected from N, NR9, O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted with one, two, three, or four substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen; (xi) A 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2-} bridge; Phenyl, either unsubstituted or substituted with one, two, three, or four substituents selected independently from the following: -S(=O) _₂N ( ^R₁₀ ) _₂ , -OH, -N( ^R₁₀ ) _₂ , _C₁ - _C₄ alkyl- _NH₂ , halogen, and _C₁ - _C₄ alkyl; or (xii) _C₄ - _C₈ cycloalkyl, either unsubstituted or substituted with one, two, three, or four substituents selected independently from the following: -OH, -N( ^R₁₀ ) _₂ , ^-S (=O) _₂R₁₀ , _C₁ - _C₄ alkyl- _NH₂ , halogen, _C₁ - _C₄ alkoxy, _C₁ - _C₄ alkyl, and phenoxy; ^R₉ is H, _C₁ - _C₄ alkyl, benzyl, _C₁ - _C₄ alkyl- ^OR₁₀. -C(=O)OR ¹⁰ or -C(=O)R ¹⁰ , and R ¹⁰ is H or _C1 - _C4 alkyl.

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- is ^-CRx = ^CRy- , ^-CRx =N- or -N= ^CRy- ; ^Rx is H, D, halogen, or _C1 - _C4 alkyl; ^Ry is H, D, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^R5 is H, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; each ^R1 is independently selected from the group consisting of: halogen, _C1 - _C4 alkyl, C2-C4 fluoroalkyl, C1 _-C4 alkoxy. _4- Alkenyl, _C2 - _C4 ynyl, C1-C4 alkoxy, _C1 - _C4 alkoxycarbonyl, _C3 - _C6 cycloalkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, pentafluorohydrothioyl, _C1 - _C4 hydroxyalkyl, _C1 - _C4 thioalkyl, azidoyl, _diC1 - _C4 alkylamino, _diC1 - _C4 alkylaminocarbonyl, D, _CD3 , cyano, methyl, phenyl, and _5- to 6 _- membered heterocycloalkyl comprising one or two ring members independently selected from N, ^NR4 , O, and ^{S ;} _L1 series -( ^CR2R3 ) _p- , -( ^CR2R3 ) _p - ^NR4- , -( ^CR2R3 ) ^p _- O-, ^-NR4 ( ^CR2R3 ) _q- , -( ^CR2R3 ) _qNR4- , ^{-O- ( CR2R3} ) _p- , or -S-( ^CR2R3 ) _p- ; R2 is H, D, halogen, or ^C1 - ^C4 alkyl; ^R3 is H, D, ^halogen , _C1 - _C4 alkyl, _C1 - _C4 alkoxy, ^OH , amino, or _t - Boc-amino; or ^R2 and ^R3 are connected together with the C atom to which they are attached to form a _C3 - _C4 cycloalkyl group, which is unsubstituted or substituted by a single substituent selected from _C1 - _C4 alkyl and lateral alkyl groups; _each ^R4 is independently selected from the group consisting of: H and _C1 - _C4 alkyl; p is 1, 2, or 3; q is 0, 1, or 2; _Z1 is N, Z _Z2 -series CR ^z , _Z3 -series N, _Z4 -series C and _Z5 -series N; or _Z1 -series N, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series C and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; or _Z1 -series N, _Z2 -series CR ^z , _Z3 -series CR ^z , _Z4 -series C and _Z5 -series N; each R ^z is independently selected from the group consisting of: H, halogens, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl; each R ⁶ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, C1- _C4 fluoroalkyl. -C ₄ fluoroalkyl and C ₁ -C ₄ hydroxyalkyl; each R ⁷ is independently selected from the group consisting of: H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl and C ₁ -C ₄ hydroxyalkyl; or R ⁶ and R ⁷ are connected together with the C atom to which they are attached to form C ₃ -C ₆ cycloalkyl, oxocyclobutyl, tetrahydrofuranyl or tetrahydropiperanyl; n is 1, 2 or 3; R ⁸ is: (i) a 4-, 5- or 6-membered heterocycloalkyl having 1, 2 or 3 ring members independently selected from N, NR ⁹ , O and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3 or 4 substituents each independently selected from: -OH, -CN, -N(R ¹⁰ ) ₂ (i) halogens, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and 5- or 6-membered monocyclic heteroaryl groups having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted; (ii) 4-, 5-, or 6-membered heterocyclic alkyl groups, wherein one ring member is S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _C1 - _C4 alkyl, and lateral alkyl groups; (iii) 4-, 5-, or 6-membered heterocyclic alkyl groups, wherein one ring member is S(=O). (iv) A partially saturated 5- or 6-membered heterocyclic group having ₁ or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from _C1 - _C4 alkyl and lateral oxygen groups; (v) A partially saturated 5- or 6-membered heterocyclic group having 1 or 2 ring members independently selected from N, NR ⁹ , O, and _S , wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _C1 - _C4 alkyl, and lateral oxygen groups; (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _C1 - _{C4 alkoxy, and C1-C4} alkyl; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, ² , 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _C1 - _C4 alkoxy, and _C1 - _C4 alkyl; (viii) A 6- or 7-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 substituents, each independently selected from -OH, -N( ^{R10 )} ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups ^; _2. Substituents of _{C1- C4} alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen; (ix) A 6-, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen; (x) Having 1 to 2 substituents independently selected from N, ^NR9 A six-membered heterocycloalkyl group having a ring member of O and S, wherein the heterocycloalkyl group has a _C1 - _C3 alkyl bridge or a _{-CH2OCH2 -} bridge; (xi) phenyl, which is unsubstituted or substituted by 1, 2, 3 or 4 substituents each independently selected from the following: -S(=O) _2N ( ^R10 ) ₂ , -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkyl; or (xii) _C4 - _C8 cycloalkyl, which is unsubstituted or substituted ^{by 1, 2, 3 or 4 substituents each independently selected from the following: -OH, -N(R10)2, -S(=O)2R10 ,} _{C1 - C4 alkyl} - _NH2 Halogen, _C1 - _C4 alkoxy, _C1 - _C4 alkyl, and syloxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N- or -N= ^CRy- ; ^Rx refers to H, D or halogen; ^Ry refers to H, D, halogen or -CN; ^R5 refers to halogen or -CN; each ^R1 is independently selected from the group consisting ^of : halogen, D, _CD3 , _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, _C3 - _C6 cycloalkyl and pentafluorohydrothio; _L1 refers to -( ^CR2R3 ) _p- , ^-NR4 ( ^{CR2R3 )} _q - or -O-(CR ² R ³ ) _p -; R ² is H, D or halogen; R ³ is H, D, halogen, OH or C ₁ -C ₄ alkyl; or R ² and R ³ are connected together with the C atoms to which they are attached to form an unsubstituted C ₃ -C ₄ cycloalkyl; R ⁴ is H or C ₁ -C ₄ alkyl; p is 1; q is 0; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is N; or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is CR ^z ; or Z ₁ is C, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is N and Z ₅ is CR ^z ; or Z ₁ is C, Z ₂ is N, Z ₃ is N, Z ₄ -series N and Z _5-series CR ^z ; each R ^z is H; each R ⁶ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl and _C1 - _C4 hydroxyalkyl; each R ⁷ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl and _C1 - _C4 hydroxyalkyl; or R ⁶ and R ⁷ are connected together with the C atom to which they are attached to form a tetrahydropiperanyl; n-series 1 or 2; R ⁸ -series: (i) having 1 or 2 independently selected from N, NR ⁹ (i) A 4-, 5-, or 6-membered heterocyclic alkyl group having a ring member of O and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1 or 2 ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 5-membered heterocyclic alkyl group having a ring member of S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by -OH and _C1 -C10. (iii) A ₆ -membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S(=O), and the other ring member is selected from N, ^NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR₉ , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , and the other ring member is selected from N, NR₉ ^{, and S.} (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, ^NR9 and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy and _C1 -C4 alkyl; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from N and ^NR9 , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a substituent; (viii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, ₃ or 4 ring members independently selected from N, NR9 and O. A partially saturated 10-membered fused bicyclic heterocyclic group having ring members of ⁹ and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) a 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) a 6-membered heterocyclic alkyl group having one or two independently selected ring members selected from N, NR ⁹ , and O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge; (xi) a phenyl group substituted with -S(=O) _2N ( ^R10 ) ₂ ; or (xii) a _C4 -C _8- cycloalkyl group, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N ₍ ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- is ^-CRx = ^CRy- , ^-CRx =N- or -N= ^CRy- ; ^Rx is H or F; ^Ry is H, F or CN; ^R5 is F, Cl or CN; each ^R1 is independently selected from the group consisting of ^: F, Cl, _Br , methyl, isopropyl, tributyl, cyclopropyl, _-CF3 , _CHF2 , _CF2CF3 , _OCF3 , and _SF5 ; _L1 is -( ^CR2R3 ) _p- , ^-NR4 ( ^{CR2R3 )} _q- or -O-( ^{CR2R3 )} _p -; ^R2 is H or F; ^R3 is H, OH, F or methyl; or ^R2 and ^R3 are connected together with the C atoms to which they are attached to form an unsubstituted cyclopropyl group; ^R4 is H, methyl or ethyl; p is 1; q is 0; _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N and _Z5 is CR ^z ; each R ^z is H; each R ^6. Independently selected from the group consisting of: H, methyl, isopropyl, _-CH₂OH and _{CH₂CF₃ ;} each ^R₇ is independently selected from the group consisting of: H, methyl, isopropyl, _-CH₂OH and _CH₂CF₃ ; or ^R₆ and ^R₇ are connected together with the C atom to which they are attached to form a tetrahydropiperanyl group; n is 1 or 2; ^R₈ is: (i) a 4-, _5- , or 6-membered heterocycloalkyl group having 1 or 2 ring members independently selected from N, ^NR₉ , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, _NH₂ , F, _CF₃ , methyl, methoxy, sideoxy, and having 1 or 2 substituents independently selected from N and NR₉. (ii) a 5- or 6-membered monocyclic heteroaryl group of a ring member of ⁹ , wherein the monocyclic heteroaryl group is unsubstituted; (iii) a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from OH and methyl; (iv) a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and the other ring member is selected from N, ^NR9 and ^O , and wherein the heterocycloalkyl group is unsubstituted or substituted with methyl; (v) A partially saturated 6-membered heterocyclic group having one ring member selected from N, NR9, and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vi) A partially saturated 6-membered heterocyclic group having one ring member selected from S(=O) ₂ and another ring member selected from N, ^NR9 , and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy, and methyl; (vii) A group having one ring member selected from N and NR9. (viii) A ⁶ -membered fused bicyclic heterocyclic group having 1, 2, or 3 independently selected ring members from N, NR ⁹ , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) A 7-membered spirobicyclic heterocyclic alkyl group having 1 independently selected ring member from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) A group having 1 to 2 independently selected ring members from N, NR 9, and O. A 6-membered heterocycloalkyl group of ring members ⁹ and O, wherein the heterocycloalkyl group has a _C1 - _{C3 alkyl} bridge or a _-CH2OCH2 -bridge; (xi) a phenyl group substituted with -S(=O) _2NH2 ; or (xii) a cyclobutyl, cyclopentyl, or cyclohexyl group substituted with ₁ , ₂ , _or 3 substituents independently selected from -OH, -NH2, -S(=O) _{2CH3 , -CH2NH2} , _F , and methoxy; and ^R9 is H, methyl, benzyl, -C(=O) _CH3 , _-C (=O)O( _{CH3 ) 3} , _CH2CH2OH , or _CH2CH2OCH3 .

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, of a stereoisomer thereof: -X=Y- is ^-CRx = ^CRy- or ^-CRx =N-; ^Rx is H; ^Ry is H, D, halogen, or -CN; ^R5 is halogen or -CN; each ^R1 is independently selected from the group consisting of: halogen, _C1 - _C4 alkyl, _C1 - _C4 ^fluoroalkyl , and pentafluorohydrothioyl; _L1 is -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) _q- , ^or -O- ^{( CR2R3} ) _p- ; ^R2 is H; ^R3 is H, OH, or _C1 - _C4 alkyl; R ^4- series H or _C1 - _C4 alkyl; p-series 1; q-series 0; _Z1 -series N, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series C and _Z5 -series N; or _Z1 -series N, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series C and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; each R ^z is H; each R ⁶ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, and _C1 - _C4 hydroxyalkyl; each R ⁷ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, and C1- _C4 hydroxyalkyl. -C ₄ hydroxyalkyl; n-system 1 or 2; R ^8- system: (i) 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N(R ¹⁰ ) ₂ , halogen, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, lateral oxy, and 5- or 6-membered monocyclic heteroaryl having 1 or 2 ring members independently selected from N and NR ⁹ , wherein the monocyclic heteroaryl is unsubstituted; (ii) 5-membered heterocycloalkyl, wherein one ring member is S(=O) _2. (iii) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O), and the other ring member is selected from N, ^NR9 , and O, and the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from _{C1 - C4 alkyl} groups; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (v) (vi) A partially saturated 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and the other ring member is selected from N, ^NR4 , and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy, and _C1 - _C4 alkyl; (vii) A 6-membered fused bicyclic heterocyclic group having 1 ring member selected from N and ^NR9 , wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with a side-oxy group; (viii) A partially saturated 10-membered fused bicyclic heterocyclic group having 1, 2, or 3 ring members independently selected from N, NR ⁹ , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with a side-oxy group; (ix) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) A 6-membered heterocyclic alkyl group having 1 to 2 ring members independently selected from N, NR ⁹ , and O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or a -CH ₂ OCH ₂ -bridge; (xi) A phenyl group substituted with -S(=O) ₂ N(R ¹⁰ ) ₂ ; Or (xii) _C4 - _C8 cycloalkyl, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N( ^R10 ) ₂ , -S(=O) _2R10 ^, _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- is ^-CRx = ^CRy- or ^-CRx =N-; ^Rx is H; ^Ry is H, F or CN; ^R5 is F or CN; each ^R1 is independently selected from the group consisting of: F ^, Cl, methyl, _-CF3 , and _SF5 ; _L1 is -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) _q- or -O-( ^CR2R3 ) _p- ; ^{R2 is} H; ^R3 is H, OH or methyl; ^R4 is H, methyl or ethyl; p is 1 ^; q is 0; _Z1 is N, _Z2 is ^CRz , Z ₃ -series N, _Z4 -series C and _Z5 -series N; or _Z1 -series N, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series C and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; each R ^z is H; each R ⁶ is independently selected from the group consisting of: H, methyl and -CH ₂ OH; each R ⁷ is independently selected from the group consisting of: H, methyl and -CH ₂ OH; n-series 1 or 2; R ^8- series: (i) having 1 or 2 independently selected from N, NR ⁹ (i) A 4-, 5-, or 6-membered heterocycloalkyl group having a ring member of O and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, _NH₂ , F, _CF₃ , methyl, methoxy, lateral oxy, and a 5- or 6-membered monocyclic heteroaryl group having 1 or 2 ring members independently selected from N and ^NR₉ , wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 5-membered heterocycloalkyl group having one ring member of S(=O) _₂ , S(=O), or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by a substituent selected from OH and methyl; (iii) A 6-membered heterocycloalkyl group having one ring member of S(=O). (iv) A partially saturated 6-membered ^heterocyclic group having _one or two independently selected ring members chosen from N, NR ⁹ , O, and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted with an oxy group; (v) A partially saturated 6-membered heterocyclic group having one ring member S(=O) ₂ and another ring member chosen from N, NR ^{9, and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with an oxy group; (vi) A partially saturated 6-membered heterocyclic group having one, two, three, or four independently selected ring members chosen from N, NR 9} , O, and S. (vii) A 5- or 6-membered monocyclic heteroaryl group having one ring member selected from N and NR ⁹ , wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy, and methyl; (vii) A 6-membered fused bicyclic heteroaryl group having one ring member selected from N and NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a side-oxy group; (viii) A partially saturated 10-membered fused bicyclic heteroaryl group having one, two, or three ring members independently selected from N, NR ⁹ , and O, wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a side-oxy group; (ix) A 5- or 6-membered monocyclic heteroaryl group having one ring member selected from N, NR 9, and methyl. (x) A 7-membered spirobicyclic heterocyclic alkyl group having one or two ring members independently selected from N, ^NR , ⁹ , and O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or a _-CH2OCH2 -bridge; (xi) A phenyl group substituted with -S(=O) _2NH2 ; or (xii) _A cyclobutyl, cyclopentyl, or cyclohexyl group substituted with one _{, two} , or three substituents independently selected from -OH, _-NH2 , -S(=O) _2CH3 , _{-CH2NH2 ,} F, and methoxy; and ^R9 is H, methyl, benzyl, -C(=O)CH _3. -C(=O)O(CH ₃ ) ₃ , CH ₂ CH ₂ OH or CH ₂ CH ₂ OCH ₃ .

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: -X=Y---CR ^x =N-; R ^x --H; R ⁵ --halogen; each R ¹ is independently selected from the group consisting of: halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl; L ₁ --(CR ² R ³ ) _p- ; R ² --H; R ³ --H or -C ₁ -C ₄ alkyl; p---1; Z ₁ --N, Z ₂ --CR ^z , Z ₃ --N, Z ₄ --C and Z ₅ --N; or Z ₁ --N, Z ₂ --CR ^z , Z ₃ --N, Z ₄ --C and Z ₅ --CR ^z ; Or _Z1 is C, _Z2 is ^CRz , _Z3 is N, _Z4 is N and _Z5 is ^CRz ; or _Z1 is C, _Z2 is N, _Z3 is N, Z4 is N and _Z5 is ^CRz ; _each Rz is H; each ^R6 is independently selected from the group consisting of H and _C1 - _C4 alkyl; each ^R7 is independently selected from the group consisting of H and _C1 - _C4 alkyl; ⁿ is 1 or 2; ^R8 is: (i) a 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl is unsubstituted or is composed of 1, 2, or 3 ring members each independently selected from -OH, halogen, _C1 - _C4 fluoroalkyl, _C1- C (ii) A 5-membered heterocycloalkyl group, wherein one ring member is S(=O) _{₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from C₁-C₄ alkyl groups; (iii) A 6-membered heterocycloalkyl group, wherein one ring member is S(=O)₂ or S ( =} O), and the other ring member is selected from N, ^NR₉ , and O, and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (iv) A partially saturated 6-membered heterocycloalkyl group having one or two ring members independently selected from O and S, wherein the partially saturated heterocycloalkyl group is unsubstituted; (v) (vi) A partially saturated 6-membered heterocyclic group, wherein one ring member is S(=O) _₂ and the other ring member is O, wherein the partially saturated heterocyclic group is unsubstituted; (vii) A 5-membered monocyclic heteroaryl group having 3 ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered fused bicyclic heterocyclic group having 1 ring member selected from ^NR₉ , wherein the fused bicyclic heterocyclic group is unsubstituted; (viii) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from N, ^NR₉ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (ix) A six-membered heterocycloalkyl group having one ring member selected from NR ⁹ , wherein the heterocycloalkyl group has a _C1 - _C3 alkyl bridge; or (x) _C4 - _C8 cycloalkyl group, which is substituted by one, two or three substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 and halogen; ^R9 is H, _C1 - _C4 alkyl, or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl.

In embodiments having formula (Ic), formula (Id), formula (Ie), or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and -CF ₃ ; L ₁ is -(CR ² R ³ ) _p- , R ² is H; R ³ is H or methyl; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is N; or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is CR ^z ; or Z ₁ is C, Z ₂ is CR ^z , Z ₃ -series N, _Z4 -series N and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N and _Z5 -series CR ^z ; each R ^z is H; each R ⁶ is independently selected from the group consisting of H and methyl; each R ⁷ is independently selected from the group consisting of H and methyl; n is 1 or 2; R ^8- series: (i) a 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, F, CF ₃ , methyl, and lateral oxygen; (ii) a 5-membered heterocycloalkyl, wherein one ring member is S (=O). (iii) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or _S (=O), and the other ring member is selected from N, ^NR₉ , and O, and the heterocyclic alkyl group is unsubstituted or substituted with methyl; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from O and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , and the other ring member is O, wherein the partially saturated heterocyclic alkyl group is unsubstituted; (vi) (vii) A 5-membered monocyclic heteroaryl group having 3 independent ring members selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered fused bicyclic heterocyclic group having 1 ring member selected from NR ⁹ , wherein the fused bicyclic heterocyclic group is unsubstituted; (viii) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from NR ⁹ and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having 1 ring member selected from NR ⁹ , wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge; or (x) Cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted by one _{, two, or three substituents independently selected from -OH, -NH2, -CH2NH2 , and} F; and ^R9 is H, methyl, or -C(=O) _CH3 .

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: -X=Y---CR x =N-; R x --H; R 5 --halogen; each R 1 is independently selected from the group consisting of: halogen, C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl; L 1 --(CR 2 R 3 ) p- ; R 2 --H; R 3 --H or -C 1 -C 4 alkyl; p---1; Z 1 --N, Z 2 --CR z , Z 3 --N, Z 4 --C and Z 5 --N; or Z 1 --N, Z 2 --CR z , Z 3 --N, Z 4 --C and Z 5 --CR z ; Each R z is H; each R 6  is independently selected from the group consisting of H and C<sub> 1 -C 4 alkyl; each R 7  is independently selected from the group consisting of H and C<sub> 1 -C 4 alkyl; n is 1 or 2; R 8  is: (i) a 4-, 5-, or 6-membered heterocyclic alkyl group having 1 or 2 ring members independently selected from N, NR9 , O, and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, halogen, C<sub> 1 -C 4  fluoroalkyl, C<sub> 1 -C 4  alkyl, and lateral oxy; (ii) a 5-membered heterocyclic alkyl group, wherein one ring member is S(=O) 2  or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by C<sub>1-C4 alkyl. (iii) A 6 - membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ or S(=O) and the other ring member is selected from N, NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted by a substituent selected from C₁ - C₄ alkyl groups; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from O and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) ₂ and the other ring member is O, wherein the partially saturated heterocyclic alkyl group is unsubstituted; (vi) (vii) A 5-membered monocyclic heteroaryl group having 3 independent ring members selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered fused bicyclic heterocyclic group having 1 ring member selected from NR 9 , wherein the fused bicyclic heterocyclic group is unsubstituted; (viii) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from N, NR 9 , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having 1 ring member selected from NR 9 , wherein the heterocyclic alkyl group has a C1 - C3 alkyl bridge; or (x) C4 -C 8- cycloalkyl group, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N( R10 ) 2 , C1 - C4 alkyl- NH2 and halogen; R9 is H, C1 - C4 alkyl, or -C(=O) R10 , and R10 is H or C1 - C4 alkyl.

In embodiments of compounds having formula (Ic), formula (Id), formula (Ie), or formula (If), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and -CF ₃ ; L ₁ is -(CR ² R ³ ) _p- , R ² is H; R ³ is H or methyl; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is N; or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is CR ^z ; each R ^z is H; each R ^6. Independently selected from the group consisting of: H and methyl; Each R ^7. Independently selected from the group consisting of: H and methyl; n is 1 or 2; R ⁸ is: (i) a 4-, 5-, or 6-membered heterocycloalkyl group having 1 or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, F, CF ₃ , methyl, and lateral oxygen; (ii) a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by methyl; (iii) a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) (iv) A partially saturated 6-membered heterocyclic group having _one or two ring members independently selected from O and ^S , wherein the partially saturated heterocyclic group is unsubstituted; (v) A partially saturated 6-membered heterocyclic group having one ring member selected from S (=O) ₂ and another ring member selected from O, wherein the partially saturated heterocyclic group is unsubstituted; (vi) A 5-membered monocyclic heteroaryl group having three ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A heterocyclic heteroaryl group having one ring member selected from NR (viii) A ⁶ -membered fused bicyclic heterocyclic group having one ring member selected from NR ^{9 and O, wherein the fused bicyclic heterocyclic group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having one ring member selected from NR 9 ,} wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge; or (x) A cyclobutyl, cyclopentyl, or cyclohexyl group substituted by one, two, or three substituents independently selected from -OH, _-NH2 , _-CH2NH2 , _and F; and ^R9 is H, methyl, or -C(=O) _CH3 .

In embodiments having formula (Ic), formula (Id), formula (Ie) or formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the following are permissible: -X=Y- series -CR ^x =N-; R ^x series H; R ⁵ series halogen; each R ¹ is independently selected from the group consisting of: halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl; L ₁ series -(CR ² R ³ ) _p- ; R ² series H; R ³ series H; p series 1; Z ₁ series N, Z 2 series CR ^z , Z ₃ series N, Z ₄ series C and Z ₅ series N; each R ^z series H; R ₈ is pyrrolidinyl groups substituted by one or two halogens and C 1-C 4 fluoroalkyl groups ^, each independently selected from halogen and C ₁ -C ₄ fluoroalkyl groups.

In embodiments of compounds having formulas (Ic) and (Id), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and CF ₃ ; L ₁ is -(CR ² R ³ ) _p- ; R ² is H; R ³ is H; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C and Z ₅ is N; each R ^z is H; R ⁸ is pyrrolidinyl groups substituted by one or two of each independently selected from F and CF ₃ .

In any of the above embodiments, the compound having formula (I) is a compound having formula (Ic) or formula (Id), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (Ic) (Id)

In any of the above embodiments, the compound having formula (I) is a compound having formula (Ic), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (Ic)

In any of the above embodiments, the compound having formula (I) is a compound having formula (Id), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (Id).

In any of the above embodiments, the compound having formula (I) is a compound having formula (Ie), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (Ie)

In any of the above embodiments, the compound having formula (I) is a compound having formula (If), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof of a stereoisomer thereof: (If).

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, -X=Y- is -CR ^x =CR ^y- , -CR ^x =N-, or -N=CR ^y- .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, -X=Y- is -CR ^x =N- or -N=CR ^y- .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, -X=Y- is -CR ^x =N-.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, -X=Y- is -N=CR ^y- .

In certain embodiments of compounds having formula (I) or its subforms, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, -X=Y- is -N=CR ^y- ;

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Rx is H, D, halogen, or _C1 - _C4 alkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^x is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^x is D.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Rx is a halogen. In certain embodiments, ^Rx is an F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Rx is a _C1 - _C4 alkyl group. In certain embodiments, ^Rx is a methyl or ethyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Rx is H, D, F or methyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Rx is H or F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Rx is H, D or F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Ry is H, D, halogen, CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Ry is H, D, halogen, or CN.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^Ry is H, halogen, or CN.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^y is H, F or CN.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^y is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^y is D.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R y  is a halogen. In certain embodiments, R y is an F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^_y is a C _₁-C_₄ alkyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, Ry is a C 1 -C 4  fluoroalkyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^_y is a C _₁-C _₄ alkoxy group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁵ -H, halogen, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl or _C1 - _C4 alkoxy.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R5 refers to H, halogen, or CN.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R5 is H, F, Cl or CN.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁵ is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R5 is a halogen. In certain embodiments, ^R5 is F or Cl. In other embodiments, ^R5 is F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R5 is a _C1 - _C4 alkyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁵ is a _C1 - _C4 fluoroalkyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R5 is a _C1 - _C4 alkoxy group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of: halogen, _C1 - _{C4 alkyl} , _C2 - _C4 alkenyl, _C2 - _C4 alkoxy, C1- _C4 alkoxycarbonyl, _{C3 - C6} cycloalkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, pentafluorohydrothio, _{C1 -C4 hydroxyalkyl} , _C1 - _C4 thioalkyl, azido, _diC1 - _C4 alkylamino, _diC1 - _C4 alkylaminocarbonyl, D, _CD3 Cyanoyl, methyl alkyl, phenyl and 5- to 6-membered heterocyclic alkyl groups comprising one or two ring members independently selected from N, ^NR , O and S.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of: halogen, D, _CD3 , _C1 - _C4 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, and pentafluorohydrothioyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of: halogens, _C1 - _C4 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, and pentafluorohydrothioyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of halogens, _C1 - _C4 alkyl groups, _C1 - _C4 fluoroalkyl groups, and pentafluorohydrothioyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from a halogen. In certain embodiments, each ^R1 is independently selected from F, Cl, or Br. In other embodiments, ^R1 is F or Cl. In other embodiments, ^R1 is F. In other embodiments, ^R1 is Cl. In other embodiments, ^R1 is Br.

In certain embodiments of a compound having formula (I) or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from a _C1 - _C4 alkyl group. In certain embodiments, each ^R1 is independently selected from methyl, ethyl, isopropyl, and tributyl. In other embodiments, each ^R1 is independently selected from methyl, isopropyl, and tributyl. In still other embodiments, each ^R1 is methyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from a _C3 - _C6 cycloalkyl group. In certain embodiments, ^R1 is cyclopropyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R1 is a _CD3 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R1 is D.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from a _C1 - _C4 fluoroalkyl group. In certain embodiments, each ^R1 is independently selected from _-CF3 , _-CHF2 , and _{-CF2CF3 .} In certain embodiments, each ^R1 is _-CF3 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from a _C1 - _C4 fluoroalkoxy group. In certain embodiments, each ^R1 is independently selected from _-OCF3 , _-OCHF2 , and _{-OCF2CF3 .} In other embodiments, ^R1 is _-OCF3 .

In embodiments of a compound having formula (I) or formula (Ia), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R1 is a pentafluorohydrothio group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of: _C1 - _C4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _C1 - _C4 hydroxyalkyl, and _C1 - _C4 thioalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of _C1 - _C4 alkoxy and _C1 - _C4 alkoxy carbonyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of: azido, _diC1 - _C4 alkylamino, _diC1 - _C4 alkylaminocarbonyl, cyano, and formyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R1 is independently selected from the group consisting of phenyl and 5- to 6-membered heterocyclic alkyl groups comprising one or two ring members independently selected from N, ^NR4 , O, and S.

In certain embodiments of compounds having formula (I) or its subformulas, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the _L1 ^bond , -( ^CR2R3 ) _p- , -( ^CR2R3 ) _p - ^NR4- , -( ^CR2R3 ) _p -O-, ^-NR4 ( ^{CR2R3 )} _q- , -( ^{CR2R3 ) qNR4- ,} -O- ^{( CR2R3} ) _p- ^, or -S-( ^{CR2R3 )} _{p- .}

In certain embodiments of compounds having formula (I) or its subformulas, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the _L1 bond, ^- ( ^CR2R3 ) _p- , ^-NR4 ( ^{CR2R3 )} _q- , or ^-O- ( ^CR2R3 ) _p- .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the _{L1 series} is present.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L1 is -( ^CR2R3 ) _p- . In certain embodiments, _L1 is _-CH2- , -CH( ^OH ), -CH( _CH3 )-, _-CF2- , or In other embodiments, _L1 is _-CH2- . In other embodiments, _L1 is -CH( _CH3 )-. In other embodiments, _L1 is -CH(OH)-. In other embodiments, _L1 is... In other implementations, _L1 is _CF2 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or _a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _L1 ^{is -NR4- ( CR2R3} ) _q- or -( ^CR2R3 ) ^pNR4- .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L1 is ^-NR4- ( ^CR2R3 ) _q- . In certain embodiments, _L1 is ^-NR4- . In other embodiments, _L1 is -NH-, -N( ^CH3 )-, or -N( _CH2CH3 )-. In other embodiments, _L1 is -NH-. In other embodiments, _L1 is -N _{( CH3} ) _{-. In other embodiments, L1 is -N(CH2CH3 ) - .}

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L1 is -O-( ^{CR2R3 )} _p- . In certain embodiments, _L1 is -O-( ^CR2R3 )-. In certain embodiments, _L1 is -O- ^CH2- _.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L1 is -( ^{CR2R3 )} _p -O-. In other embodiments, _L1 is -( ^CR2R3 )-O-. In still other embodiments, _L1 is _-CH2 ^- O-.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L1 is -( ^{CR2R3 )} _p - ^NR4- . In other embodiments, _L1 is -( ^CR2R3 ) ^-NR4- . In still other embodiments, _L1 is _-CH2 ^{- NR4-} .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L1 is -S-( ^{CR2R3 )} _p- . In certain embodiments, _L1 is -S-( ^CR2R3 )-. In certain embodiments, _L1 is -S- ^CH2- _.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R2 is H, D, halogen, or _C1 - _C4 alkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R2 is H, halogen, or _C1 - _C4 alkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R2 is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R2 is D.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R2 is a halogen. In certain embodiments, ^R2 is an F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R3 is H, D, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, OH, amino, or t -Boc-amino.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ³ is a H, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, OH, amino, or t -Boc-amino group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R3 is H, _C1 - _C4 alkyl or OH.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ³ is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ³ is D.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R3 is a halogen. In certain embodiments, ^R3 is an F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R3 is a _C1 - _C4 alkyl group. In certain embodiments, ^R3 is a methyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R3 is a _C1 - _C4 alkoxy group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R3 is a hydroxyl group.

In certain embodiments of compounds having formula (I) or its subforms, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R3 is an amino group.

In certain embodiments of compounds having formula (I) or its subforms, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R3 is a t -Boc-amino group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R2 is a _C1 - _C4 alkyl group. In certain embodiments, ^R2 is a methyl group.

In certain embodiments of compounds having formula (I) or its derivatives, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R2 and ^R3 are linked together with the C atoms to which they are attached to form a _C3 - _C4 cycloalkyl group, which is unsubstituted or substituted with a single substituent selected from _C1 - _C4 alkyl and an alkyl group. In other embodiments, ^R2 and ^R3 are linked together with the C atoms to which they are attached to form an unsubstituted _C3 - _C4 cycloalkyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^R4 is independently selected from the group consisting of H and _C1 - _C4 alkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁴ is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R4 is a _C1 - _C4 alkyl group. In other embodiments, ^R4 is methyl or ethyl. In other embodiments, ^R4 is methyl. In other embodiments, ^R4 is ethyl.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^the _L2 bond, -( ^{CR6R7 )} _n- or -( ^CR6R7 ) _nO- *, wherein * indicates an attachment point with ^R8 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the _{L2 series} is present.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L2 is -( ^{CR6R7 )} _n- or - ^{( CR6R7} ) _nO- .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts ^, _L2 is -( ^CR6R7 ) _n- . In certain embodiments, _L2 is -( ^CR6R7 )-. In other embodiments, _L2 is _-CH2- or ^-CH2CH2- . In other embodiments, L2 is _-CH2- . In _other embodiments, _L2 is _-CH2CH2- . In other embodiments, _L2 is -C _{( CH3 ) 2-} . In other embodiments, _L2 is -CH( _{CH2OH )} -.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, _L₂ is -( ^CR₆R₇ ) _ₙO- *, where * indicates the attachment point with ^R₈ . In certain embodiments, _L₂ is -( ^CR₆R₇ )O-. In other embodiments, _L₂ is _-CH₂O- or -( ^CR₆R₇ )O-*, ^where * indicates the attachment point with ^R₈ . In other embodiments, _L₂ is _-CH₂O- . In ^other embodiments ^, _L₂ is _{-CH₂CH₂O-} . In other embodiments, _L₂ is -C( _{CH₃ ) ₂O-} .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each R ⁶ is independently selected from the group consisting of H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁶ is H.

In certain embodiments of compounds having formula (I) or its derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable stereoisomers, ^R6 is a _C1 - _C4 alkyl group. In other embodiments, ^R6 is methyl, ethyl, or isopropyl. In other embodiments, ^R6 is methyl or isopropyl. In other embodiments, ^R6 is methyl. In other embodiments, ^R6 is isopropyl.

In certain embodiments of compounds having formula (I) or its derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R6 is a _C1 - _C4 fluoroalkyl _group . In other embodiments, ^R6 is _-CF3 or _-CH2CF3 . In other embodiments, ^R6 is _{-CH2CF3 .} In other embodiments, ^R6 is _-CF3 .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R6 is a _C1 - _C4 hydroxyalkyl group. In certain embodiments, ^R6 is _-CH2OH .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each R ⁷ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁷ is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R7 is a _C1 - _C4 alkyl group. In other embodiments, ^R7 is methyl, ethyl, or isopropyl. In other embodiments, ^R7 is methyl or isopropyl. In other embodiments, ^R7 is methyl. In other embodiments, ^R7 is isopropyl.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable stereoisomers, ^R7 is a _C1 - _C4 fluoroalkyl _group . In other embodiments, ^R7 is _-CF3 or _-CH2CF3 . In other embodiments, ^R7 is _{-CH2CF3 .} In other embodiments, ^R7 is _-CF3 .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R7 is a _C1 - _C4 hydroxyalkyl group. In certain embodiments, ^R7 is _-CH2OH .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R6 and ^R7 are linked together with the C atoms to which they are attached to form _C3 - _C6 cycloalkyl, oxocyclobutyl, tetrahydrofuranyl, or tetrahydropiperanyl.

In certain embodiments of compounds having formula (I) or its subforms, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R6 and ^R7 are linked together with the C atoms to which they are attached to form a tetrahydropiperanyl group.

In certain embodiments of compounds having formula (I) or its derivatives, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof, ^R6 and ^R7 are connected together with the C atom to which they are attached to form a _C3 - _C6 cycloalkyl group. In certain embodiments, ^R6 and ^R7 are connected together with the C atom ^{to which} they are attached to form a cyclopropyl group. In certain embodiments, ^R6 and ^R7 are connected together with the C atom to which they are attached to form a cyclopentyl group. In certain embodiments, ^R6 and ^R7 are connected together with the C atom to which they are attached to form a cyclohexyl group.

In certain embodiments of compounds having formula (I) or its subforms, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R6 and ^R7 are linked together with the C atoms to which they are attached to form an oxocyclobutane.

In certain embodiments of compounds having formula (I) or its subforms, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R6 and ^R7 are linked together with the C atoms to which they are attached to form a tetrahydrofuranyl group.

In certain embodiments of compounds having formula (I) or its derivatives, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R8 (i) has a 4-, 5-, or 6-membered heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and having 1, 2, 3, or 4 substituents independently selected from N, ^NR9 (i) a 5- or 6-membered monocyclic heteroaryl group of ring members of O and S, wherein the monocyclic heteroaryl group is unsubstituted; (ii) a 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents each independently selected from -OH, _C1 - _C4 alkyl and lateral oxygen groups; (iii) a 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and 1, 2 or 3 other ring members are independently selected from N, NR (iv) A partially saturated _5- or 6-membered heterocyclic group having 1 or 2 ring members independently selected from N, ^NR9 , ^O , and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _{C1-C4 alkyl ,} and lateral oxygen; (v) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ , and 1, 2, or 3 other ring members are independently selected from N, ^NR9 , O, and S. (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 - _C4 alkoxy, and C1-C4 alkyl; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 -C4 alkoxy, and C1- _C4 alkyl; ( ^vii ) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, C1-C4 alkoxy, and _C1 - _C4 alkyl ^. (viii) A 6- or 7-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 substituents, each independently selected from -OH, -N( ^{R10 )} ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups ^; _2. Substituents of _{C1- C4} alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen; (ix) A 6-, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen; (x) Having 1 to 2 substituents independently selected from N, ^NR9 A six-membered heterocycloalkyl group having a ring member of O and S, wherein the heterocycloalkyl group has a _C1 - _C3 alkyl bridge or a _{-CH2OCH2 -} bridge; (xi) phenyl, which is unsubstituted or substituted by 1, 2, 3 or 4 substituents each independently selected from the following: -S(=O) _2N ( ^R10 ) ₂ , -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkyl; or (xii) _C4 - _C8 cycloalkyl, which is unsubstituted or substituted ^{by 1, 2, 3 or 4 substituents each independently selected from the following: -OH, -N(R10)2, -S(=O)2R10 ,} _{C1 - C4 alkyl} - _NH2 Halogens, _C1 - _C4 alkoxy groups, _C1 - _C4 alkyl groups, and lateral alkoxy groups.

In certain embodiments of compounds having formula (I) or its derivatives, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R8 is a 4-, 5-, or 6-membered heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and having 1, 2, 3, or 4 substituents independently selected from N, ^NR9 Five or six monocyclic heteroaryl groups of the O and S ring members, wherein the monocyclic heteroaryl group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 4-, 5-, or 6-membered heterocycloalkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by one, two, or three substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral oxy, and a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 4-, 5-, or 6-membered heterocycloalkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by one, two, or three substituents each independently selected from -OH, -CN, _NH2 , F, _CF3 , methyl, methoxy, serooxy, and a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 4-, 5-, or 6-membered heterocycloalkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by one, two, or three substituents each independently selected from -OH, halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, and lateral alkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 4-, 5-, or 6-membered heterocycloalkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by one, two, or three substituents independently selected from -OH, -F, _CF3 , methyl, and lateral oxy groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , , , , , , , , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from -OH, _C1 - _C4 alkyl, and lateral oxy groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from -OH and _C1 - _C4 alkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ , S(=O) or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from OH and methyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from _C1 - _C4 alkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a methyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 4-, 5-, or 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and one, two, or three other ring members are independently selected from N, ^NR9 , and O, and wherein the heterocycloalkyl group is unsubstituted or substituted by one, two, three, or four substituents, each independently selected from _C1 - _C4 alkyl and lateral alkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and another ring member is selected from N, ^NR9 , and O, and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from _C1 - _C4 alkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁸ is a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) ₂ or S(=O), and another ring member is selected from N, ^NR9 , and O, and wherein the heterocycloalkyl group is unsubstituted or substituted with a methyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 5- or 6-membered heterocyclic group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by one, two, three, or four substituents independently selected from -OH, _C1 - _C4 alkyl, and lateral oxy groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 6-membered heterocyclic group having one or two independently selected ring members chosen from N, ^NR9 , O and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a lateral oxygen group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 6-membered heterocyclic group having one or two independently selected ring members chosen from O and S, wherein the partially saturated heterocyclic group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ , and one, two, or three other ring members are independently selected from N, ^NR9 , O, and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by one, two, three, or four substituents independently selected from -OH, _C1 - _C4 alkyl, and lateral oxy groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and the other ring member is selected from N, ^NR9 , and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a lateral group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and the other ring member is O, wherein the partially saturated heterocyclic group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, ^NR9 , O and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from -OH, _C1 - _C4 alkoxy and _C1 - _C4 alkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, ^NR9 and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, methoxy and methyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 5-membered monocyclic heteroaryl group having 3 independent ring members selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 6- or 7-membered fused bicyclic heterocyclic group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by one, two, three, or four substituents each independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 6-membered fused bicyclic heterocyclic group having a ring member selected from N and ^NR9 , wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with a side-oxy group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 6-membered fused bicyclic heterocyclic group having a ring member selected from ^NR9 , wherein the fused bicyclic heterocyclic group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 8-, 9-, 10-, 11-, or 12-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 ring members independently selected from N, ^NR9 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a partially saturated 10-member fused bicyclic heterocyclic group having 1, 2, or 3 independently selected ring members chosen from N, ^NR9 , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with a side-oxy group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 6-, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxy groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from ^NR9 and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... .

In certain embodiments of compounds having formula (I) or its subformulas, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R8 is a 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a 6-membered heterocycloalkyl group having a ring member selected from ^NR9 , wherein the heterocycloalkyl group has a _C1 - _C3 alkyl bridge.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a phenyl group that is unsubstituted or substituted with one, two, three or four substituents each independently selected from -S(=O) _₂N ( ^R₁₀ ) _₂ , -OH, -N( ^R₁₀ ) _₂ , _C₁ - _C₄ alkyl- _NH₂ , halogen and _C₁ - _C₄ alkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a phenyl group substituted with -S(=O _{) 2NH2} .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a _C4 - _C8 cycloalkyl group that is unsubstituted or substituted by one, two, three or four substituents independently selected from the following: -OH, -N( ^R10 ) ₂ , -S(=O ⁾ _2R10 , C1- _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkoxy, _C1 - _C4 alkyl, and septoxy.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a _C4 - _C8 cycloalkyl group substituted with one, two or three substituents independently selected from -OH, -N( ^R10 ) ₂ , -S( ^=O)2R10 _{, C1} - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with one, two, or three substituents independently selected from -OH, _-NH2 , _-S (=O) _{2CH3 , -CH2NH2 ,} F, and methoxy.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is a _C4 - _C8 cycloalkyl group substituted with one, two or three substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 and halogen.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R8 is cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted by one, _two , or three substituents independently selected from -OH, _-NH2 , _-CH2NH2 , and F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^R8 series... , , ,or .

In certain embodiments of compounds having formula (I) or its derivatives, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 , or -C(=O) ^R10 . In certain embodiments, ^R9 is H, methyl, benzyl, -C(=O) _CH3 , -C(=O)O( _{CH3 ) 3} , _CH2CH2OH , _{or CH2CH2OCH3 .}

In certain embodiments of compounds having formula (I) or its derivatives, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^R9 is H, _C1 - _C4 alkyl, or -C(=O) ^R10 . In certain embodiments, ^R9 is H, methyl, or -C(=O) _CH3 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ⁹ is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R9 is a _C1 - _C4 alkyl group. In other embodiments, ^R9 is a methyl group.

In certain embodiments of compounds having formula (I) or its subforms, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R9 is -C(=O) ^R10 . In certain embodiments, ^R9 is -C(=O) _CH3 .

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, ^R9 is -C(=O)OR ^10. In certain embodiments, ^R9 is -C(=O)O( _CH3 ) ₃ .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R9 is benzyl.

In certain embodiments of compounds having formula (I) or its derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable stereoisomers, ^R9 is _C1 - _C4 alkyl- ^OR10 . In _other embodiments, ^R9 is _-CH2OH . In other embodiments, ^R9 is _-CH2CH2OH . In _other embodiments, ^R9 is _{-CH2CH2OCH3 .}

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R10 is H or _C1 - _C4 alkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ¹⁰ is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^R10 is a _C1 - _C4 alkyl group. In other embodiments, ^R10 is methyl, ethyl, or tributyl. In other embodiments, ^R10 is methyl or tributyl. In other embodiments, ^R10 is methyl. In other embodiments, ^R10 is ethyl. In other embodiments, ^R10 is tributyl.

In some embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, n is 1, 2, or 3. In other embodiments, n is 1 or 2. In still other embodiments, n is 1.

In some embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, p refers to 1, 2, or 3. In other embodiments, p refers to 1 or 2. In still other embodiments, p refers to 1.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, q is 0, 1, or 2. In other embodiments, q is 0 or 1. In still other embodiments, q is 0.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N or C; _Z2 is N or CR ^z ; _Z3 is N or CR ^z ; _Z4 is N or C; _Z5 is N or CR ^z ; wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl; and the condition is that at least two, and no more than four, of _Z1 , _Z2 , _Z3 , _Z4 and _Z5 are N.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N and _Z5 is CR ^z ; or _Z1 is N, _Z2 is CR ^z , _Z3 is CR ^z , _Z4 is C and _Z5 is N; wherein each R ^z is independently selected from the following groups: H, halogens, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is CR ^z ; or _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N and _Z5 is CR ^z ; or _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N and _Z5 is CR ^z ; wherein each Rz is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is N; or _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is CR ^z ; wherein each Rz is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is N, wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N, _Z2 is CR ^z , _Z3 is N, _Z4 is C and _Z5 is CR ^z , wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is C, _Z2 is CR ^z , _Z3 is N, _Z4 is N and _Z5 is CR ^z , wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is C, _Z2 is N, _Z3 is N, _Z4 is N and _Z5 is CR ^z , wherein each R ^z is independently selected from the group consisting of: H, halogens, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, _Z1 is N, _Z2 is CR ^z , _Z3 is CR ^z , _Z4 is C and _Z5 is N, wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^Rz is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl or _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^Rz is independently selected from the group consisting of H or halogen.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, each ^Rz is independently selected from the group consisting of H or F.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R_^z is H.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R z  is a halogen. In other embodiments, R z  is an F.

In certain embodiments of compounds having formula (I) or its subformulas, or their stereoisomers, It , , , , , , , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA refers to: (i) an unsubstituted or substituted phenyl group with 1, 2, 3, or 4 ^R1 groups; (ii) a partially saturated 9-, 10-, 11-, or 12-membered bicyclic carbocyclic group that is unsubstituted or substituted with 1 to 4 ^R1 groups; (iii) a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 ^R1 groups; or (iv) a compound having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 A partially saturated 8-, 9-, 10-, 11-, or 12-member fused bicyclic heterocyclic group of O and S ring members, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a phenyl group that is unsubstituted or substituted with 1, 2, 3 or 4 ^R1 groups.

In certain embodiments of compounds having formula (I) or its subforms, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^RA is an unsubstituted phenyl group.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a phenyl group substituted with one or two ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a phenyl group substituted with one or two substituents independently selected from halogen, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and pentafluorohydrothioyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or _a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a phenyl group substituted with one or two substituents independently selected from F, _CF3 , _CF2CF3 and _SF5 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a partially saturated 9-, 10-, 11-, or 12-membered bicyclic carbocyclic group that is unsubstituted or substituted by 1 to 4 ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the ^RA is a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, ^NR4 , O and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the RA ^group is a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and NR ⁴ , wherein the monocyclic heteroaryl group is substituted by one or two R ¹ groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and NR ⁴ , wherein the monocyclic heteroaryl group is substituted by one or two substituents independently selected from halogens, _C1 - _C4 alkyl groups, and _C1 - _C4 fluoroalkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a 5- or 6-membered monocyclic heteroaryl group having one or two ring members independently selected from N and NR ⁴ , wherein the monocyclic heteroaryl group is substituted by one or two substituents independently selected from F, Cl, CF ₃ , and methyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a pyrazolyl or pyridyl group substituted with one or two ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a pyrazolyl or pyridyl group substituted with one or two substituents independently selected from halogens, _C1 - _C4 alkyl groups, and _C1 - _C4 fluoroalkyl groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a pyrazolyl or pyridyl group substituted with one or two substituents independently selected from F, Cl, _CF3 , and methyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a partially saturated 8-, 9-, 10-, 11-, or 12-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a partially saturated 8-, 9-, or 10-member fused bicyclic heterocyclic group having 1, 2, or 3 independently selected ring members chosen from N, ^NR4 , and O, wherein the fused bicyclic heterocyclic group is substituted by 1, 2, or 3 ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a partially saturated 8-, 9-, or 10-membered fused bicyclic heterocyclic group having 1, 2, or 3 ring members independently selected from N, ^NR4 , and O, wherein the fused bicyclic heterocyclic group is substituted with 1, 2, or 3 substituents independently selected from halogen, _C1 - _C4 alkyl, and _C1 - _C4 fluoroalkyl.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R ^A -series chromyl, 3,4-dihydro-2H-piperano[2,3-b]pyridyl, 3,4-dihydro-2H-benzo[b][1,4]carbazyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]carbazyl, 5,6-dihydrocyclopentadienano[c]pyrazol-1(4H)-yl), 2,3-dihydrobenzo[b][1,4]dicarbazyl, 4,5,6,7-tetrahydro-1H-indazolyl, 1H-benzo[d]imidazolyl, or 2,3-dihydrobenzofuranyl, each of which is unsubstituted or substituted with one or two ^R1 groups.

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, ^RA is a partially saturated 10-membered fused bicyclic heterocyclic group having one or two independent ring members selected from N and O, wherein the fused bicyclic heterocyclic group is substituted with one substituent selected from halogen, _C1 - _C4 alkyl, and _C1 - _C4 fluoroalkyl.

In certain embodiments of compounds having formula (I) or its subforms, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, ^RA is chromium or 3,4-dihydro-2H-piperano[2,3-b]pyridyl, which is substituted with _CF3 .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , , , , , , , , , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the R ^A system , , , , , , , , , , , , or .

In certain embodiments of a compound having formula (I) or a subformula thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof,

In embodiments of a compound having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the compound having formula (I) is selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and .

In embodiments of a compound having formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the compound having formula (I) is selected from: N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)thomen-3-methylamine; (R or S)-N-(5-fluoro-6-(4-((R or S)-2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)thomen-3-methylamine; (R)-N-(5-fluoro-6-(4-((R or S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)chromium-3-methylamine; (S)-N-(5-fluoro-6-(4-((R or S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)chromium-3-methylamine; N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-cyano-6-(1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide; N-(3-fluoro-4-(1-(2-epoxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(3-fluoro-4-(1-(2-epoxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; (R)-N-(3-fluoro-4-(1-(2-epoxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; (S)-N-(3-fluoro-4-(1-(2-sideoxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(pentafluoro-λ6-hydrothio)phenyl)acetamide; N-(3,5-difluoro-4-(1-(piperidin-4-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-((1R,2R)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea; (R or S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea; N-(6-(4-(1,1-di-dioxythio-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-fluoro-6-(4-(3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(4-(lbrin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(1,2-lin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R)-N-(5-fluoro-6-(4-(1,2-lin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(5-fluoro-6-(4-(1,2-lin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(isoazolidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(2-methylisoazolidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(5-fluoro-6-(4-(2-(3-hydroxypyrrolidin-1-yl)prop-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(2-(2-sideoxypyrrolidin-1-yl)prop-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; N-(5-fluoro-6-(4-(2-sideoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; N-(6-(4-(5,6-dihydro-1,4-oxathiin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(4,4-dioxy-5,6-dihydro-1,4-oxathiin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(4,4-di-oxy-1,4-oxothiocyclohexane-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-methoxypyridin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(4-methyl-3-oxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; N-(6-(4-((1r or 1s, 3r or 3s)-3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(((1R or 1S),(2R or 2S))-2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; N-(5-fluoro-6-(4-(((1R),(2R))-2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; N-(5-fluoro-6-(4-(((1R),(2S))-2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(((1S),(2R))-2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(((1S),(2S))-2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-3-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-1-methylurea; N-(4-(1-((1-benzyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(2-(1,3,4-diazol-2-yl)propyl-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(4-(1-((1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(1,1-dioxythiolino-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(1,1-dioxythiolino-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(1,1-dioxythiolino-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(4-(1,1-dioxythiolino-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(2-(trifluoromethyl)oxocyclobutane-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(1-imino-1-sideoxytetrahydro-1H-1λ6-thiophen-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(2-(5-methyl-4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(2-(5-methyl-1,3,4-diazol-2-yl)prop-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(6-(4-((1H-tetrazol-5-yl)methyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-((3-sideoxypiperazol-1-yl)methyl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (2R,4R)-2-cyano-4-(4-(3-cyano-5-(2-(3-(trifluoromethyl)phenoxy)acetaminopheno)pyridin-2-yl)-1H-pyrazol-1-yl)pyrrolidone-1-carboxylic acid tributyl ester; N-(5-fluoro-6-(4-(3-methyl-1-epoxy-1,2-thiazolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetaminophen; (R or S)-N-(5-fluoro-6-(4-(3-methyl-1-epoxy-1,2-thiazolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(3-methyl-1-epoxy-1,2-thiazolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(3-methyl-1-epoxy-1,2-thiazolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(3-(2-(2-epoxypyrrolidin-1-yl)prop-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(5-chloro-3-(trifluoromethyl)-1H-pyridin-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(5-chloro-3-(trifluoromethyl)-1H-pyridin-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(3-chloro-5-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrolin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrolin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(folin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(folin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(5-folin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-methylpyrrolidin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(pyrrolidin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R or S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(flavolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(flavolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(3-methylflavolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(3-methyl-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(azolin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(azolin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(azolin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(olin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid; (R or S)-N-(5-fluoro-6-(4-((R or S)-2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid; (R)-N-(5-fluoro-6-(4-((R)-2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid; (S)-N-(5-fluoro-6-(4-(((R)-2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid; (R)-N-(5-fluoro-6-(4-((S)-2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid; (S)-N-(5-fluoro-6-(4-((S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(4-(1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-hydroxylino-1H-imidazol-1-yl)pyridin-3-yl)-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(tetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(3,3-dimethylpiperazol-1-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-olino-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-methylpiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(1,1-dioxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(4-(1,1-dioxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(6-(4-(1,1-di-oxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (S)-N-(6-(4-(1,1-di-oxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-fluoro-6-(4-(4-methyl-2-epoxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-sideoxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(1-methyl-5-sideoxypyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(1-methyl-5-sideoxypyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(1-methyl-5-epoxypyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(1-methyl-5-epoxypyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; N-(5-fluoro-6-(4-(2-epoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-hydroxy-2-sideoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-hydroxy-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; N-(6-(4-(5,6-dihydro-1,4-diazol-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(1,4-diazol-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(4-(1,4-diazol-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(6-(4-(1,4-difluoropyrrolidone-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (S)-N-(6-(4-(1,4-difluoropyrrolidone-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(4,4-difluoropyrrolidone-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (S)-N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-cyano-6-(1-(3,3-difluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide; N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R or S)-N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R)-N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R or S)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophenin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridin-2-methylamine; N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R)-N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(4-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; N-(6-(4-(1-amino-3,3-difluorocyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridin-2-methylamine; N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (S)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-fluoro-6-(4-(1-hydroxycyclohexyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(5-fluoro-6-(4-(1-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-sideoxypiperidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(3-hydroxy-1-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R or S)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-hydroxy-1,1-dioxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-hydroxy-1,1-dioxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-hydroxy-1,1-dioxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-hydroxy-1,1-dioxytetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea; (R or S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea; (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(1,3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea; (S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(1,3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea; N-(6-(4-(3,9-dioxane-7-azabicyclo[3.3.1]nonane-7-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (R)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (2-(4-chloro-3-(trifluoromethyl)-1H-pyridin-1-yl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(4-chloro-3-(trifluoromethyl)-1H-pyridin-1-yl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(piperidin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(5-fluoro-6-(4-(4-hydroxytetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(acetazol-2-ylmethyl)-1H-pyridin-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(3-aminooxocyclobutane-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-cyano-6-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-4-(1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-4-(1-(3,3-difluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyl-1-oxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(4-(tetrahydrofuran-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(tetrahydrofuran-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(tetrahydrofuran-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(tetrahydrofuran-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R or S)-N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R)-N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (S)-N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)acetamide; N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (S)-N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(1-acetyl-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide; N-(5-fluoro-6-(3-(olin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(3-(oinolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(5-fluoro-6-(3-(oinolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(5-fluoro-6-(3-(olyolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(3-(1-amino-3,3-difluorocyclobutyl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(3-(3-methylphosphonolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(3-(3-methylphosphonolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(5-fluoro-6-(3-(3-methylphosphonolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(5-fluoro-6-(3-(3-methylphosphonolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(3-(3,3-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R or S)-N-(6-(3-(3,3-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R)-N-(6-(3-(3,3-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (S)-N-(6-(3-(3,3-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (S)-N-(6-(3-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(1,1-dioxythiolin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide; (R or S)-N-(6-(4-(1,1-dioxythiolino-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(1,1-dioxythiolino-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(4-(1,1-dioxythiolino-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(tetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(tetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(1,1-di-oxythio-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(4-(1,1-di-oxy-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(6-(4-(1,1-di-oxy-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide;) (S)-N-(6-(4-(1,1-di-oxythio-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(1,1-di-oxy-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(4-(1,1-di-oxy-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide;) (R)-N-(6-(4-(1,1-dioxythiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (S)-N-(6-(4-(1,1-dioxythiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-((1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(5-azaspiro[2.4]hept-6-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(5-azaspiro[2.4]hept-6-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R)-N-(6-(4-(5-azaspiro[2.4]hept-6-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (S)-N-(6-(4-(5-azaspiro[2.4]hept-6-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-((1S,3R,4R)-2-azabicyclo[2.2.1]hept-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-((1R,3S,4S)-2-azabicyclo[2.2.1]hept-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(5-fluoro-6-(4-(4-hydroxytetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(perfluoroethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro-16-hydrothio)phenoxy)acetamide; N-(5-fluoro-6-(3-(1-imino-1-sideoxytetrahydro-1H-116-thiophene-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(6-(4-(1-acetylopyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; (R or S)-N-(6-(4-(1-acetylopyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-((1-methyl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(4-(1-(2-(4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(4-(1-(2-(1,3,4-diazol-2-yl)propyl-2-yl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-3-yl)-1H-pyrazol-4-yl)phenyl)-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro-16-hydrothio)phenoxy)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(1-acetylpiperidin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R or S)-N-(6-(4-(1-acetylpiperidin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R or S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (R)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; (S)-2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(4-(1-acetylpiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-fluoro-6-(4-(2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R or S)-N-(5-fluoro-6-(4-(2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (R)-N-(5-fluoro-6-(4-(2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; (S)-N-(5-fluoro-6-(4-(2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(1-(trifluoro-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(3-fluoro-4-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; 4-(4-(2-cyano-6-fluoro-4-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide)phenyl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tributyl ester; N-(3-cyano-5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-(1-(2-hydroxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(2-hydroxy-1-(1-methoxycyclobutyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(4-(1-((2,3-dihydrobenzo[b][1,4]dichloro-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(4-aminosulfonylureaphenyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(4-(1-((1-benzylpyrrolidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(4-(1-(4,4-dimethyl-2-epoxytetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-((3-methyloxocyclobutane-3-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-((1-(methylsulfonylurea)cyclohexyl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(1-methyl-2-epoxypyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(pyrrolidin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(4-(1-((3S,4R)-4-(1H-pyrazol-1-yl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(2-hydroxyl-ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(2-((tetrahydrofuran-3-yl)oxy)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-((5-sideoxytetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(3,5-difluoro-4-(1-((6-sideoxypiperidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(2-(2-sideoxypyridin-1(2H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; (R)-N-(3,5-difluoro-4-(1-(1-(1-methyl-1H-1,2,3-triazol-5-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(4-(1-(2-(1H-pyrazol-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-((4-sideoxy-3,5,7,8-tetrahydro-4H-piperano[4,3-d]pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid; N-(6-(4-((3-aminooxocyclobutane-3-yl)methyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(6-(1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-5-cyanopyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(6-(1-(2-oxozyrospiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-5-cyanopyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide; N-(3-cyano-5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-cyano-5-fluoro-4-(1-(pyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3-fluoro-4-(1-(2-sideoxypiperidin-4-yl)-1H-pyrazole-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(4-(1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazole-4-yl)-3-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-fluoro-4-(1-(6-epoxypiperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(3-fluoro-4-(1-(2-(4-methylpiperidin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3-fluoro-4-(1-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(1-(2-(4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)-3,5-difluorophenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(3,5-difluoro-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-methoxypiperidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-side-oxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-side-oxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-hydroxytetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide; N-(6-(3-(1-amino-3,3-difluorocyclobutyl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl); N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-3-yl)-1H-pyridin-4-yl)phenyl)-2-(3-(pentafluoro-16-hydrothio)phenoxy)acetamide; N-(3,5-difluoro-4-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide; and N-(5-fluoro-6-(4-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide.

In embodiments having formula (I), formula (Ia), and formula (Ic), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the compound is (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and having the structure .

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the compound is crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide.

In embodiments of compounds having formula (I), formula (I-a), and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, wherein the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a powder X-ray diffraction pattern, when measured with Cu-Kα radiation at a wavelength of 0.15406 nm at a temperature in the range of 20°C to 40°C, comprising at least four reflections at an angle of 2θ selected from the group consisting of: (12.36 ± 0.2)°, (16.90 ± 0.2)°, (17.49 ± 0.2)°, (19.21 ± 0.2)°, (20.15 ± 0.2)°, (21.77 ± 0.2)°, (23.01 ± 0.2)°, (23.47 ± 0.2)°, (25.91 ± 0.2)° and (29.88 ± 0.2)°.

In embodiments of compounds having formula (I), formula (I-a), and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, wherein the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a powder X-ray diffraction pattern, which, when measured with Cu-Kα radiation at a wavelength of 0.15406 nm at a temperature in the range of 20°C to 40°C, includes (16.90 ± 0.2)°, (17.49 ± 0.2)°, and (17.49 ± 0.2)°. Reflections at 2θ angles of 0.2°, (23.01 ± 0.2°), (25.91 ± 0.2°) and (29.88 ± 0.2°).

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a powder X-ray diffraction pattern as shown in Figure 1.

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, wherein the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a differential scanning calorimeter curve that, when measured at a heating rate of 10°C/min, includes an endothermic peak with a peak temperature of (176.8 ± 0.5)°C.

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a differential scanning calorimeter curve as shown in Figure 2.

In embodiments of compounds having formula (I), formula (I-a), and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a thermal... The reanalysis curve, when heated from 20°C to 350°C at a rate of 10°C/min, shows a mass loss of no more than 3.56% by weight, based on the weight of crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide.

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide is characterized by having a thermogravimetric analysis curve as shown in Figure 3.

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide is a (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate.

In embodiments having formula (I), formula (Ia), and formula (Ic), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the compound is (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide monohydrate and having the structure .

In embodiments of compounds having formula (I), formula (I-a) and formula (I-c), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, the compound is amorphous (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide.

Depending on the choice of starting materials and procedures, the compound may exist in one of the possible isomer forms or as a mixture of them (e.g., as a purely optical isomer or as a mixture of isomers, such as racemic and nonmirror isomer mixtures), depending on the number of asymmetric carbon atoms. This invention aims to include all such possible isomers, including racemic mixtures, nonmirror isomer mixtures, and optically pure forms. Optically active ( R )- and ( S )- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomers are also intended to be included.

As used herein, the term "salt" refers to the acid addition salt or base addition salt of the compounds of the invention. "Salt" specifically includes "pharmaceutically acceptable salt." As used herein, "pharmaceutically acceptable salt" means a salt that retains the biological efficacy and properties of the compounds of the invention and is generally not biologically or otherwise undesirable. In many cases, the compounds of the invention can form acids and/or bases due to the presence of amino and/or carboxyl groups or similar groups.

Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. The organic or inorganic acids used to form the pharmaceutically acceptable acid addition salts of the compounds of this invention include, but are not limited to, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, decanoic acid, theophylline, citric acid, ethanedioic acid, fumaric acid, D-glycerol-D-guloheptonic acid, galactopyric acid, galactopyric acid/mucilage, gluconic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutaric acid, glycolic acid, hippuric acid, and hydrobromic acid. Hydrochloric acid, hydroiodic acid, hydroxyethyl sulfonic acid, lactic acid, lactobionic acid, dodecyl sulfuric acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, methyl sulfonic acid, mucilage, naphthoic acid, 1-hydroxy-2-naphthoic acid, naphthalenesulfonic acid, 2-naphthalenesulfonic acid, niacin, nitric acid, octadecanoic acid, oleic acid, oxalic acid, palmitic acid, succinic acid, phosphoric acid, polygalacturonic acid, propionic acid, sebacic acid, stearic acid, succinic acid, sulfosalicylic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, and triphenylacetic acid.

The salt form of the compound of the present invention can be converted into the free compound by treatment with a suitable alkaline reagent.

Pharmaceutically acceptable acid addition salts of the compounds of this invention include, but are not limited to, acetates, adipicates, ascorbic acid salts, aspartate salts, benzoates, besylates, benzenesulfonates, bicarbonates/carbonates, bisulfates/sulfates, bromides/hydrobromoates, camphor sulfonates, dextrorotatory camphor sulfonates, decanoates, chlorides/hydrochlorides, theophylline, and citric acid. Salts, edisylate, ethanedisulfonate, fumarate, gluceptate, glucoheptonate, glucuronate, gluconate, glutarate, glutamate, glycolate, hippurate, hydroiodate/iodide, hydroxyethylsulfonate, lactate, lactobionate, lauryl sulfonate Salts, malic acid salts, maleate salts, malonate salts, amygdalin salts, mesylate salts, methanesulfonate salts, methyl sulfate salts, mucilage salts, naphthate salts, nappsylate salts, 2-napsylate salts, naphthalenesulfonate salts, 2-naphthalenesulfonate salts aphthalenesulfonate), nicotinic acid salts, nitrates, stearate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthate salts, phosphates/hydrogen phosphates/dihydrogen phosphates, polygalacturonic acid salts, propionates, sebate salts, stearates, succinates, sulfosalicates, sulfates, tartrates, toluenesulfonates, p-toluenesulfonates, trifluoroacetate salts, triphenylacetate salts, triphenylacetate salts, and sine salts.

The pharmaceutically acceptable salts of this invention can be synthesized from the base or acid portion using conventional chemical methods. Typically, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxides of Na, Ca, Mg, or K, carbonates, bicarbonates, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Typically, such reactions are carried out in water, in an organic solvent, or in a mixture of both. Generally, where feasible, it is desirable to use a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

Any formulas given herein are also intended to represent the unlabeled and isotopically labeled forms of such compounds. Except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number, the isotopically labeled compounds have the structures described by the formulas given herein. Isotopes that may be incorporated into the compounds of the invention include, for example, isotopes of hydrogen.

Furthermore, the doping with certain isotopes, particularly deuterium (i.e., ^₂H or D), can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, or improved treatment index or tolerability. It should be understood that, in this context, deuterium is considered a substituent in the compounds of the present invention. The concentration of deuterium can be defined by the isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance. If the substituent in the compound of the invention is indicated as deuterium, then such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). It should be understood that the term "isotope enrichment factor" can be applied to any isotope in the same way as it is described for deuterium.

Other examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ^3H , ^11C , ^13C , ^14C , ^15N , ^18F , ^31P , ^32P , ^35S , ^36Cl , ^123I , ^124I , and ^125I , respectively. Therefore, it should be understood that the present invention includes compounds incorporating one or more of the aforementioned isotopes (including, for example, radioactive isotopes such as ^3H and ^14C ), or compounds in which non-radioactive isotopes (such as ^2H and ^13C ) are present. Such isotopically labeled compounds can be used for metabolic studies (using ^14C ), reaction kinetic studies (using, for example, ^2H or ^3H ), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including the determination of drug or substrate tissue distribution), or for radiation therapy of patients. In particular, ^18F or labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using an appropriate isotopically labeled reagent instead of an unlabeled previously used reagent.

The compounds of this invention can exist in a deuterated form, as illustrated by the following examples: ; ; ,and .

Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present invention may be present in a racemic or mirror-isomer-enriched form (e.g., ( R )-, ( S )-, or ( R,S )- configuration). In some embodiments, each asymmetric atom has a (R)- or (S)- configuration with at least 50% mirror isomer excess, at least 60% mirror isomer excess, at least 70% mirror isomer excess, at least 80% mirror isomer excess, at least 90% mirror isomer excess, at least 95% mirror isomer excess, or at least 99 % mirror isomer excess. If possible, substitutions on atoms with unsaturated double bonds can exist in cis- ( Z )- or trans- ( E )- form.

Therefore, as used herein, the compounds of the invention may be in the form of possible isomers, rotational isomers, rotational isomers, tautomers, or mixtures thereof, for example as essentially pure geometric (cis or trans) isomers, non-mirror isomers, optical isomers (enantiomers), racemates, or mixtures thereof.

Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, non-mirror isomers, racemates, for example by chromatography and/or fractional crystallization, based on the physicochemical differences of the components.

The racemic derivatives of any resulting final product or intermediate can be resolved into optical enantiomers by known methods, for example, by separating the non-mirror isomer salts obtained with optically active acids or bases and releasing optically active acidic or basic compounds. In particular, the compounds of the invention can therefore be resolved into their optical enantiomers using an alkaline moiety, for example, by fractional crystallization of salts formed with optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetylated tartaric acid, di- O,O' -p-tolyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic products can also be resolved by chiral chromatography (e.g., high-pressure liquid chromatography (HPLC) using chiral adsorbents).

Method for Preparing the Compounds of the Invention This document describes a general procedure for preparing the compounds of the invention. In the described reactions, reactive functional groups (e.g., hydroxyl, amino, imine, or carboxyl groups, which are desirable in the final product) may be protected to prevent their unnecessarily participation in the reaction. Within the scope of this document, unless the context otherwise requires, only easily removable groups that are not components of a specific desired final product of the compounds of the invention are designated as "protecting groups". Such protection of functional groups, the protection of the protection groups themselves, and their cleavage reactions are described in, for example, in standard reference works such as J. F. W. McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd edition, Wiley, New York 1999.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or exemplary languages (e.g., "such") provided herein is intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

Method for Synthesizing the Compounds of the Invention The compounds of the invention are prepared by the process described herein and as shown in the examples. Various combinations of structural units and intermediates described herein can be used to produce the compounds of the invention. Non-limiting examples of synthetic schemes for preparing the compounds of the invention are illustrated in Schemes 1 to 8 below. Further instructions can be found in the Examples section.

General synthetic routes are described in the following schemes, outlining several methods for preparing the compounds disclosed herein. Starting materials and intermediates are prepared by purchase, from known procedures, or according to other instructions. In some cases, the order of steps in the reaction scheme can be altered to facilitate the reaction or avoid undesirable reactions. The R groups and other variables in the schemes correspond to those defined in equation (I).

Option 1:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in Scheme I. Aromatic amine I-1 reacts with carboxylic acid I-2 in a solvent (such as DCM, THF, or DMF) under standard amide bond formation conditions, for example, in the presence of an amide coupling agent (such as HATU, T3P, EDCI, or 1-chloro-N,N,2-trimethylpropyleneamine) and a base (such as DIPEA, _Et3N , or pyridine). For some compounds having formula (I), the ^R8 group may have one or more atoms that are (a) initially protected, for example, N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, for example, S → _SO2 , or (c) reduced, for example, C=C → HC-CH. Groups ^RA , _L1 , X, Y, ^R5 , _Z1 , _Z2 , _Z3 , _Z4 , _Z5 , _L2 and ^R8 are as defined herein, for example, according to any of claims 1 to 11.

Option II:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme II. Halogenated aromatic II-1 can be reacted with heteroaryl II-2 containing a coupling compatibilizer (such as boric acid/ester (or stanane)) via suzuwood (or Stieler) coupling in the presence of a palladium catalyst (such as Pd(dppf) Cl₂ , Pd(dtbpf) Cl₂ , XPhos-Pd-G₃, or ( Ph₃P ) ₄Pd ) and a base ( such as K₂CO₃ , Na₂CO₃ , Cs₂CO₃ , NaHCO₃ , or K₃PO₄ ) in a solvent (such as dimethyl ether, DME , DMF , or toluene). For certain compounds having formula (I), the R8 group may have one or more atoms that are (a) initially protected, such as N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → SO2 , or (c) reduced, such as C=C → HC-CH. The groups R A , L 1 , X, Y, R 5 , Z 1 , Z 2 , Z3,Z4 , Z 5 , L 2  , and R8 are as defined herein, for example, according to any one of claims 1 to 11.

Option III:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme III. Aromatic III-1 coupling complexes (such as borate/ester (or stanzane)) can be coupled with halogenated heteroaryl III-2 via suzerain (or Stieler) coupling in the presence of a palladium catalyst (such as Pd( dppf ) Cl2 , Pd(dtbpf) Cl2 , XPhos-Pd-G3 or ( Ph3P ) 4Pd ) and a base (such as K2CO3 , Na2CO3 , Cs2CO3 , NaHCO3 or K3PO4 ) in a solvent (such as dimethyl ether, DME, DMF or toluene). For certain compounds having formula (I), the R8 group may have one or more atoms that are (a) initially protected, such as N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → SO2 , or (c) reduced, such as C=C → HC-CH. The groups R A , L 1 , X, Y, R 5 , Z 1 , Z 2 , Z3,Z4 , Z 5 , L 2  , and R8 are as defined herein, for example, according to any one of claims 1 to 11.

Option IV:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme IV. The halogenated heteroaryl IV-1 can be coupled with IV-2 coupling complexes (such as borate/ester (or stanane)) via Suzuki (or Stieler) coupling in the presence of a palladium catalyst (such as Pd(dppf) Cl₂ , Pd(dtbpf) Cl₂ , XPhos -Pd - G₃, or ( Ph₃P ) ₄Pd ) and a base (such as K₂CO₃ , Na₂CO₃ , Cs₂CO₃ , NaHCO₃ , or K₃PO₄ ) in a solvent (such as dimethyl ether, DME, DMF , or toluene). For certain compounds having formula (I), the R8 group may have one or more atoms that are (a) initially protected, such as N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → SO2 , or (c) reduced, such as C=C → HC-CH. The groups R A , L 1 , X, Y, R 5 , Z 1 , Z 2 , Z3,Z4 , Z 5 , L 2  , and R8 are as defined herein, for example, according to any one of claims 1 to 11.

Option V:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme V. The alkynyl-substituted aromatic V-1 can react with the azide V-2 in a metal catalyst (such as CuSO₄ · 5H₂O , Cu(OAc) ₂ · H₂O, CuI, [CuBr( PPh₃ ) ₃ ] or Cp*RuCl( PPh₃ ) ₂ ), with or without additives (such as sodium ascorbate, DBU, DABCO/HOAc, or L-proline), in a solvent (such as DMSO, DMF, H₂O /tBuOH, dichloroisocyanurate, or DCM). For certain compounds having formula (I), the R8 group may have one or more atoms that are (a) initially protected, such as N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → SO2 , or (c) reduced, such as C=C → HC-CH. The groups R A , L 1 , X, Y, R 5 , Z 1 , Z 2 , Z3,Z4 , Z 5 , L 2  , and R8 are as defined herein, for example, according to any one of claims 1 to 11.

Option VI:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme VI. Acetamine VI-1 can be arylated with halogenated heteroaryl VI-2 in the presence of a palladium-catalyst system (such as Pd(dppf) _Cl2 , Pd(OAc) ₂ , Brettphos-Pd-G3 or _Pd2 (dba) ₃ ) and a ligand (such as dppp, _BINAP , Xantphos or t-BuBrettphos) and a base (such as _K2CO3 , _Na2CO3 , _Cs2CO3 or _{K3PO4 )} in a solvent (such as _dimethyl ether, DME, DMF, t _- BuOH or toluene). Alternatively, a _copper catalyst system (such as CuI) with a ligand (such as 1,2-diaminocyclohexane or N,N'-dimethylethylenediamine) and a base (such as _K₂CO₃ , _Na₂CO₃ , _Cs₂CO₃ or _K₃PO₄ ) in a solvent (such as _{dimethylsiloxane} , _DME , DMF, t-BuOH or toluene) can be used. For certain compounds having formula (I), the ^R₈ group may have one or more atoms that are ( _a ) initially protected, such as N-Boc, N-Bn, N-Cbz or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → _SO₂ , or (c) reduced, such as C=C → HC-CH. Groups ^RA , _L1 , X, Y, ^R5 , _Z1 , _Z2 , _Z3 , _Z4 , _Z5 , _L2 and ^R8 are as defined herein, for example, according to any of claims 1 to 11.

Option VII:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme VII. Amine VII-1 can react with aromatic amine VII-2 in the presence of a coupling agent (such as CDI, phosgene, or triphosgene), in the presence of a base (such as DIPEA or _Et3N ), or in a solvent (such as DMSO, DMF, NMP, or DCM). For some compounds having formula (I), the ^R8 group can have one or more atoms that are (a) initially protected, for example, N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, for example, S → _SO2 , or (c) reduced, for example, C=C → HC-CH. Groups ^RA , _L1 , X, Y, ^R5 , _Z1 , _Z2 , _Z3 , _Z4 , _Z5 , _L2 and ^R8 are as defined herein, for example, according to any of claims 1 to 11.

Option VIII:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme VIII. Halogenated heteroaryl VIII-1 can react with nitrogen-containing heterocyclic VIII-2 via Buchwald/Hartwig coupling in the presence of a palladium catalyst (such as tBuXPhos-Pd-G3 or _Pd2 (dba) ₃ ), with or without a ligand (such as t- _BuXphos , _Me4 -di-t-BuXPhos or t-BuBrettphos ₎ , in the presence of an alkali (such as _K2CO3 , _Na2CO3 , _Cs2CO3 or _K3PO4 ) in a solvent (such as dimethyl ether, _DME , DMF or toluene ₎ . Alternatively, copper catalyst systems (such as CuI, CuBr, or _Cu₂O ) can be used in the presence of an alkali ( _K₂CO₃ , Na₂CO₃, _Cs₂CO₃ , or KOH) in a solvent (such as DME, DMF, DMSO, or ACN), with or without a coordinating group (such as _1,2 - _{diaminocyclohexane} or N, _N' - _{dimethylethylenediamine} ). For certain compounds having formula (I), the ^R₈ group may have one or more atoms that are (a) initially protected, for example, N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, for example, S → _SO₂ , or (c) reduced, for example, C=C → HC-CH. Groups ^Ra , _L1 , X, Y, ^R5 , ^Z1 , _Z2 , _{Z3, Z4, Z5} ^, _{L2 ,} and ^R8 are as defined herein, for example, according to any one of claims 1 to 11. _Z2 , _Z3 , _Z4 , _Z5 , _{L2 ,} ^and _R8 are as defined herein, for example _, according to any one of claims 1 to 11.

Option IX:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme IX. Halogenated heteroaryl IX-1 can react with nitrogen-containing heterocyclic IX-2 via Buchwald/Hartwig coupling in the presence of a palladium catalyst (such as tBuXPhos-Pd-G3, Pd-PEPPSI-Ipent, or Pd2 (dba) 3 ), with or without a ligand (such as BINAP, t-BuXphos, Me4 -di-t-BuXPhos, or t-BuBrettphos), in the presence of an alkali (such as NaOt -Bu, Cs2CO3 , or K3PO4 ) in a solvent (such as dimethyl ether, DME, DMF , or DMA). Alternatively, a copper catalyst system (such as CuI) with a coordinating group (such as 1,2-diaminocyclohexane, N,N'-dimethylethylenediamine, or trans-(1r,2r)-N,N' - dimethyl-1,2-cyclohexanediamine ) can be used in the presence of an alkali (such as K₂CO₃ , Na₂CO₃ , Cs₂CO₃ , or KOH ) in a solvent (such as dimethyl ether, DME, DMF, DMSO, or ACN). For certain compounds having formula (I), the R8 group may have one or more atoms that are (a) initially protected, such as N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → SO2 , or (c) reduced, such as C=C → HC-CH. The groups R A , L 1 , X, Y, R 5 , Z 1 , Z 2 , Z3,Z4 , Z 5 , L 2  , and R8 are as defined herein, for example, according to any one of claims 1 to 11.

Option X:

Compounds having formula (I) as disclosed herein can be synthesized as outlined in scheme X. The heteroaryl group XI contains a functional group G that can be converted to an R 8 group, such as (i) an amine, which can be alkylated and/or acetylated, or (ii) an acid, which can be converted to an acehydrazine and then cyclized with trimethyl orthoformate or ethyl acetoimide to give an oxadiazole or triazole, or (iii) a ketone, which can react with trimethyl styrene ylide to give an oxadiazole, or (iv) an aldehyde, which can be reductively amination with an amine, or (v) a nitrile, which can react with NaN 3 to give a tetrazolium, or (vi) tetrahydrothiophene, which can react with NH 4 OAc and (diethoxyiodide)benzene to give a 1,2-thiazoline 1-oxide. For certain compounds having formula (I), the R8 group may have one or more atoms that are (a) initially protected, such as N-Boc, N-Bn, N-Cbz, or O-trialkylsilyl, and subsequently deprotected, (b) oxidized, such as S → SO2 , or (c) reduced, such as C=C → HC-CH. The groups R A , L 1 , X, Y, R 5 , Z 1 , Z 2 , Z3,Z4 , Z 5 , L 2  , and R8 are as defined herein, for example, according to any one of claims 1 to 11.

On the other hand, this document provides a method for preparing a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein an intermediate is prepared, and wherein the compound having formula (I) is (I), wherein groups R A , L 1 , X, Y, R 5 , Z1 , Z2 , Z3 , Z 4 , Z 5 , L 2 and R8 are as defined herein, for example, as defined by any one of claims 1 to 11.

Administration Directions and Pharmaceutical Compositions For therapeutic use of compounds having formula (I) and its sub-formulas, such compounds may be administered alone or as part of a pharmaceutical composition. Therefore, in another aspect, this document provides pharmaceutical compositions comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises a compound having formula (I-a) or formula (I-b) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. Pharmaceutical compositions may be formulated for specific administration directions, such as oral and parenteral administration (e.g., by injection or infusion). In some embodiments, pharmaceutical compositions comprising compounds having formula (I), formula (I-a), or formula (I-b) may be formulated for intramuscular, intravenous, subcutaneous, or oral administration.

The pharmaceutical composition of this invention can be formulated in solid form (including but not limited to capsules, tablets, pellets, granules or powders) or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can be film-coated or enteric-coated according to methods known in the art.

Typically, a pharmaceutical composition comprises an active ingredient along with the following tablets or gelatin capsules: a) a diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine; b) a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salts, and/or polyethylene glycol; for tablets, it also comprises c) a binder, such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone; and, if desired, d) Disintegrants, such as starch, agar, alginate or its sodium salts, or effervescent mixtures; and/or e) Adsorbents, colorants, flavorings, and sweeteners.

Suitable compositions for oral administration include pharmaceutical compositions comprising a compound having formula (I) in the form of tablets, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical preparations selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide a pharmaceutically refined and palatable formulation. Tablets may contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets are uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations intended for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

Some injectable formulations are isotonic solutions or suspensions. These formulations may be sterile and/or contain excipients such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts and/or buffers for osmotic pressure regulation. Additionally, they may contain other therapeutically valuable substances. These formulations are prepared according to conventional mixing, granulation, or coating methods and contain approximately 0.1%–75%, or approximately 1%–50%, of the active ingredient.

Compounds having formula (I) or pharmaceutical compositions comprising compounds having formula (I) for use in subjects (e.g., humans) are typically administered orally or parenterally at therapeutic doses. Generally, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. In some embodiments, compounds having formula (I-a) or pharmaceutical compositions comprising compounds having formula (I-a) for use in subjects (e.g., humans) are typically administered orally or parenterally at therapeutic doses. Generally speaking, the therapeutically effective dose of a compound, drug composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity.

Therefore, this document provides pharmaceutical compositions comprising a compound having formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises a compound having formula (I-a), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

This document also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound having formula (I-a), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

On the other hand, this document provides pharmaceutical compositions comprising a compound having formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents. In some embodiments, the pharmaceutical composition comprises a compound having formula (I-a), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

On the other hand, this document provides pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents. In some embodiments, the pharmaceutical composition comprises a compound having formula (I-a), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

Pharmacology and Efficacy The compounds having formula (I) and its derivatives (i.e., formulas (I-a) and (I-b)) in free form or in pharmaceutically acceptable salt form, as described herein, exhibit valuable pharmacological properties. In particular, compounds having formula (I) and its derivatives (i.e., formulas (I-a) and (I-b)) bind to PNPLA3I148M, thereby normalizing lipolysis; therefore, such compounds can be used to treat PNPLA3I148M-related diseases. PNPLA3I148M-related diseases can be liver diseases, particularly fatty liver disease (MASLD) associated with metabolic dysfunction. PNPLA3I148M-related diseases can be liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, PNPLA3I148M-related diseases are alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

Furthermore, the compounds having formula (I) and its sub-formulas (i.e., formulas (I-a) and (I-b)) provided herein are compounds that bind to PNPLA3I148M, thereby disrupting the complex of ABHD5 and PNPLA3I148M (i.e., PNPLA3I148M-ABHD5), leading to normalization of lipolysis, and therefore such compounds can be used to treat PNPLA3I148M-related diseases. PNPLA3I148M-related diseases can be liver diseases, particularly fatty liver disease (MASLD) associated with metabolic dysfunction. PNPLA3I148M-related diseases can be liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, PNPLA3I148M-related diseases are alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

The compounds having formula (I) and its sub-formulas (i.e., formula (I-a) and formula (I-b)) provided herein bind to PNPLA3I148M to normalize lipolysis, as indicated by the in vitro experiments provided herein.

Therefore, the compounds having formula (I) and its sub-formulas (i.e., formulas (I-a) and (I-b)) provided herein can be used in therapies, for example, to treat diseases related to PNPLA3I148M. Diseases related to PNPLA3I148M can be liver diseases, particularly fatty liver disease (MASLD) associated with metabolic dysfunction. Diseases related to PNPLA3I148M can be liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, diseases related to PNPLA3I148M are alcoholic liver disease (ALD). In another embodiment of this aspect, diseases related to PNPLA3I148M are fatty liver disease (MASH), non-alcoholic fatty liver disease (NASH), alcoholic fatty liver disease (ASH), cirrhosis with fibrosis, or hepatocellular carcinoma (HCC) associated with metabolic dysfunction. In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolic steatohepatitis (MASH). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic steatohepatitis (NASH). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic steatohepatitis (ASH). In another embodiment of this aspect, the PNPLA3I148M-related disease is cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

Furthermore, the compounds having formula (I) and its sub-formulas (i.e., formula (I-a) and formula (I-b)) provided herein can be used as research chemicals, for example as tool compounds.

In another aspect, this article discloses a method for treating PNPLA3I148M-related diseases, comprising administering to a subject in need a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this document discloses a method for treating PNPLA3I148M-related diseases, comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article discloses a method for treating PNPLA3I148M-related diseases by normalizing lipolysis, wherein the method comprises administering to a subject of need a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article discloses a method for treating PNPLA3I148M-related diseases by normalizing lipolysis, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article discloses a method for normalizing lipolysis by administering to a subject in need a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a method for normalizing lipolysis by administering a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need.

On the other hand, this article discloses a method for normalizing lipolysis by disrupting the PNPLA3I148M-ABHD5 complex, wherein the method comprises administering to a subject in need a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a method for normalizing lipolysis by disrupting the PNPLA3I148M-ABHD5 complex, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

On the other hand, this article discloses a compound having formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use as a drug.

This article also provides the use of compounds having formula (I) or formula (I-a) or pharmaceutically acceptable salts thereof in therapy.

In another aspect, this document discloses a compound having formula (I) and its sub-formulas (i.e., formulas (I-a) and (I-b)), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the treatment of PNPLA3I148M-related diseases. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this document discloses the use of a compound having formula (I) and its sub-formulas (i.e., formulas (I-a) and (I-b)), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the treatment of diseases associated with PNPLA3I148M. In one embodiment of this aspect, the disease associated with PNPLA3I148M is a liver disease. In another embodiment of this aspect, the disease associated with PNPLA3I148M is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the disease associated with PNPLA3I148M is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the disease associated with PNPLA3I148M is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

In another aspect, this document discloses the use of a compound having formula (I) and its sub-formulas (i.e., formula (I-a) and formula (I-b)), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating diseases associated with PNPLA3I148M. In one embodiment of this aspect, the disease associated with PNPLA3I148M is a liver disease. In another embodiment of this aspect, the disease associated with PNPLA3I148M is fatty liver disease associated with metabolic dysfunction (MASLD). In another embodiment of this aspect, the disease associated with PNPLA3I148M is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the disease associated with PNPLA3I148M is alcoholic liver disease (ALD). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, PNPLA3I148M-related diseases include metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include alcoholic steatohepatitis (ASH). In one embodiment of this aspect, PNPLA3I148M-related diseases include cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

Another aspect provided herein is a method for treating PNPLA3I148M-related diseases in patients of need, the method comprising (a) determining the presence of a missense variant (I148M) in protein 3 (PNPLA3) containing a potato glycoprotein-like phospholipase domain, and (b) administering to the patient a therapeutically effective amount of a compound having formula (I) or a subset thereof (i.e., formulas (I-a) and (I-b)), or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the PNPLA3I148M-related disease is a liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease associated with metabolic dysfunction (MASLD). In yet another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolic disorder-related steatohepatitis (MASH). In one embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic steatohepatitis (ASH). In one implementation of this approach, PNPLA3I148M-related diseases are cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this document provides a method for disrupting the PNPLA3I148M-ABHD5 complex in cells, the method comprising contacting the cells with an effective amount of a compound having formula (I) or its derivatives (i.e., formulas (I-a) and (I-b)) or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the contact is in vitro, while in another embodiment, the contact is in vivo.

Application and Combination Therapy In some cases, it may be advantageous to administer a compound having formula (I) or its sub-formulas (i.e., formulas (I-a) and (I-b)) or its pharmaceutically acceptable salt in combination with one or more other therapeutic agents. A compound having formula (I) or its sub-formulas (i.e., formulas (I-a) and (I-b)) or its pharmaceutically acceptable salt may be administered separately by the same or different routes of administration, or together with one or more other therapeutic agents in the same pharmaceutical composition. A therapeutic agent is, for example, a compound, peptide, antibody, antibody fragment, or nucleic acid, which, when administered to a patient in combination with a compound having formula (I) or its sub-formulas (i.e., formulas (I-a) and (I-b)) or a pharmaceutically acceptable salt thereof, has therapeutic activity or enhances therapeutic activity.

On the other hand, this article discloses a pharmaceutical combination comprising a compound having formula (I) or a subformula thereof (i.e., formula (I-a) and formula (I-b)), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

On the other hand, this article discloses a pharmaceutical combination comprising a therapeutically effective amount of a compound having formula (I) or a subformula thereof (i.e., formula (I-a) and formula (I-b)), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

Therefore, another aspect provided herein is a combination for treating PNPLA3I148M-related diseases, wherein a compound having formula (I) or its sub-formulas (i.e., formula (I-a) and formula (I-b)) or a pharmaceutically acceptable salt thereof is used in combination with one or more other active agents. In some embodiments of this invention, the one or more active agents are selected from: a) Antifibrinogenic and anti-inflammatory agents: e.g., galactagogue 3 inhibitors, such as belapectin; b) Glucose transport regulators: e.g., SGLT-2 inhibitors, such as dapagliflozin; c) Immunomodulators: e.g., CCR5 antagonists, such as leronlimab; d) Insulins: e.g., prandial insulin; e) Lipid regulators: e.g., THRβ agonists, such as resimeltiro, and ω-3 fatty acids, such as icosabuturate; f) Metabolic regulators: e.g., GLP-1 agonists, such as semaglutide; g) PPAR modulators: such as the pan-PPAR agonist Lanifibranor: h) HSD17B13 inhibitors

In one embodiment of this aspect, the PNPLA3I148M-related disease is liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is metabolically impaired fatty liver disease (MASLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolically impaired steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolic steatohepatitis (MASH). In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic steatohepatitis (NASH). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic steatohepatitis (ASH). In another embodiment of this aspect, the PNPLA3I148M-related disease is cirrhosis with liver fibrosis or hepatocellular carcinoma (HCC).

On the other hand, this article provides a product comprising a compound having formula (I) or its sub-formulas (i.e., formulas (Ia) and (Ib)) or a pharmaceutically acceptable salt thereof, used simultaneously, separately or successively in a therapy as a combination preparation, and at least one other therapeutic agent. In one embodiment, the therapy is for the treatment of diseases related to PNPLA3I148M. Such products provided as combination formulations include compositions comprising a compound having formula (I) or its sub-formulas (i.e., formulas (Ia) and (Ib)) together in the same pharmaceutical composition (fixed-formula composition), or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents, or in separate forms (non-fixed-formula composition) (e.g., in a set) of a compound having formula (I) or its sub-formulas (i.e., formulas (Ia) and (Ib)) or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents. In one embodiment of this aspect, the PNPLA3I148M-related disease is liver disease. In another embodiment of this aspect, the PNPLA3I148M-related disease is fatty liver disease (MASLD) associated with metabolic dysfunction. In another embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). In another embodiment of this aspect, the PNPLA3I148M-related disease is alcoholic liver disease (ALD). In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with fibrosis, or hepatocellular carcinoma (HCC). In one embodiment of this aspect, the PNPLA3I148M-related disease is metabolic dysfunction-related steatohepatitis (MASH). In one embodiment of this aspect, the PNPLA3I148M-related disease is non-alcoholic steatohepatitis (NASH). In one embodiment of this aspect, the disease associated with PNPLA3I148M is alcoholic steatohepatitis (ASH). In another embodiment, the disease associated with PNPLA3I148M is cirrhosis with fibrosis or hepatocellular carcinoma (HCC). In one embodiment, the kit includes a device for individually retaining the component, such as a container, separate bottle, or separate foil pouch. Examples of such kits are blister packs, as typically used for packaging tablets, capsules, etc. In some embodiments, the kit can be used to administer different dosage forms (e.g., oral and parenteral), to administer individual components at different dose intervals, or to titrate individual components relative to each other. To aid compliance, the kit typically includes instructions for use. Experiments

Preparation of Compounds The compounds of the present invention can be prepared as described in the following examples, which are intended to illustrate the invention and should not be construed as limiting the invention. All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to prepare the compounds of the present invention are commercially available or can be produced by organic synthetic methods known to those skilled in the art. Furthermore, the compounds of the present invention can be produced by organic synthetic methods known to those skilled in the art, as shown in the following examples.

The structures of all end products, intermediates, and starting materials were confirmed by standard analytical spectral characterization (e.g., MS, IR, NMR). The absolute stereochemistry of representative examples 33a and 106b was determined by X-ray crystal structure analysis. In all other cases where X-ray structures were unavailable, stereochemistry was assigned to chiral structural units with known absolute configurations. In the case of the absolute stereochemistry of the compounds in the specified examples, stereochemistry descriptors were assigned to the examples using the Cahn-Ingold-Prelog system.

Normal operating temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation is carried out under reduced pressure, typically between approximately 4 mm Hg and 75 mm Hg (= 5-100 mbar). Diatomaceous Earth Hyflo: ^Celite® (Celite Corporation) - Diatomaceous Earth-based filter aid phase separator: Biotage - Isolute phase separator - (Part No.: 120-1908-F, 70 ml, and Part No.: 120-1909-J, 150 ml) ^SiliaMetS® Thiol: SiliCYCLE thiol metal remover - (R51030B, particle size: 40-63 µm) Si-TMT: TCI - 2,4,6-tris(trimethyl)siloxane silicate - (S0865) [CAS No. 1226494-16-1]

Instrumental NMR : Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz), Bruker Ultrashield™ Plus 600 (600 MHz), Bruker Ascend ^™ 400 (400 MHz), Bruker Avance™ DRX 500 (500 MHz), Varian Agilent (400 MHz), or Varian Unityplus 400 (400 MHz) spectrometer, with and without tetramethylsilane as an internal standard.

Chemical shifts (δ values) are reported in low-field ppm for tetramethylsilane. Spectral splitting modes are designated as single signal (s), double signal (d), triple signal (t), quartet signal (q), multiple signal, unresolved or more overlapping signals (m), and wide signal (br). Only observed proton signals that do not overlap with solvent peaks are reported. The solvent is given in parentheses. Unless otherwise specified, spectra are measured at 298 K and referenced relative to solvent resonances.

UPLC-MS and MS UPLC-MS-1: XBridge BEH C18; Particle size: 2.5 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 5 mM _NH₄OH ; Eluent B: ACN + 5 mM _NH₄OH ; Gradient: 2% to 98% B in 1.40 min, then 98% B for 0.60 min; Flow rate: 1 ml/min; Column temperature: 80°C.

UPLC-MS-2: CORTECS C18+; Particle size: 2.7 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 4.76% IPA + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: IPA + 0.05% HCOOH; Gradient: 1% to 50% B in 1.40 min, 50% to 98% B in 0.30 min, then 98% for 0.10 min; Flow rate: 1 ml/min; Column temperature: 80°C.

UPLC-MS-3: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 100 mm; Eluent A: _H₂O + 4.76% IPA + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: IPA + 0.05% HCOOH; Gradient: 1% to 60% B in 8.40 min, then 60% to 98% B in 1 min; Flow rate: 0.4 ml/min; Column temperature: 80°C.

UPLC-MS-4: Acquity HSS T3; Particle size: 1.8 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: ACN + 0.04% HCOOH; Gradient: 5% to 98% B over 1.40 min, then 98% B for 0.40 min; Flow rate: 1 ml/min; Column temperature: 60°C.

UPLC-MS-5: Waters CSH-C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 0.2% HCOOH; Eluent B: ACN; Gradient: 5% to 98% B in 1.40 min, then to 100% B in 0.5 min; Flow rate: 1 ml/min; Column temperature: 40°C.

UPLC-MS-6: Waters HSS-CN; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 0.2% HCOOH; Eluent B: ACN; Gradient: 5% to 98% B in 1.40 min, then to 100% B in 0.5 min; Flow rate: 1 ml/min; Column temperature: 40°C.

UPLC-MS-7: CORTECS C18+; Particle size: 2.7 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 4.76% IPA + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: IPA + 0.05% HCOOH; Gradient: from 1% curve to 98% B in 1.70 min; Flow rate: 1 ml/min; Column temperature: 80°C.

UPLC-MS-8: CORTECS C18+; Particle size: 2.7 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: IPA + 0.05% HCOOH; Gradient: 5% to 50% B in 1.40 min, 50% to 98% B in 0.30 min, then 98% for 0.10 min; Flow rate: 1 ml/min; Column temperature: 80°C.

UPLC-MS-9: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 100 mm; Eluent A: _H₂O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: IPA + 0.05% HCOOH; Gradient: 5% to 60% B in 8.40 min, 60% to 98% B in 1 min, then 98% for 0.4 min; Flow rate: 0.4 ml/min; Column temperature: 80°C.

HPLC -MS 1: Synergi 2.5 μm MAX-RP 100 A Mercury; Eluent: 0.1% HCOOH (A)/ACN (B) in _H₂O ; Gradient: 0.1/5, 0.5/5, 1.0/95, 1.5/95, 2.0/5, 3.0/5; Flow rate: 2.0 ml/min; Column temperature: 40°C

HPLC-MS-2: Kinetex EVO 2.6 µm; 50 x 4.6 mm; mobile phase: 0.1% HCOOH (A)/ACN (B) in _H₂O ; gradient (time/%B): 0/30, 0.5/30, 1.0/95, 2.4/95, 2.5/30, 3.0/30; flow rate: 2.0 ml/min

HPLC-MS-3: Evo ESI 3200 2.6 µm; 50 x 4.6 mm; Mobile phase: 0.1% HCOOH (A) in _{H₂O /} 0.1% HCOOH (B) in ACN; Gradient (time/%B): 0/30, 0.2/30, 0.7/95, 2.0/95, 2.5.0/30, 3.5/30;

HPLC-MS-4: Kinetex EVO C18 5 µm; 30 x 2.1 mm; Eluent A: _H₂O + 0.0375% TFA; Eluent B: ACN + 0.01875% TFA; Gradient: 5% to 95% B in 0.8 min, 95% B for 0.4 min, 95% to 5% B in 0.01 min, then 5% B for 0.29 min; Flow rate: 1.5 ml/min; Column temperature: 50°C.

HPLC-MS-5: Kinetex 2.6 μm, 100 A 30 x 3 mm; Mobile phase: 0.1% HCOOH (A) in _H₂O / 0.1% HCOOH (B) in ACN; Gradient (time/%B): 0.1/20, 0.25/20, 0.75/95, 1.75/95, 2.0/20, 2.5/20; Flow rate: 1.0 ml/min; Temperature: 40°C

HPLC-MS-6: CORTECS C18+; Particle size: 2.7 µm; Column size: 4.6 x 30 mm; Eluent A: _H₂O + 0.05% HCOOH; Eluent B: ACN + 0.05% HCOOH; Gradient: 5% to 95% B over 1 min, then 95% for 1 min; Flow rate: 1.8 ml/min; Column temperature: 45°C.

HPLC-MS-7: Synergi 2.5 μ MAX-RP 100 A Mercury; Eluent A: _H₂O + 0.1% HCOOH; Eluent B: ACN; Gradient (time/%B): 0.1/5, 0.5/5, 1.0/95, 1.5/95, 2.0/5, 3.0/5; Flow rate: 2.0 ml/min; Column temperature: 40°C.

HPLC-MS-8: Agilent Poroshell 120 SB-C18 2.7 µm, 30 x 4.6 mm; Eluent A: _H₂O + 0.1% TFA; Eluent B: ACN + 0.1% TFA; Gradient (time/%B): 0.00/1, 0.01/1, 1.50/100, 1.73/100, 1.74/1; Flow rate: 3.0 ml/min; Column temperature: 60°C.

HPLC-MS-9: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: _H₂O + 0.1% HCOOH + 2 mM ammonium acetate; Eluent B: ACN + 0.1% HCOOH; Gradient (time/%B/flow rate): 0.01/5/0.55, 0.6/70/0.60, 0.80/90/0.65, 1.10/100/0.65 (hold for 0.6 min), 1.71/5/0.55 (hold for 0.29 min); Column temperature: room temperature.

Normal-phase ( NP ) chromatography: Unless otherwise specified, normal-phase chromatography is performed using a pre-packed column (described below) on silicone, or using a glass column according to standard rapid chromatography. System 1 Teledyne ISCO, CombiFlash RF System 2 Biotage Isolera column Pre-packed RediSep RF column, or SNAP column Sample adsorption on Isolute, or on silicone, or as a solution

Chiral NP methods ( C-NP ): Reversed-phase achiral ( RP-HPLC ) and chiral HPLC ( C-HPLC ): RP-HPLC-1: Column: YMC Triart C18 5 µm; 150 x 20 mm; mobile phase; flow rate: 19 ml/min.

RP-HPLC-2: Column: Waters X-Bridge C18 OBD 5 µm; 100 x 30 mm; mobile phase; flow rate: 40 ml/min.

RP-HPLC-3: Column: Waters X-Bridge C18 OBD 5 µm; 100 x 30 mm; mobile phase; flow rate: 50 ml/min.

RP-HPLC-4: Column: Waters X-Bridge C18 OBD 5 µm; 100 x 50 mm; mobile phase; flow rate: 140 ml/min.

RP-HPLC-5: Column: LUNA C18 OBD 5 µm; 250 x 21.2 mm; mobile phase; flow rate: 18 ml/min.

C-HPLC-1: Column: Chiralpak IG 5 µm; 250 x 4.6 mm; mobile phase; flow rate: 1 ml/min; column temperature: 25°C.

C-HPLC-2: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 25 ml/min; column temperature: 25°C.

C-HPLC-3: Column: Chiralcel OJ-H 5 µm; 240 x 30 mm; mobile phase; flow rate: 40 ml/min; column temperature: 30°C.

C-HPLC-4: Column: Chiralcel OJ-3 3 µm; 100 x 3 mm; mobile phase; flow rate: 0.42 ml/min; column temperature: 25°C.

C-HPLC-5: Column: Chiralpak AD-3 3 µm; 100 x 3 mm; mobile phase; flow rate: 0.42 ml/min; column temperature: 25°C.

C-HPLC-6: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 16 ml/min; column temperature: 25°C.

C-HPLC-7: Column: Chiralcel OD-3 3 µm; 100 x 3 mm; mobile phase; flow rate: 0.42 ml/min; column temperature: 25°C.

C-HPLC-8: Column: Lux cellulose-4 5 µm; 250 x 21.2 mm; mobile phase; flow rate: 15 ml/min.

C-HPLC-9: Column: Lux cellulose-4 5 µm; 150 x 4.6 mm; mobile phase; flow rate: 1.0 ml/min; column temperature: 25°C.

C-HPLC-10: Column: Regis(S,S) Whelk-01 5 µm; 250 x 4.6 mm; mobile phase; flow rate: 1.0 ml/min; column temperature: 25°C.

C-HPLC-11: Column: ChiralPak ID 10 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 25°C.

C-HPLC-12: Column: ChiralPak ID 5 µm; 250 x 4.6 mm; mobile phase; flow rate: 1.0 ml/min; column temperature: 25°C.

Chiral SFC method ( C-SFC ): C-SFC-1: Column: Chiralpak AS-H 10 µm; 250 x 50 mm; mobile phase; flow rate: 100 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-2: Column: Chiralpak AS 5 µm; 150 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 40°C; back pressure: 1800 psi.

C-SFC-3: Column: Chiralpak IN 5 µm; 250 x 30 mm; mobile phase; flow rate: 95 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-4: Column: Chiralpak IG 5 µm; 250 x 50 mm; mobile phase; flow rate: 100 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-5: Column: Chiralpak IG 5 µm; 100 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 40°C; back pressure: 1800 psi.

C-SFC-6: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-7: Column: Chiralpak AD 5 µm; 100 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 40°C; back pressure: 1800 psi.

C-SFC-8: Column: Lux cellulose 2 (similar to OZ) 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 140 bar.

C-SFC-9: Column: Chiralpak AD 5 µm; 250 x 30 mm; mobile phase; flow rate: 100 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-10: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 130 bar.

C-SFC-11: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-12: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 90 ml/min; column temperature: 36°C; back pressure: 130 bar.

C-SFC-13: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 110 ml/min; column temperature: 40°C; back pressure: 130 bar.

C-SFC-14: Column: Chiralpak IC 5 µm; 100 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 40°C; back pressure: 1800 psi.

C-SFC-15: Column: Chiralcel OZ 5 µm; 100 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 40°C; back pressure: 1800 psi.

C-SFC-16: Column: Lux Cel-2 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 36°C; back pressure: 120 bar.

C-SFC-17: Column: Chiralpak OZ 5 µm; 233 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-18: Column: Chiralpak IG 5 µm; 250 x 50 mm; mobile phase; flow rate: 110 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-19: Column: Lux Cel-2 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 36°C; back pressure: 130 bar.

C-SFC-20: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-21: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 110 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-22: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 130 bar.

C-SFC-23: Column: Chiralpak IC 5 µm; 100 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 40°C; back pressure: 1800 psi.

C-SFC-24: Column: Chiralpak AD 3 µm; 50 x 4.6 mm; mobile phase; flow rate: 3 ml/min; column temperature: 35°C; back pressure: 100 bar.

C-SFC-25: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 95 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-26: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 100 bar.

C-SFC-27: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 95 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-28: Column: Lux Cel-2 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-29: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 36°C; back pressure: 130 bar.

C-SFC-30: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 36°C; back pressure: 130 bar.

C-SFC-31: Column: Chiralpak AD 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-32: Column: Lux cellulose 2 (similar to OZ) 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-33: Column: Chiralpak AD 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 130 bar.

C-SFC-34: Column: Chiralpak IG 10 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 38°C; back pressure: 100 bar.

C-SFC-35: Column: Lux cellulose 2 (similar to OZ) 5 µm; 250 x 30 mm; mobile phase; flow rate: 75 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-36: Column: Chiralpak OZ 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-37: Column: Chiralpak AD 5 µm; 250 x 30 mm; mobile phase; flow rate: 75 ml/min; column temperature: 40°C; back pressure: 140 bar.

C-SFC-38: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 100 bar.

C-SFC-39: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 120 bar.

C-SFC-40: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 75 ml/min; column temperature: 40°C; back pressure: 110 bar.

C-SFC-41: Column: Chiralpak IB-N 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 130 bar.

C-SFC-42: Column: Chiralpak IC 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 ml/min; column temperature: 40°C; back pressure: 90 bar.

The XRPD method was used to obtain X-ray powder diffraction (XRPD) patterns using an advanced Bruker AXS D8 instrument in a Bragg-Brentano configuration. The powder was analyzed using a Si zero-background sample holder. The radiation was Cu Kα (λ = 1.5406 Å). The pattern was measured between 4° and 45°2θ. Sample size: 5–10 mg. Sample holder: Si zero-background sample holder XRPD parameters. Instruments Bruker AXS D8 Advance Detector LYNXEYE features an opening for receiving a 3° narrow gap detector. Radiation CuKα (0.15406 nm) Monochromator Kb-Filter (0.5% Ni) X-ray generator power 40 kV, 40 mA Step length 0.005°/step Time/Step 1 s/step Scanning range 4° to 45° (2θ value) Scanning time 2.5 h Narrow seam The main axial Soler narrow gap is 2.5°, the diverging narrow gap is 0.6 mm (= 0.34°), the detector narrow gap is 8.0 mm, and the secondary axial Soler narrow gap is 2.5°.

Abbreviations: ACN (acetonitrile), Ar, B2Pin2, Bis(phenanthrol)diboron, BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl _{, Boc2O} , dibutyl dicarbonate, BrettPhos-Pd-G3, [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, CDI, 1,1'-carbonyldiimidazole, DAST, diethylaminosulfur trifluoride, DCE, 1,2-dichloroethane, DCM, dichloromethane, DIPEA, diisopropylethylamine, DIAD, diisopropyl azodicarboxylate, DMAP, 4-dimethylaminopyridine, DME 1,4-Dimethoxyethane (DMF), N,N-Dimethylformamide (DMP), Dys-Martin oxidant (DMSO), Dimethyl sulfoxide (EDCI.HCl), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (eq. equivalent), Et _3, N, Triethylamine (EtOAc), EtOAc, EtOH, Ethanol (h, hours), HATU, 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-benzotriazolomethylene hexafluorophosphate (1-)3-oxide (HCl), Hydrochloride or hydrochloric acid (HFIP), Hexafluoro-2-propanol (HOAc), Acetic acid (HOBt). 1-Hydroxyl-7-azabenzotriazole ( _HOTs.H₂O ), p-Toluenesulfonic acid monohydrate (IPA), Isopropanol (LAH), Lithium aluminum hydroxide (LCMS) by liquid chromatography and mass spectrometry (LDA), Diisopropylaminolithium LED (LiHMDS), Bis(trimethylsilyl)aminolithium (mCPBA), 3-Chloroperoxybenzoic acid (MeI), Methyliodine (MeOH), Methanol (MS) by mass spectrometry (MsCl), Methylsulfonylurea chloride (mg, min, min, ml, mmol, mmol/z, m/z, mass-to-charge ratio) (NBS), N-bromosuccinimide ( _PdCl₂ (dppf)). _{CH₂Cl₂ )} 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex PdCl2(dtbpf) 1,1′-bis-(di-tert-butylphosphino-)ferrocene-palladium(II)dichloromethane _Pd2 (dba) ₃ -tris-(dibenzylacetone)-dipalladium(O) Pd-PEPPSI-Ipent [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II)dichloromethane PPTS Pyridinium 4-toluenesulfonate rac Racemic Rt Retention time RT Room temperature SFC Supercritical fluid chromatography TBAF Tetra-n-butylammonium fluoride TBME Methyl tert-butyl ether TFA Trifluoroacetic acid THF Tetrahydrofuran TMSOTf Trimethylsilyltrifluoromethanesulfonate (TosMIC), Toluenesulfonylmethylisocyanate (T3P), Propylphosphonic anhydride (wt.), Xphos, 2-Dicyclohexylphosphono-2′,4′,6′-triisopropylbiphenyl (XPhos-Pd-G3) (2-Dicyclohexylphosphono-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation is carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods (e.g., trace analysis and spectroscopic characterization (e.g., MS, IR, NMR)). Abbreviations used are those commonly used in the art.

All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be prepared by organic synthetic methods known to those skilled in the art. Furthermore, the compounds of the present invention can be produced by organic synthetic methods known to those skilled in the art, as illustrated in the following examples.

Synthesis of intermediate A: Intermediate A - M1 : 2-(3-(perfluoroethyl)phenyl)acetic acid

Step 1: 3-Methylphenylboronic acid pinacol ester [CAS No. 380151-86-0] (5.80 g, 25 mmol), KF (4.36 g, 75 mmol), tri-oxopropylphosphine (0.761 g, 2.500 mmol), benzyltriethylammonium chloride (0.569 g, 2.500 mmol), and _Pd₂ (dba) _₃ (0.687 g, 0.750 mmol) were suspended in 30 ml THF under argon. The mixture was degassed with argon for 5 min, and then ethyl 2-bromoacetate (4.16 ml, 37.5 mmol) was added. The resulting suspension was stirred at 60°C under argon for 2 days. The reaction mixture was then cooled to room temperature and quenched with _H₂O and extracted with EtOAc ( _3x ). The combined organic layer was dried ( _Na₂SO₄ ) and concentrated under vacuum. The residue was purified by silica gel NP chromatography to give ethyl 2-(3-methoxyphenyl)acetate. UPLC-MS-2: Rt = 0.68 min; MS m/z [M+H] ⁺ 193.2.

Step 2: Dissolve ethyl 2-(3-methoxyphenyl)acetate (Step 1, 1 g, 5.20 mmol) in 5 mL DMF, add CsF (0.079 g, 0.520 mmol), and cool the reaction mixture to 0°C. Add trimethyl(trifluoromethyl)silane (1.002 mL, 6.76 mmol) dropwise at 0°C. Stir the resulting solution at 0°C–5°C for 2 h. Then, add 1 M TBAF dropwise in THF (5.20 mL, 5.20 mmol) at 0°C and continue stirring at 0°C–5°C for 30 min. Add _H₂O to the reaction mixture, followed by extraction with TBME (3x). The combined organic layer was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under vacuum. The residue was purified by silica gel chromatography to give ethyl 2-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)acetate. UPLC-MS-2: Rt = 0.83 min; MS m/z [M+H] ⁺ 263.1.

Step 3: Ethyl 2-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)acetate (Step 2, 900 mg, 2.78 mmol)) was dissolved in 20 ml DCM, and _NaHCO3 (934 mg, 11.12 mmol) and DMP (4127 mg, 9.73 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. Then, _H2O was added and the resulting mixture was stirred at room temperature for 1 h, followed by extraction with DCM (3x). The combined organic phase was washed with _H2O and brine, dried ( _Na2SO4 ), and concentrated under _vacuum . The residue was purified by silica gel chromatography to yield ethyl 2-(3-(2,2,2-trifluoroacetyl)phenyl)acetate. UPLC-MS-2: Rt = 0.84 min (broad peak); MS m/z [M+ _H₂O + _NH₄ ] ⁺ 296.2.

Step 4: Ethyl 2-(3-(2,2,2-trifluoroacetyl)phenyl)ethyl acetate (Step 3, 700 mg, 2.56 mmol)) was dissolved in 25 mL of DCE. DAST (2.026 mL, 15.33 mmol) was added at room temperature, and the resulting mixture was heated at 50°C for 18 h in a sealed vial. The reaction mixture was then slowly added to 100 mL of MeOH with stirring, followed by concentration under vacuum. The residue was purified by silica gel chromatography to give ethyl 2-(3-(perfluoroethyl)phenyl)ethyl acetate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.66 - 7.56 (m, 4H), 4.09 (q, 2H), 3.84 (s, 2H), 1.18 (t, 3H).

Step 5: Dissolve ethyl 2-(3-(perfluoroethyl)phenyl)acetate (Step 4, 455 mg, 1.612 mmol) in 24 ml THF, add 12 ml _H₂O , followed by LiOH· _H₂O (1000 mg, 23.83 mmol). Stir the resulting suspension vigorously at room temperature for 18 h. Then add more _H₂O and extract the mixture with _Et₂O . Remove the _Et₂O phase and acidify the aqueous layer by adding 4N HCl aqueous solution (5.97 ml, 23.86 mmol). The mixture was extracted with EtOAc (3x), and the combined organic phase was washed with brine, dried ( _Na₂SO₄ ) _, and the solvent was evaporated. Toluene was then added and the mixture was concentrated under vacuum (this procedure was repeated twice) to give 2-(3-(perfluoroethyl)phenyl)acetic acid, which was used without further purification. UPLC-MS-2: Rt = 1.02 min; MS m/z [MH] ^- 253.1.

Intermediate A-M2 : 2-(3-(pentafluoro- ^λ6 -hydrothio)phenoxy)acetic acid

Step 1: A mixture of 3-(pentafluoro- ^λ6 -hydrothio)phenol (2 g, 9.08 mmol), _K₂CO₃ ( _2.51 g, 18.17 mmol), and ethyl 2-bromoacetate (1.209 ml, 10.90 mmol) in ACN (20 ml) was stirred at 80°C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with _H₂O (3x) and brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by NP chromatography (eluent: EtOAc/cyclohexane 0:100 to 30:70, over 20 min) to give ethyl 2-(3-(pentafluoro- ^λ6 -hydrothio)phenoxy)ethyl acetate. UPLC-MS-2: Rt = 1.18 min; MS m/z [M+ _NH4 ] ⁺ 324.2.

Step 2: A mixture of ethyl 2-(3-(pentafluoro- ^λ6 -hydrothio)phenoxy)acetic acid (Step 1, 2.56 g, 8.36 mmol) and LiOH· _H₂O (1.503 g, 35.8 mmol) in THF (24 ml) and _H₂O (12 ml) was stirred at room temperature for 3 h. After dilution with EtOAc, the reaction mixture was neutralized with 1 N HCl aqueous solution and then extracted with EtOAc (3x). The combined organic phase was washed with _H₂O and brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure to give 2-(3-(pentafluoro- ^λ6 -hydrothio)phenoxy)acetic acid. UPLC-MS-2: Rt = 0.86 min; MS m/z [MH] ^- 277.1.

Intermediate A-M3 : 7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridine-2-carboxylic acid

Step 1: Under argon atmosphere, 2-chloro-6-(trifluoromethyl)nicotinaldehyde (5.5 g, 26.2 mmol) was dissolved in 200 ml THF. Ethyl 2-sideoxy-3-(triphenyl- ^λ5 -phosphaneylidene)propionate (10.37 g, 27.6 mmol) was added to the solution, and the mixture was stirred at reflux temperature for 18 h. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography to give ethyl (E)-4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-sideoxybut-3-enoate. UPLC-MS-2: Rt = 1.06 min; MS m/z [M+H] ⁺ 308.

Step 2: Ethyl (E)-4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-sideoxybut-3-enoate (Step 1, 430 mg, 1.398 mmol) and RhCl( _PPh3 ) ₃ (129 mg, 0.14 mmol) in 28 ml DCM were hydrogenated overnight in a high-pressure autoclave (20 bar _H2 , 60°C). The reaction mixture was then concentrated under vacuum, and the resulting residue was stirred and ultrasonically treated in _Et2O . The suspension was filtered, and the filter cake was washed with n-hexane. The combined filtrate was concentrated under vacuum to give ethyl 4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxybutyrate. UPLC-MS-3: Rt = 4.64 min; MS m/z [M+H] ⁺ 312.

Step 3: Ethyl 4-(2-chloro _- 6-(trifluoromethyl)pyridin-3-yl)-2-hydroxybutyrate (Step 2, 5.33 g, 17.1 mmol) was dissolved in 150 ml ACN, and _Cs₂CO₃ (11.1 mg, 34.2 mmol) was added. The mixture was heated to about 100°C (reflux) and stirred at this temperature for a total of about 6 h (a second equivalent of _Cs₂CO₃ was added after 2 h). The reaction mixture was then cooled to room temperature, _H₂O was added _, and the resulting mixture was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried, and concentrated under vacuum to give ethyl 7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridine-2-carboxylate, which was purified by silica gel column chromatography. UPLC-MS-2: Rt = 0.83 min; MS m/z [M+H] ⁺ 276.

Step 4: Ethyl 7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridine-2-carboxylate (Step 3, 230 mg, 0.501 mmol) was dissolved in 8 ml THF, and a solution of LiOH· _H₂O (42.1 mg, 1.003 mmol) in 2 ml _H₂O was added. The mixture was stirred at room temperature for 1 h. Subsequently, the reaction mixture was diluted with _H₂O and extracted with TBME (2x), and the aqueous layer was freeze-dried to give 7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridine-2-carboxylic acid (containing LiOH) as a lithium salt. UPLC-MS-2: Rt = 0.47 min; MS m/z [M+H] ⁺ 248.

Intermediate A-M4 : 2-(6-(trifluoromethyl)pyridin-2-yl)acetamide

To a solution of methyl 2-(6-(trifluoromethyl)pyridin-2-yl)acetate (200 mg, 0.913 mmol) in MeOH (2 ml), _NH₄OH (28%-30% in _H₂O ) (2 ml, 0.913 mmol) was added, and the reaction mixture was stirred overnight at 60°C. The reaction mixture was evaporated to dryness and purified by silica gel column chromatography (elution with a gradient of MeOH (0-10%) in DCM). The fractions containing the desired product were combined and evaporated to give 2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. ¹ HNMR (600 MHz, DMSO-d ₆ ) δ 8.03 (t, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.63 (s, 1H), 7.07 (s, 1H), 3.70 (s, 2H). UPLC-MS-2: Rt = 0.36 min; MS m/z [M+H] ⁺ 205.1.

Intermediate A-M5 : 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

Step 1: A solution of 2-fluoro-3-(trifluoromethyl)phenylacetic acid (500 mg, 2.251 mmol) in 1.25 M HCl in MeOH (4 ml, 5.00 mmol) was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was absorbed with DCM and washed with a saturated aqueous solution of _NaHCO3 . The organic layer was dried and evaporated using a phase separator to give methyl 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetate, which was used for the next step without further purification. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 7.74–7.69 (m, 2H), 7.39 (t, 1H), 3.88 (s, 2H), 3.65 (s, 3H). 8.03 (t, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.63 (s, 1H), 7.07 (s, 1H), 3.70 (s, 2H). UPLC-MS-2: Rt = 1.05 min; MS m/z [M+NH ₄ ] ⁺ 254.2.

Step 2: Add _NH₄OH (28%-30% in _H₂O ) (5 ml, 2.066 mmol) to a solution of methyl 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetate (Step 1, 488 mg, 2.066 mmol) in MeOH (5 ml). Stir the reaction mixture at 60°C for 3 h. Evaporate the reaction mixture to dryness and purify by silica gel column chromatography (using a gradient elution of EtOAc (0-100%) in cyclohexane). Combine and evaporate the fractions containing the desired product to give 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.66 (tt, 2H), 7.60 (s, 1H), 7.35 (t, 1H), 7.06 (s, 1H), 3.56 (d, 2H). UPLC-MS-2: Rt = 0.67 min; MS m/z [M+H] ⁺ 222.2.

Intermediate B , B-M1 : 4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazole

Step 1: 1-Bromo-3-chloropropane (787.2 g, 5.0 mol) was added dropwise to a mixture of 2-methylethyl 2-propane (500 g, 4.2 mol) and _K₂CO₃ (580.5 g, 4.2 mol) in acetone (2.5 L) at 15°C, and the mixture was then heated to 60°C. After ₁₆ h, the mixture was cooled to 15°C and filtered. The filter cake was washed with acetone and the filtrate was concentrated to give 2-((3-chloropropyl)thio)ethyl acetate, which was used directly in the next step without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.17 (q, 2H), 3.66 (dt, 2H), 3.20 (m, 2H), 2.79 (m, 2H), 2.01 (m, 2H), 1.30 (m, 3H).

Step 2: KOt-Bu (460.1 g, 4.1 mol) was added in five portions to a solution of ethyl 2-((3-chloropropyl)thio)ethyl acetate (Step 1, 856.1 g, 3.4 mol) in DMF (5.1 L) at -20°C. After stirring for 30 min, the mixture was heated to 15°C. After 16 h, the reaction mixture was acidified with 1 N HCl aqueous solution (pH 5-6) and extracted with 1:1 EtOAc/heptane. The organic phase was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure to give tetrahydrothiophene-2-carboxylate, which was used directly in the next step without purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.16 (m, 2H), 3.90 (dd, 1H), 2.91 (m, 2H), 2.26 (m, 2H), 1.99 (m, 2H), 1.26 (t, 3H).

Step 3: LiHMDS (1 M, 3.5 l, 3.5 mol) and then MeI (496.8 g, 3.5 mol) were added to a solution of tetrahydrothiophene-2-carboxylate (Step 2, 400 g, 2.3 mol) in THF (2 l) at 0°C. After 1 h, the reaction mixture was quenched with a saturated _NH4Cl aqueous solution, diluted with TBME and _H2O , stirred for 10 min, and then the phases were separated. The aqueous phase was extracted with TBME. The combined organic phase was washed with a 10% brine aqueous solution, _dried ( _Na2SO4 ), and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/heptane 1:10) to yield ethyl 2-methyltetrahydrothiophene-2-carboxylate. ^¹H NMR (300 MHz, _CDCl₃ ) δ 4.13 (m, 2H), 3.22 (m, 2H), 2.50 (m, 1H), 2.16 (m, 2H), 1.68 (m, 1H), 1.60 (s, 3H), 1.26 (t, 3H).

Step 4: LAH (2 M/THF) (1 L, 2 mol) was added dropwise to a solution of ethyl 2-methyltetrahydrothiophene-2-carboxylate (Step 3, 310 g, 1.7 mol) in THF (2.2 L) at -30°C. After 1 h, the reaction mixture was quenched with _H₂O (93 g), 15% NaOH aqueous solution (93 g), and _H₂O (279 g), and then _Na₂SO₄ (3.7 kg) was added. After stirring for ₃₀ min, the mixture was filtered and the filtrate was concentrated under reduced pressure to give (2-methyltetrahydrothiophene-2-yl)methanol, which was used directly in the next step without purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.82 (t, 1H), 3.32 (dd, 1H), 3.15 (dd, 1H), 2.73 (m, 2H), 1.75-2.01 (m, 3H), 1.43 (m, 1H), 1.24 (s, 3H).

Step 5: (COCl) _₂ (330 g, 2.6 mol) was added dropwise to a solution of DMSO (507.8 g, 6.5 mol) in DCM (2.8 L) at -78°C. After stirring for 30 min, a solution of (2-methyltetrahydrothiophene-2-yl)methanol (Step 4, 186.7 g, 1.3 mol) in DCM (934 mL) was added dropwise. After 1 h, the reaction mixture was quenched with _Et₃N (708.3 g, 7 mol) and then warmed to room temperature. After stirring for 1 h, _H₂O was added and the phases were separated. The organic phase was washed with a 10% brine solution, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure to give 2-methyltetrahydrothiophene-2-carboxaldehyde, which was used directly in the next step without purification. ^¹H NMR (300 MHz, DMSO- _d₆ ) δ 9.19 (d, ¹H), 3.00 (dt, ¹H), 2.85 (dt, ¹H), 1.99–2.27 (m, ³H), 1.76 (m, ¹H), 1.37 (s, ³H).

Step 6: Ti(OEt) _₄ (361.1 g, 1583.2 mmol) was added to a solution of 2-methyltetrahydrothiophene-2-carboxaldehyde (Step 5, 110 g, 791.6 mmol) and 2-methylpropane-2-sulfinamide (115.1 g, 949.9 mmol) in THF (1.1 l) at 15°C. After 16 h, the reaction mixture was diluted with EtOAc and brine, stirred for 30 min, and then filtered. The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/heptane 1:30) to give (E)-2-methyl-N-((2-methyltetrahydrothiophene-2-yl)methylene)propane-2-sulfinamide. ^¹H NMR (300 MHz, DMSO- _d⁶ ) δ 7.78 (d, 1H), 2.88–3.13 (m, 2H), 2.03–2.30 (m, 3H), 1.86 (m, 1H), 1.55 (s, 3H), 1.12 (d, 9H).

Step 7: _K₂CO₃ (86.8 g, 628.3 mmol) and TosMIC (73.6 g, 377 mmol) were added to _a solution of (E)-2-methyl-N-((2-methyltetrahydrothiophene-2-yl)methylene)propane-2-sulfinamide (Step 6, 70 g, 251.3 mmol) in MeOH (700 ml) at 15°C. After stirring for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM and _H₂O , stirred for 30 min, and then the phases were separated. The organic phase was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: DCM/MeOH 10:1) to give 4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazole. ^¹H NMR (300 MHz, DMSO- _d⁶ ) δ 7.52 (d, 1H), 6.87 (d, 1H), 2.94 (t, 2H), 2.30 (m, 1H), 2.06 (m, 2H), 1.85 (dt, 1H), 1.65 (s, 3H).

Intermediate B-M2 : Tributyl 4,4-difluoro-2-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid

Step 1: At room temperature, _NH₄Cl (4.033 g, 75.4 mmol), HATU (2.15 g, 5.655 mmol), and DIPEA (1.31 ml, 7.54 mmol) were added to a solution of 1-(tributoxycarbonyl)-4,4-difluoropiperidin-2-carboxylic acid [CAS No. 661458-34-0] (1 g, 3.77 mmol) in DMF (15 ml). After 60 h, the reaction mixture was diluted with EtOAc and washed with saturated _NH₄Cl aqueous solution and saturated _NaHCO₃ aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure to give tributyl 2-aminomethoxy-4,4-difluoropiperidine-1-carboxylic acid, which was used in the next step without further purification. UPLC-MS-2: Rt = 0.57 min; MS m/z [M-Boc] ⁺ 165.2.

Step 2: 1,1-Dimethoxy-N,N-dimethylmethylamine (901.8 mg, 7.568 mmol) was added to a solution of 2-aminomethyl-4,4-difluoropiperidine-1-carboxylic acid tributyl ester (Step 1, 1 g, 3.784 mmol) in toluene (20 ml). After stirring at 100°C for 18 h, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in HOAc (20 ml). Hydrazine monohydrate (50%, 485.1 mg, 7.568 mmol) was added, and the mixture was stirred at 90°C. After 2 h, the reaction mixture was poured onto ice and extracted with EtOAc (3x). The combined organic layer was washed with saturated _NaHCO3 aqueous solution and brine, dried ( _Na2SO4 ) _, and concentrated under reduced pressure to give tributyl 4,4-difluoro-2-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid, which was used for the next step without further purification. UPLC-MS-2: Rt = 0.71 min; MS m/z [M+H] ⁺ 289.1.

Intermediate B-M3 : 3,3-Difluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester

Step 1: A mixture of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tributyl ester [CAS No. 161157-50-2] (111 mg, 0.557 mmol) and 4-bromo-1H-pyrazole (90 mg, 0.613 mmol ₎ , _Cs₂CO₃ (272 mg, 0.836 mmol) in DMSO (4.1 ml) was heated at 100°C in a sealed tube. After 2.5 h, the reaction mixture was diluted with _H₂O and extracted with EtOAc (2x). The combined organic layer was washed with brine, dried (phase separator), and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 40:60) to give tributyl 4-(4-bromo-1H-pyrazol-1-yl)-3-hydroxypiperidine-1-carboxylic acid. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.98 (d, 1H), 7.53 (s, 1H), 5.26 (d, 1H), 3.85–4.16 (m, 3H), 3.63 (m, 1H), 2.81 (m, 1H), 2.59 (m, 1H), 1.76–1.94 (m, 2H), 1.41 (s, 9H). UPLC-MS-2: Rt = 0.92 min; MS m/z [M-Boc] ⁺ 246.2/248.1.

Step 2: DMP (31.9 mg, 0.075 mmol) was added to a solution of 4-(4-bromo-1H-pyrazol-1-yl)-3-hydroxypiperidine-1-carboxylic acid tributyl ester (Step 1, 20 mg, 0.058 mmol) in DCM (0.58 ml) at room temperature under Ar. After 2 h, the reaction mixture was filtered. The filtrate was diluted with _H2O and extracted with DCM (3x). The combined organic layers were dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 50:50) to give tributyl 4-(4-bromo-1H-pyrazol-1-yl)-3-sideoxypiperidine-1-carboxylic acid. UPLC-MS-2: Rt = 0.89 min; MS m/z [M+H] ⁺ 344.3/346.3 and 362.3/364.3 (mixture of ketone and hydrate).

Step 3: At -78°C under Ar, XtalFluor-E (1.018 g, 4.44 mmol), Et ₃ N.3HF (0.483 ml, 2.96 mmol), and then Et ₃ N (0.205 ml, 1.48 mmol) were continuously and slowly added to a solution of 4-(4-bromo-1H-pyrazol-1-yl)-3-sideoxypiperidine-1-carboxylic acid tributyl ester (Step 2, 510 mg, 1.48 mmol) in DCM (25 ml). After 1 h, the mixture was warmed to room temperature. After 2 h, the reaction mixture was cooled to 0°C and quenched with saturated NaHCO3 aqueous solution, stirred for 30 min, and then extracted with DCM (3x). The combined organic layers were dried (using a phase separator) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 40:60) to give tributyl 4-(4-bromo-1H-pyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 7.63 (s, 1H), 5.00 (m, 1H), 4.23 (m, 1H), 4.09 (m, 1H), 3.42 (m, 1H), 3.09 (m, 1H), 2.29 (m, 1H), 2.06 (m, 1H), 1.42 (s, 9H). UPLC-MS-3: Rt = 5.61 min; MS m/z [M-Boc] ⁺ 266.0/268.0.

Step 4: A mixture of 4-(4-bromo-1H-pyrazol-1-yl)-3,3-difluoropiperidin-1-carboxylic acid tributyl ester (Step 3, 358 mg, 0.978 mmol), KOAc (480 mg, 4.89 mmol), and B2Pin2 [CAS No. 73183-34-3] (745 mg, 2.93 mmol) in DMF (3.3 ml) was degassed by bubbling with Ar for 5 min. _PdCl2 (dppf) (71.5 mg, 0.098 mmol) was added, the vial was sealed, and the mixture was heated to 80°C. After 16 h, the reaction mixture was diluted with _H2O and extracted with DCM (3x). The combined organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 30:70) to give tributyl 3,3-difluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid. UPLC-MS-2: Rt = 1.20 min; MS m/z [M+H] ⁺ 414.5.

Intermediate B-M4 : 3-(4-bromo-1H-pyrazol-1-yl)pyrrolidone-2-one

At 0°C, DIAD (0.794 ml, 4.08 mmol) was added to a solution of 4-bromo-1H-pyrazole (300 mg, 2.04 mmol), 3-hydroxypyrrolidone-2-one (227 mg, 2.24 mmol), and _Ph3P (803 mg, 3.06 mmol) in THF (5 ml) and DMF (1 ml), and the mixture was then warmed to room temperature. After stirring overnight, the reaction mixture was diluted with _H2O and extracted with EtOAc ( _3x ). The combined organic layer was dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/hexane) to yield 3-(4-bromo-1H-pyrazol-1-yl)pyrrolidone-2-one. HPLC-MS: Rt 1.54 min; MS m/z [M+H] ⁺ 230.1/232.1.

Intermediate B-M5 : 3-(1H-imidazol-4-yl)tributyl 3-(1H-imidazol-4-yl)-lino-4-carboxylic acid

Step 1: Ethyl titanium oxide (1.36 g, 1.24 ml, 5.97 mmol) was added dropwise to a solution of tributyl 3-formylphosphono-4-carboxylate (642 mg, 2.98 mmol) and 2-methylpropane-2-sulfinamide (559 mg, 4.47 mmol) in THF (12 ml), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (10 ml) and brine (10 ml) and stirred at room temperature for 30 min. The precipitate was removed by filtration through a ^Celite® mat, and the two-phase filtrate was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was dried and evaporated using a phase separator. The crude product was purified by silica gel column chromatography (using a gradient elution of EtOAc (0-50%) in cyclohexane). The fractions containing the product were combined and evaporated to give tributyl 3-(((tributylsulfinyl)imino)methyl)carboxylate-4-carboxylate. UPLC-MS-2: Rt = 0.94 min; MS m/z [M+H+Na] ⁺ 341.1.

Step 2: Add _K₂CO₃ (949 mg, 2.5 mmol) and TosMIC (1.07 g, 5.50 mmol) to a solution of ₃ -(((tri-butylsulfinyl)imino)methyl)carboxylin-4-carboxylic acid tributyl ester (Step 1, 875 mg, 2.75 mmol) in MeOH (20 ml), and stir the reaction mixture at room temperature for 24 h. Filter the reaction mixture through a ^Celite® mat, wash with DCM/MeOH, and evaporate the filtrate to dryness to give 3-(1H-imidazol-4-yl)carboxylin-4-carboxylic acid tributyl ester, which is used without further purification. UPLC-MS-2: Rt = 0.36 min; MS m/z [M+H] ⁺ 254.1.

Intermediate B-M6 : (2-(1H-imidazol-4-yl)propyl-2-yl)aminocarbamate tributyl ester

Step 1: Ethyl titanium oxide (2.2 ml, 11 mmol) was added at room temperature to a mixture of (2-methyl-1-sideoxyprop-2-yl)aminocarbamate tributyl ester (1 g, 5.3 mmol) and 2-methylpropane-2-sulfinamide (0.78 g, 6.4 mmol) in THF (35 ml). After 3 days, the reaction mixture was quenched with _H₂O and extracted with EtOAc ( _2x ). The combined organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give (E)-(1-((tributylsulfinyl)imino)-2-methylprop-2-yl)aminocarbamate tributyl ester, which was used for the next step without further purification. UPLC-MS-2: Rt = 1.07 min; MS m/z [M+Na] ⁺ 313.2.

Step 2: _K₂CO₃ ( _1.88 g, 13.6 mmol) and TosMIC (1.17 g, 6 mmol) were added to a solution of (E)-(1-((tri-butylsulfinyl)imino)-2-methylpropyl-2-yl)aminocarbamate (Step 1, 1.76 g, 5.45 mmol) in MeOH (25 ml) at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, filtered through a phase separator column, and the filtrate was concentrated under reduced pressure to yield tributyl (2-(1H-imidazol-4-yl)propyl-2-yl)aminoformate, which was used without further purification. UPLC-MS-2: Rt = 0.31 min; MS m/z [M+H] ⁺ 226.1.

Intermediate B-M7 : 6-(1H-imidazol-4-yl)oline-3-one

Step 1: Add Et ₃ N (2.458 ml, 17.73 mmol) to a solution of 1-triphenylmethyl-1H-imidazol-4-carboxaldehyde [CAS No. 33016-47-6] (3 g, 8.86 mmol) in nitromethane (50 ml, 927 mmol) and stir the resulting solution at room temperature for 4 h. Add another nitromethane (20 ml, 8.86 mmol) and continue stirring at room temperature for 2 h. Evaporate the reaction mixture to dryness, and grind the solid with Et ₂ O (30 ml), filter, wash with Et ₂ O (2 x 20 ml), and dry to give 2-nitro-1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol-1-ol. UPLC-MS-2: Rt = 1.11 min; MS m/z [M+Na] ⁺ 422.1.

Step 2: Under argon atmosphere, 2-nitro-1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol-1-ol (Step 1, 1 g, 2.378 mmol), ammonium formate (0.750 g, 11.89 mmol), and Pd/C 10% (0.253 g, 0.238 mmol) were added to a microwave ^-safe vial. THF (10 ml) and MeOH (10 ml) were added, and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was filtered through a Celite® mat, washed with MeOH, and evaporated. The crude product was purified by reversed-phase column chromatography (eluting with a gradient of ACN (10% to 100%) in _H₂O + 0.1% HCOOH). Fractions containing the desired product were combined, frozen, and freeze-dried to give 2-amino-1-(1-triphenylmethyl-1H-imidazol-4-yl)ethane-1-ol. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 7.42–7.38 (m, 9H), 7.32 (d, 1H), 7.09 (dd, 6H), 6.78 (s, 1H), 4.56 (dd, 1H), 2.97 (dd, 1H), 2.80 (dd, 1H). UPLC-MS-2: Rt = 0.82 min; MS m/z [M+Na] ⁺ 392.4.

Step 3: Add 2-chloroacetyl chloride (0.365 ml, 4.58 mmol) dropwise to a solution of 2-amino-1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol (Step 2, 1.731 g, 4.17 mmol) and Et ₃ N (1.155 ml, 8.33 mmol) in DCM (25 ml). Stir the reaction mixture at 0°C for 2 h. Dilute the reaction mixture with DCM and wash with H ₂ O. Separate the phases and extract the aqueous layer with DCM. The combined organic layer was dried and evaporated using a phase separator to give 2-chloro-N-(2-hydroxy-2-(1-triphenylmethyl-1H-imidazol-4-yl)ethyl)acetamide, which was used in the next step without further purification. UPLC-MS-2: Rt = 1.18 min; MS m/z [M+Na] ⁺ 544.3.

Step 4: Add tBuOK (935 mg, 8.33 mmol) to a solution of crude 2-chloro-N-(2-hydroxy-2-(1-triphenylmethyl-1H-imidazol-4-yl)ethyl)acetamide (Step 3, 1.739 g, 1.092 mmol) in t-BuOH (25 ml) and stir the reaction mixture at room temperature for 1 h. Dilute the reaction mixture with _H₂O and DCM. Add saturated aqueous solution of _NH₄Cl and separate the phases. Extract the aqueous layer with DCM (2x). Dry and evaporate the combined organic layers using a phase separator. Purify the crude product by silica gel column chromatography (eluting with a gradient of MeOH (0-40%) in DCM). The fractions containing the desired product were combined and evaporated to give 6-(1-triphenylmethyl-1H-imidazol-4-yl) 3-oxoline-3-one. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 8.04 (d, 1H), 7.44–7.37 (m, 9H), 7.36 (d, 1H), 7.09–7.05 (m, 6H), 6.87 (d, 1H), 4.69 (dd, 1H), 4.08 (d, 1H), 4.02 (d, 1H), 3.47 (dd, 1H), 3.38–3.34 (m, 1H). UPLC-MS-2: Rt = 1.02 min; MS m/z [M+Na] ⁺ 432.4.

Step 5: A solution of 6-(1-triphenylmethyl-1H-imidazol-4-yl)trimonin-3-one (Step 4, 614 mg, 1.469 mmol), TFA (1.132 ml, 14.69 mmol), and triethylsilane (0.258 ml, 1.616 mmol) in DCM (12 ml) was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the residue was absorbed in DCM/ _H₂O . A 1 M aqueous solution of HCl was added and the phases were separated. The aqueous layer was washed with DCM (2x), frozen, and freeze-dried to give 6-(1H-imidazol-4-yl)trimonin-3-one. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 14.70 (m, 2H), 9.14 (d, 1H), 8.29 (d, 1H), 7.76 (t, 1H), 5.01 (dd, 1H), 4.22 (d, 1H), 4.16 (d, 1H), 3.57 - 3.50 (m, 2H). UPLC-MS-2: MS m/z [M+H] ⁺ 168.0.

Intermediate B-M8 : 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl) tributyl isozonidine-2-carboxylate

Step 1: Add Et ₃ N (0.589 ml, 4.23 mmol) to a solution of 4-hydroxyisoazolidine-2-carboxylic acid tributyl ester (400 mg, 2.114 mmol) in DCM (20 ml). Cool the reaction mixture to 0°C in an ice bath and add methanesulfonyl chloride (0.329 ml, 4.23 mmol) dropwise. Warm the reaction mixture to room temperature and stir for 72 h. Dilute the reaction mixture with DCM, wash the organic layer with a saturated aqueous solution of _NaHCO3 , and dry it using a phase separator. Evaporate the resulting solution to give 4-((methanesulfonyl)oxy)isoazolidine-2-carboxylic acid tributyl ester, which is used directly in the next step without further purification. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 5.62 - 5.59 (m, 1H), 4.06 (dd, 1H), 4.00 (dd, 1H), 3.82 (d, 1H), 3.81 (s, 1H), 3.26 (s, 3H), 1.42 (s, 9H). UPLC-MS-2: MS [M-Boc+H] ⁺ 168.1.

Step 2: Add 4-((methanesulfonyl)oxy)isoazolidine-2-carboxylic acid tributyl ester (Step 1, 600 mg, 2.110 mmol) and _Cs₂CO₃ (2073 mg, 6.36 mmol) to a solution of pyrazolium borate pinacol _ester (200 mg, 1.010 mmol) in ACN (10 ml), and stir the reaction overnight at 80°C. Dilute the reaction mixture with _H₂O and DCM. The aqueous layer was extracted with DCM (2x), the combined organic layer was washed with brine, dried and evaporated using a phase separator to give tributyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)isoazolidine-2-carboxylic acid, which was used without further purification. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H), 7.62 (s, 1H), 5.48 - 5.43 (m, 1H), 4.20 - 4.15 (m, 2H), 3.95 (dd, 1H), 3.86 (dd, 1H), 1.41 (s, 9H), 1.24 (s, 12H). UPLC-MS-2: MS [M-Boc+H] ⁺ 266.4.

Intermediate B-M9 : 1-(1H-imidazol-4-yl)-2-azabicyclic[2.1.1]hexane-2-carboxylic acid tributyl ester

Step 1: At 0°C, isopropyl magnesium chloride (2 M/THF) (852 mg, 4.14 ml, 8.29 mmol) was added dropwise to a solution of 2-azabicyclo[2.1.1]hexane-1,2-dicarboxylic acid 2-(tributyl)-1-methyl ester (1.00 g, 4.14 mmol) and N,O-dimethylhydroxyamine hydrochloride (606 mg, 6.22 mmol) in THF (5 ml). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with EtOAc and washed with saturated _NH4Cl solution. The phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried and evaporated using a phase separator. The crude product was purified by reversed-phase column chromatography (using a gradient elution of ACN (10%-100%) in _H₂O + 0.1% HCOOH). The fractions containing the desired product were combined, a saturated aqueous solution _{of NaHCO₃} was added, and the aqueous solution was extracted with DCM (3x). The combined organic layers were dried and evaporated using a phase separator column to give tributyl 1-(methoxy(methyl)aminomethoxy)-2-azabicyclo[2.1.1]hexane-2-carboxylate, which was used for the next step without further purification. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 3.61 (s, 3H), 3.32 - 3.30 (m, 2H), 3.10 (s, 3H), 2.67 (t, 1H), 2.19 - 2.03 (m, 1H), 2.02 - 1.88 (m, 1H), 1.82 - 1.67 (m, 1H), 1.50 - 1.41 (m, 1H), 1.35 (s, 9H). UPLC-MS-2: Rt = 0.67 min; MS m/z [M+H] ⁺ 271.2.

Step 2: At 0°C under argon, a solution of 1-(methoxy(methyl)aminomethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tributyl ester (Step 1, 454.0 mg, 1.579 mmol) in THF (15 ml) was treated with a solution of LiAlH4 (1 M/THF) (89.87 mg, 2.368 ml, 2.368 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was carefully quenched with _H2O at 0°C, saturated aqueous solution of _NaHCO3 was added, and the mixture was stirred at room temperature for 10 min and extracted with EtOAc (2x). The combined organic layer was concentrated to give tributyl 1-methacryl-2-azabicyclo[2.1.1]hexane-2-carboxylate, which was used in the next step without further purification. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 9.66 (d, ¹H), 3.37 (s, 2H), 2.76 (d, ¹H), 2.00 (ddd, 2H), 1.51 (dd, 2H), 1.42–1.36 (m, 9H). UPLC-MS-2: Rt = 0.81 min; MS m/z [M+H-Boc] ⁺ 112.0.

Step 3: Add ethyl titanium oxide (526.6 mg, 480.4 µL, 2.308 mmol) to a solution of 1-methoxy-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tributyl ester (Step 2, 329.5 mg, 1.154 mmol) and 2-methylpropane-2-sulfinamide (216.3 mg, 97% wt, 1.731 mmol) in THF (8.0 ml), and stir the reaction mixture at room temperature for 36 h. Dilute the reaction mixture with EtOAc and brine and stir at room temperature for 30 min. Remove the precipitate by filtration through a ^Celite® mat, separate the filtrate, and extract the aqueous layer with EtOAc (2x). The combined organic layers were dried and evaporated using a phase separator. The crude product was purified by silica gel column chromatography (using gradient elution of EtOAc (0-60%) in cyclohexane). The fractions containing the desired product were combined and evaporated to give (E)-1-(((tri-butylsulfinyl)imino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tributyl ester. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 3.39 (s, 2H), 2.80 (t, 1H), 2.19 - 2.11 (m, 1H), 1.95 - 1.88 (m, 1H), 1.83 - 1.68 (m, 1H), 1.55 - 1.48 (m, 1H), 1.36 (s, 9H), 1.13 (s, 9H). UPLC-MS-2: Rt = 1.11 min; MS m/z [M+H-Boc] ⁺ 215.1.

Step 4: Add K₂CO₃ (328.2 mg, 2.5 equivalents, 2.375 mmol) and TosMIC (370.9 mg, 1.900 mmol) to a solution of (E)-1-(((tri-butylsulfinyl)imino)methyl)-2-azabicyclo[2.1.1]hexane- ₂ -carboxylate (Step ₃ , 298.7 mg) in MeOH (3.0 ml). Stir the reaction mixture at room temperature for 18 h. The reaction mixture was filtered through a ^Celite® mat, washed with DCM/MeOH, and the filtrate was evaporated to dryness to give tributyl 1-(1H-imidazol-4-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, which was used without further purification. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 3.39 (s, 2H), 2.80 (t, 1H), 2.19 - 2.11 (m, 1H), 1.95 - 1.88 (m, 1H), 1.83 - 1.68 (m, 1H), 1.55 - 1.48 (m, 1H), 1.36 (s, 9H), 1.13 (s, 9H). UPLC-MS-2: Rt = 0.67 min; MS m/z [M+H] ⁺ 250.1.

Intermediate B-M10 : Tributyl 4,4-difluoro-2-(1H-imidazol-4-yl)piperidine-1-carboxylic acid

TosMIC (188 mg, 962 µmol) was added to a solution of 4,4-difluoro-2-methylpiperidine-1-carboxylic acid tributyl ester (218 mg, 875 µmol) in ethanol (4.00 ml). The suspension was cooled to 0°C under argon atmosphere, and NaCN (6.43 mg, 0.15 equivalent, 131 µmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness. The intermediate was dissolved in ammonia (7 M/MeOH) (700 mg, 5.87 ml, 4 mmol), transferred to a microwave-safe vial, sealed, and stirred at 100°C for 20 h. The reaction mixture was cooled to room temperature and concentrated. The residue was ground with DCM, and the precipitate was filtered and washed with DCM. The filtrate was concentrated to give tributyl 4,4-difluoro-2-(1H-imidazol-4-yl)piperidine-1-carboxylic acid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.22 (d, 1H), 8.98 (dd, 1H), 8.46 (t, 1H), 7.60 (d, 1H), 5.49 (d, 1H), 4.11 (d, 1H), 3.09 (s, 1H), 2.79 (t, 1H), 2.39 - 2.26 (m, 2H), 2.02 - 1.99 (m, 1H), 1.43 (s, 9H). UPLC-MS-2: Rt = 1.05 min; MS m/z [M+H] ⁺ 428.2.

Intermediate B-M11 4-(1H-imidazol-4-yl) α-line

Step 1: Add Et ₃ N (1.333 ml, 9.53 mmol) to a solution of 4-bromo-1H-imidazole (700 mg, 4.76 mmol) in DMF (8 ml) and stir the reaction mixture for 15 min. Then add (chloromethanetriyl)triphenyl (1461 mg, 5.24 mmol). Stir the suspension at room temperature for 48 h. Add another 8 ml of DMF and (chloromethanetriyl)triphenyl (1461 mg, 5.24 mmol), and sonicate the reaction mixture at 65°C for 2 h. Dilute the reaction mixture with EtOAc and filter the suspension to give 4-bromo-1-triphenylmethyl-1H-imidazole, which is used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.04 (s, 1 H) 7.11 (d, 6 H) 7.37 - 7.46 (m, 10 H). UPLC-MS-2: Rt = 1.34 min.

Step 2: 4-Bromo-1-triphenylmethyl-1H-imidazole (Step 1, 200 mg, 0.514 mmol), NaOtBu (148 mg, 1.541 mmol), and Pd-PEPPSI IPent (40.7 mg, 0.051 mmol) were mixed under argon atmosphere. Anhydrous DMA (4 ml) and α-porphyrin (0.135 ml, 1.541 mmol) were added, and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with EtOAc and washed twice with a _saturated aqueous solution of _NaHCO3 . The organic phase was dried ( _Na2SO4 ) and concentrated. The crude material was purified by silica gel column chromatography (using gradient elution of EtOAc in cyclohexane). Fractions containing the desired product were collected and concentrated to give 4-(1-triphenylmethyl-1H-imidazol-4-yl) α-lin. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 7.42–7.33 (m, 9H), 7.13–7.09 (m, 6H), 7.08 (d, 1H), 6.05 (d, 1H), 3.66–3.59 (m, 4H), 2.91–2.83 (m, 4H). UPLC-MS-2: Rt = 1.20 min; MS m/z [M+H] ⁺ 396.2.

Step 3: At 25°C, triethylsilane (48.5 mg, 66.6 µl, 417 µmol) and TFA (432 mg, 292 µl, 3.79 mmol) were added to a mixture of 4-(1-triphenylmethyl-1H-imidazol-4-yl) 4-hydroxyl (Step 2, 150 mg, 379 µmol) in DCM (3 ml). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by reversed-phase column chromatography (using a gradient elution of ACN (0-10%) in _H₂O + 0.1% _NH₄OH ). The fraction containing the desired compound was collected and freeze-dried to give 4-(1H-imidazol-4-yl) 4-hydroxyl. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.62 (s, 1H), 7.35 (d, 1H), 6.31 (d, 1H), 3.70 - 3.65 (m, 4H), 2.94 - 2.87 (m, 4H). UPLC-MS-2: Rt = 0.13 min; MS m/z [M+H] ⁺ 154.0.

Intermediate B-M12 : 3-(1H-imidazol-4-yl)tributyl 3-(1H-imidazol-4-yl)-3-lin-4-carboxylate

Step 1: Add _{K₂CO₃ (} 5.75 g, 41.6 mmol) and benzyl bromide (2.72 ml, 22.90 mmol) to a solution of 1H-imidazol-4-carboxaldehyde (2 g, 20.81 mmol) in ACN (200 ml). Stir the reaction mixture at room temperature for 72 h, concentrate, dissolve the residue in EtOAc and wash with _H₂O and brine. Dry and evaporate the organic layer using a phase separator to give a crude mixture of regional isomers. Purify the crude mixture by silica gel column chromatography (using a gradient elution of MeOH (0-10%) in DCM). The fractions containing the desired product were combined, evaporated, and purified again by silica gel column chromatography (using a gradient elution of MeOH (0-10%) in DCM). The fractions containing the desired product were combined and evaporated to give 1-benzyl-1H-imidazol-4-carboxaldehyde. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 9.70 (s, 1H), 8.12 (d, 1H), 8.00 (d, 1H), 7.39–7.36 (m, 2H), 7.33 (d, 3H), 5.29 (s, 2H). UPLC-MS-2: Rt = 0.42 min; MS m/z [M+H] ⁺ 187.2.

Step 2: Add 1-benzyl-1H-imidazol-4-carboxaldehyde (Step 1, 521 mg, 2.52 mmol) to an oven-dried flask containing molecular sieve 4A (1 g), followed by a solution of 2-((trimethylsilyl)methoxy)ethyl-1-amine (SLAP M) reagent (Aldrich) (445 mg, 3.02 mmol) in anhydrous DCM (10 ml). Stir the reaction mixture overnight at room temperature under an inert atmosphere. Filter the reaction mixture through a ^Celite® mat and concentrate the filtrate to give crude uncyclized imine as a product. Dissolve the imine in ACN (18 ml) and HFIP (2 ml) and transfer to their respective reaction vessels. 2,4,6-Triphenylpiperonium tetrafluoroborate (200 mg, 0.504 mmol) and TMSOTf (0.546 ml, 3.02 mmol) were added, and the reaction mixture was stirred and irradiated with a blue LED at room temperature for 72 h. Another 2,4,6-triphenylpiperonium tetrafluoroborate (200 mg, 0.504 mmol) and TMSOTf (0.546 ml, 3.02 mmol) were added, and the reaction mixture was stirred and irradiated with a blue LED at room temperature for 24 h. The reaction mixture was concentrated, adsorbed onto an isolute, and purified by reversed-phase column chromatography (using a gradient elution of ACN (10%-100%) in _H₂O + 0.1% HCOOH). The fractions containing the desired product were combined and purified by reversed-phase column chromatography (using a gradient elution of ACN (5%-100%) in _H₂O + 7.3 mM _NH₄OH ). The fractions containing the desired product were combined, frozen, and lyophilized to give 3-(1-benzyl-1H-imidazol-4-yl) α-line. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.65 (d, 1H), 7.35 (tt, 2H), 7.31 - 7.27 (m, 1H), 7.27 - 7.25 (m, 2H), 6.97 (t, 1H), 5.12 (s, 2H), 3.79 (dd, 1H), 3.66 (dd, 2H), 3.36 (dd, 1H), 3.20 - 3.14 (m, 1H), 2.81 - 2.73 (m, 2H). UPLC-MS-1: Rt = 0.54 min; MS m/z [M+H] ⁺ 244.2.

Step 3: Add _Boc₂O (0.185 ml, 0.798 mmol) and _Et₃N (0.221 ml, 1.597 mmol) to a solution of 3-(1-benzyl-1H-imidazol-4-yl)trimoline (Step 2, 200 mg, 0.532 mmol) in DCM (5 ml), and stir the reaction mixture overnight at room temperature. Dilute the reaction mixture with a saturated aqueous solution _{of NaHCO₃} and extract with DCM (2x). Dry and evaporate the combined organic layers using a phase separator. Purify the crude product by silica gel column chromatography (eluting with a gradient of MeOH (0-10%) in DCM). The fractions containing the desired product were combined, evaporated, and purified again by reversed-phase column chromatography (using a gradient elution of ACN (0-100%) in _H₂O + 7.3 mM _NH₄OH ). The fractions containing the desired product were combined, evaporated, and purified again by reversed-phase column chromatography (using a gradient elution of ACN (5%-100%) in _H₂O + 7.3 mM _NH₄OH ). The fractions containing the desired product were combined, frozen, and lyophilized to give tributyl 3-(1-benzyl-1H-imidazol-4-yl)carboxylate-4-carboxylic acid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.69 (d, 1H), 7.35 (tt, 2H), 7.31 - 7.28 (m, 1H), 7.27 - 7.24 (m, 2H), 6.90 (t, 1H), 5.15 (d, 2H), 4.80 (s, 1H), 4.16 (d, 1H), 3.76 - 3.66 (m, 1H), 3.61 - 3.54 (m, 2H), 3.36 (dd, 1H), 3.04 (s, 1H), 1.34 (s, 9H). UPLC-MS-2: Rt = 0.66 min; MS m/z [M+H] ⁺ 344.4.

Step 4: Add a solution of 3-(1-benzyl-1H-imidazol-4-yl)tributyl 3-(1H-imidazol-4-yl)carboxylate (Step 3, 60 mg, 0.157 mmol) in MeOH (1.57 ml) to a vial, then add Pd(OH) _₂ (11.04 mg, 0.016 mmol), and place the resulting reaction mixture in an autoclave and stir overnight at room temperature under _H₂ (10 bar). Filter the reaction mixture through a ^Celite® mat and evaporate the filtrate to give 3-(1H-imidazol-4-yl)carboxylate-4-yl. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.72 (d, 1H), 7.00 (t, 1H), 5.10 - 5.05 (m, 1H), 4.26 (d, 1H), 3.88 (dd, 1H), 3.78 (td, 2H), 3.54 (ddd, 1H), 3.20 (ddd, 1H), 1.48 (s, 9H). UPLC-MS-2: Rt = 0.35 min; MS m/z [M+H] ⁺ 254.3.

Intermediate B-M13 : 3-Hydro-3-(1H-imidazol-4-yl)tetrahydrothiophene 1,1-dioxide

Step 1: At -78°C, n-butyllithium (1.6 M in hexane) (5.673 ml, 9.076 mmol) was added dropwise to a solution of 4-iodo-1-triphenylmethyl-1H-imidazole [CAS No. 96797-15-8] (1800 mg, 4.126 mmol) in THF (42 ml). The reaction mixture was stirred at -78°C for 10 min, and then dihydrothiophene-3(2H)-one [CAS No. 1003-04-9] (506 mg, 4.951 mmol) was added dropwise to THF (42 ml). The reaction mixture was then warmed to room temperature for 1.5 h. The reaction mixture was treated with a saturated aqueous solution of _NaHCO3 and extracted with EtOAc (2x) and washed with brine. The organic phase was dried (using a phase separator) and concentrated under vacuum. The residue was purified by normal-phase chromatography (eluent: cyclohexane/EtOAc 95:5 to 20:80, over 23 min). A second purification was performed using RP-HPLC (eluent: _H₂O /ACN 90:10 to 0:100, over 20 min) to give 3-(1-triphenylmethyl-1H-imidazol-4-yl)tetrahydrothiophene-3-ol. UPLC-MS-2: Rt = 1.18 min; MS m/z [MH] ^- 411.3.

Step 2: Add mCPBA (383 mg, 2.219 mmol) to a solution of 3-(1-triphenylmethyl-1H-imidazol-4-yl)tetrahydrothiophene-3-ol (Step 1, 1089 mg, 41% wt, 1.082 mmol) in DCM (4.2 ml) at -78°C. Stir the reaction at -78°C for 2 h and then allow it to warm to room temperature. After ₂ h, dilute the reaction mixture with DCM and wash with 0.1 M _{Na₂S₂O₃ aqueous} solution and saturated _NaHCO₃ aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal phase chromatography (eluent: cyclohexane/EtOAc 100:0 to 30:70) to give 3-hydroxy-3-(1-triphenylmethyl-1H-imidazol-4-yl)tetrahydrothiophene 1,1-dioxide. UPLC-MS-2: Rt = 1.03 min; MS m/z [M+H] ⁺ 445.2.

Step 3: At room temperature, 3-hydroxy-3-(1-triphenylmethyl-1H-imidazol-4-yl)tetrahydrothiophene 1,1-dioxide (Step 2, 547 mg, 1.23 mmol) was dissolved in DCM (15.4 ml). TFA (0.948 ml, 12.3 mmol) was added to this solution, followed by triethylsilane (0.216 ml, 1.354 mmol). After 2 h at room temperature, _H₂O and DCM were added, and the layers were separated. The organic layer was washed again with _H₂O , and the combined aqueous layer was extracted again with DCM. The aqueous layer was freeze-dried to give 1,1-dioxide of 3-hydroxy-3-(1H-imidazol-4-yl)tetrahydrothiophene as a TFA salt. UPLC-MS-2: Rt = 0.12 min; MS m/z [M+H] ⁺ 203.1.

Intermediate B-M14 : 7-(1H-imidazol-4-yl)-3,9-dioxa-7-azabicyclic[3.3.1]nonane

Step 1: 3,9-dioxa-7-azabicyclo[3.3.1]nonane hydrochloride [CAS No. 1803587-96-3] (207 mg, 58% wt, 0.725 mmol) was added to a mixture of 4-iodo-1-triphenylmethyl-1H-imidazole [CAS No. 96797-15-8] (316 mg, 0.725 mmol), NaOtBu (2 M/THF) (1.45 ml, 2.90 mmol), and Pd-PEPPSI-Ipent (57.4 mg, 0.072 mmol) in DMA (3.2 ml) at room temperature under Ar. After rinsing with Ar, the reaction vial was sealed and warmed to 100°C. One h later, the reaction mixture was diluted with EtOAc and washed with a saturated _NaHCO3 aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure, and the residue was purified by normal phase chromatography (eluent: cyclohexane/EtOAc 100:0 to 0:100, over 16 min) to give 7-(1-triphenylmethyl-1H-imidazol-4-yl)-3,9-dioxa-7-azabicyclo[3.3.1]nonane. UPLC-MS-2: Rt = 1.12 min; MS m/z [M+H] ⁺ 438.3.

Step 2: At room temperature, 7-(1-triphenylmethyl-1H-imidazol-4-yl)-3,9-dioxa-7-azabicyclo[3.3.1]nonane (Step 1, 171 mg, 0.328 mmol) was dissolved in DCM (4 ml). TFA (0.253 ml, 3.28 mmol) was added to the solution, followed by triethylsilane (0.058 ml, 0.361 mmol). After 2 h at room temperature, _H₂O and DCM were added, and the layers were separated. The organic layer was washed again with _H₂O , and the combined aqueous layer was extracted again with DCM. The aqueous layer was freeze-dried to give 7-(1H-imidazol-4-yl)-3,9-dioxa-7-azabicyclo[3.3.1]nonane as a TFA salt. UPLC-MS-2: Rt = 0.13 min; MS m/z [M+H] ⁺ 196.1.

Intermediate B-M15 : Tributyl 2-(1H-imidazol-4-yl)piperidin-1-carboxylic acid

Step 1: At room temperature and under Ar, tributyl 2-acetylopiridine-1-carboxylate (837 mg, 3.68 mmol) was dissolved in THF (8 ml) and then cooled to -78°C. LiHMDS (1 M/THF) (5.15 ml, 5.16 mmol) was added dropwise, and the mixture was stirred at -78°C for 1 h. TMSCl (0.941 ml, 7.36 mmol) was added dropwise, and the reaction mixture was warmed to 0°C for 0.5 h. The mixture was then cooled to -78°C, bromine (0.247 ml, 4.79 mmol) was added, and the mixture was warmed to room temperature and stirred for 35 min. The reaction mixture was quenched with 10 ml of 10% _{Na₂S₂O₃} aqueous solution and 30 ml _of saturated _NH₄Cl aqueous solution and extracted with EtOAc (2x). The combined organic phase was eluted by a separating phase column _, dried, and evaporated to give a residue, which was purified by normal phase chromatography (eluent: cyclohexane/EtOAc 100:0 to 60:40, over 16 min) to give tributyl 2-(2-bromoacetylated)piperidine-1-carboxylic acid. UPLC-MS-2: Rt = 1.07 min; MS m/z [M+H] ⁺ 206.1/208.1 (-Boc).

Step 2: 2-(2-bromoacetylated)piperidin-1-carboxylic acid tributyl ester (Step 1, 721 mg, 2.355 mmol) and formamidine acetate (1226 mg, 11.77 mmol) were dissolved in ethylene glycol (4.7 ml), and the mixture was heated to 130°C for 1 h. _H₂O was added to the reaction mixture, and the mixture was extracted with EtOAc (2x). The combined organic phase was eluted by a separating phase column, dried, and then evaporated to give 2-(1H-imidazol-4-yl)piperidin-1-carboxylic acid tributyl ester. UPLC-MS-2: Rt = 0.53 min; MS m/z [M+H] ⁺ 252.2.

Intermediate B-M16 : 1-((1-benzyl-1H-imidazol-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole

_Cs₂CO₃ (5.04 g, 15.46 mmol) and 1-benzyl-2-(chloromethyl)-1H-imidazolium (CAS No. 269410-08-4) (1 g, 5.15 mmol) were added to a solution of _4- (4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-imidazolium (CAS No. 19276-03-0) (1.879 g, 7.73 mmol) in 20 ml of ACN. The reaction mixture was stirred at 80°C for 18 h. The reaction mixture was diluted with DCM and then washed with 20 ml of _H₂O . The organic phase was dried (phase separator) and concentrated under vacuum. The residue was purified by normal-phase chromatography (elution buffer: cyclohexane/EtOAc 100:0 to 60:40, over 35 min) to give 1-((1-benzyl-1H-imidazol-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole. UPLC-MS-2: Rt = 0.79 min; MS m/z [M+H] ⁺ 365.3.

Intermediate B-M17 : Tributyl 4,4-difluoro-2-(1H-imidazol-4-yl)-2-methylpyrrolidone-1-carboxylic acid

Step 1: Under argon atmosphere, tributyl 4,4-difluoro-2-(hydroxymethyl)-2-methylpyrrolidone-1-carboxylate [CAS No. 1823389-65-6] (900.0 mg, 1 equivalent, 3.582 mmol) was dissolved in 30 ml DCM and cooled to 0°C. Des-Martin oxidant (1.823 g, 1.2 equivalent, 4.298 mmol) was added to the mixture. The ice bath was removed, and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with DCM and washed with a saturated _NaHCO3 aqueous solution (2x). The aqueous layer was extracted with DCM. The combined organic layers were filtered, dried, and concentrated in a vacuum to give a light gray solid containing tributyl 4,4-difluoro-2-methoxy-2-methylpyrrolidone-1-carboxylate. 1H NMR (600 MHz, DMSO) δ 9.42 (s, 1H), 8.13 - 8.05 (m, 1H), 8.05 - 7.98 (m, 1H), 7.87 (dd, J = 8.3, 0.9 Hz, 1H), 7.81 - 7.75 (m, 1H), 3.97 - 3.80 (m, 2H), 2.68 (ddt, J = 44.2, 22.3, 13.1 Hz, 1H), 2.41 - 2.28 (m, 1H), 2.26 (s, 3H), 1.50 - 1.36 (m, 9H), 1.34 (s, 5H). A 5:6 mixture of the desired product and a byproduct of the Des-Martin reagent. Estimated purity 45%. Provisionally interpreted UPLC-MS and 1H NMR data support the proposed structural designation of tributyl 4,4-difluoro-2-methoxy-2-methylpyrrolidone-1-carboxylate (2.000 g, 3.6 mmol, 100%, 45% purity).

Step 2: At room temperature under argon, tributyl 4,4-difluoro-2-methoxy-2-methylpyrrolidone-1-carboxylate (Step 1, approx. 2 g, 45%, 1 equivalent, 3.791 mmol) was dissolved in THF (35 ml). 2-Methylpropane-2-sulfinamide (643.3 mg, 1.4 equivalent, 5.308 mmol) and ethyl titanium oxide (2.594 g, 2.367 ml, 3.0 equivalent, 11.37 mmol) were added to the mixture, which was stirred at room temperature for 3 days. The reaction mixture was then quenched with _H₂O and diluted with EtOAc to obtain a slurry. After stirring at room temperature for 30 min, the mixture was extracted with EtOAc (2x). The combined organic phase was washed with brine, dried in a filter, and concentrated under vacuum to give tributyl (E)-2-(((tributylsulfinyl)imino)methyl)-4,4-difluoro-2-methylpyrrolidone-1-carboxylate. UPLC-MS-8: Rt = 1.24/1.26 min; MS m/z [M-Boc+H] ⁺ = 253.2 (bimodal indicates nonmirror isomer).

Step 3: Add K₂CO₃ (1.470 g, 2.5 equivalents, 10.64 mmol) and TosMIC (830.9 mg, 1 equivalent, 4.256 mmol) to a solution of (E)-2-(((tri-butylsulfinyl)imino)methyl)-4,4-difluoro- ₂ -methylpyrrolidone-1-carboxylic acid tributyl ester (Step ₂ , 1.500 g, 1 equivalent, 4.256 mmol) in MeOH (30.00 mL). Stir the mixture at room temperature for 18 hours. The mixture was then concentrated under vacuum, and the residue containing tributyl 4,4-difluoro-2-(1H-imidazol-4-yl)-2-methylpyrrolidone-1-carboxylate and 4-methylbenzenesulfinic acid was used directly in the next step without further purification. UPLC-MS-8: Rt = 0.49 - 0.58 min (broad peak); MS m/z [M+H] ⁺ = 288.2.

Intermediate B-M18 : (S)-4,4-difluoro-2-(1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester

Step 1: (S)-4,4-difluoropyrrolidone-1,2-dicarboxylic acid 1-(tributyl)-2-methyl ester [CAS No. 21149-99-5] (5.100 g, 1 equivalent, 19.23 mmol) was dissolved in ammonia (7 N/MeOH) (39.4 g, 50 ml). The solution was stirred at 56°C for 18 h (gentle reflux). More ammonia (7 N/MeOH) (39.4 g, 50 ml) was added and stirring was continued at 56°C for 3 days. The reaction mixture was then concentrated under vacuum to give tributyl (S)-2-aminomethylformyl-4,4-difluoropyrrolidone-1-carboxylic acid. UPLC-MS-8: Rt = 0.55 min; MS m/z [M-Boc+H] ⁺ = 151.1.

Step 2: At room temperature, 1,1-dimethoxy-N,N-dimethylmethylamine (4.590 g, 5.12 ml, 2 equivalents, 38.52 mmol) was added to a stirred suspension of (S)-2-aminomethoxy-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (Step 1, 4.820 g, 1 equivalent, 19.26 mmol) in 75 ml toluene, and the reaction mixture was heated to 100°C. The suspension was stirred at 100°C for 18 h. Afterward, the reaction mixture was concentrated under vacuum and dried at HV. The residue was dissolved in HOAc (75 ml), followed by the slow addition of hydrazine monohydrate (2.469 g, 2.418 ml, 50% wt, 2 equivalents, 38.52 mmol) at room temperature (exothermic reaction). The mixture was stirred at 90°C for 45 min and maintained at room temperature for 16 h. The reaction mixture was then poured onto ice/ _H₂O and extracted with EtOAc (3x). The combined organic layer was washed with saturated _NaHCO₃ (3x) and brine, dried ( _Na₂SO₄ ), and concentrated under _vacuum . Co-evaporation with toluene (3x) was performed to completely remove HOAc. (S)-4,4-difluoro-2-(1H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylic acid tributyl ester was thus obtained. UPLC-MS-8: Rt 0.63 min; MS m/z [MH] ^- = 273.1.

Intermediate B-M19 : 2,2,2-trifluoro-1-(1H-imidazol-4-yl)ethyl-1-one

Step 1: Suspend 1H-imidazole (2.094 g, 4 equivalents, 30.75 mmol) in a 12 ml microwave-safe vial of 2,2,2-trifluoro-1-methoxyethanol-1-ol (1000 mg, 1 equivalent, 7.688 mmol) and cap. Stir the reaction mixture in a heating block at 150°C for 3 h and then cool to room temperature. Transfer the reaction mixture to a flask, wash with MeOH, and then concentrate under vacuum to give a crude product, which is purified on silicone (TBME/EtOH) to give 2,2,2-trifluoro-1-(1H-imidazol-4-yl)ethanol-1-ol, which is used in the next step in a mixture of approximately 1:2 with imidazole.

Step 2: Dissolve 2,2,2-trifluoro-1-(1H-imidazol-4-yl)ethanol-1-ol (Step 1, 2.3 g, 33% wt, 1 equivalent, 4.6 mmol) in 50 ml DCM. Add _NaHCO3 (1.5 g, 4 equivalent, 18 mmol) and DMP (6.8 g, 3.5 equivalent, 16 mmol). Stir the reaction mixture at room temperature for 1 h. Then add _H2O and stir the resulting mixture for 30 min to give precipitate. Add saturated _NaHCO3 solution to adjust the pH of the mixture to 8. Extract the mixture with DCM (3x). The combined organic phases were washed with _H₂O and brine, _dried ( _Na₂SO₄ ), and concentrated under vacuum to give a crude product, which was then purified on silica gel (TBME/EtOH) to give 2,2,2-trifluoro-1-(1H-imidazol-4-yl)ethyl-1-one. UPLC-MS: Rt = 0.38 min; MS m/z [M+H] ^⁺ = 165.0.

Intermediate B-M20 : (1-Side-oxy-2-(1H-1,2,4-triazol-3-yl)tetrahydro- ^1λ6 -thiophene-1-ylidene)benzyl aminocarbamate

Step 1: At room temperature and under argon, add phenyl-λ3-iodoalkyl diacetate (12.10 g, 1.5 equivalent, 37.55 mmol) to a slurry of tetrahydrothiophene 1-oxide (2608 mg, 1 equivalent, 25.04 mmol), benzyl carbamate (5.677 g, 1.5 equivalent, 37.55 mmol), magnesium oxide ( ^4.04 g, 4.0 equivalent, 100.1 mmol), and rhodium(II) acetate dimer (553.3 mg, 0.05 equivalent, 1.252 mmol) in 200 ml DCM to form a slurry. Continue stirring overnight at 40°C. Then cool the reaction mixture to room temperature and dilute with DCM. _H₂O and a saturated aqueous solution of _NaHCO₃ were added, and the mixture was extracted with DCM (3x). The combined organic phase was dried over a SPE column and concentrated under vacuum. The residue was purified on silica gel (cyclohexane/TBME/EtOH) to give benzyl (1-sideoxytetrahydro- ^1λ6 -thiophene-1-yl)aminocarbamate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.30 - 7.39 (m, 5H), 5.03 (s, 2H), 3.50 - 3.56 (m, 2H), 3.33 - 3.37 (m, 1H), 2.16 - 2.22 (m, 2H), 2.05 - 2.12 (m, 2H). UPLC-MS-8: Rt = 0.63 min; MS m/z [M+H] ⁺ = 254.

Step 2: Dissolve (1-sideoxytetrahydro- ^1λ6 -thiophene-1-yl)aminobenzyl carbamate (Step 1, 3.000 g, 1 equivalent, 11.84 mmol) in anhydrous ABS. Place 100.0 ml of THF under argon at room temperature and cool to -78°C. Slowly add bis(trimethylsilyl)aminolithium (3.765 g, 22.50 ml, 1.000 mol, 1.9 equivalent, 22.50 mmol) to 5 ml of THF at -78°C and continue stirring at -78°C for 40 min. Then, methyl chloroformate (1.790 g, 1.6 equivalents, 18.95 mmol, dissolved in THF) was added dropwise to the reaction mixture over 5 min while maintaining the temperature below -70°C. The resulting solution was stirred at -78°C for 30 min. Subsequently, the mixture was warmed to room temperature, followed by the addition of _H₂O and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried in a phase separator, and concentrated under vacuum. The residue was purified on silicone (cyclohexane/TBME/EtOH) to give 1-(((benzyloxy)carbonyl)imino)tetrahydro-1H- ^1λ6 -thiophene-2-carboxylate 1-oxide. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.43–7.28 (m, 5H), 5.06 (s, 1H), 5.05–4.95 (m, 1H), 4.67–4.41 (m, 1H), 3.82–3.64 (m, 4H), 3.64–3.36 (m, 1H), 2.47–2.13 (m, 3H), 2.12–2.00 (m, 1H). UPLC-MS-8: Rt = 0.63 min; MS m/z [M+H] ⁺ = 312.

Step 3: Methyl 1-(((benzyloxy)carbonyl)imino)tetrahydro-1H- ^1λ6 -thiophene-2-carboxylate 1-oxide (Step 2, 1.86 g, 90% wt, 1 equivalent, 5.3850 mmol) was absorbed in approximately 22 ml of ammonia (7 M/MeOH) and transferred to a 20 ml microwave-safe vial and stirred overnight at 60°C. The reaction mixture was then concentrated under vacuum to give (2-aminomethoxy-1-sideoxytetrahydro- ^1λ6 -thiophene-1-yl)aminobenzyl carboxylate. UPLC-MS-8: Rt = 0.41/0.48 min (two peaks, attributed to a nonmirror isomer mixture); MS m/z [M+H] ⁺ = 297.

Step 4: Benzyl (2-aminomethoxy- ¹ -sideoxytetrahydro-1λ6-thiophene-1-yl)carbamate (Step 3, 1.5462 g, 1 equivalent, 5.2177 mmol) was dissolved in 25 mL of toluene, and 1,1-dimethoxy-N,N-dimethylmethylamine (1.2435 g, 1.39 mL, 2 equivalents, 10.435 mmol) was added to the mixture, which was then stirred at 100°C for 2 h. The mixture was then concentrated under vacuum, and the residue was diluted with 25 mL of HOAc and treated with hydrazine hydrate (522.4 mg, 508.2 μl, 2 equivalents, 10.435 mmol). The mixture was heated to 90°C and stirred for 1 h. Ice/ _H₂O was then added to the reaction mixture at room temperature, followed by extraction with EtOAc (3x). The combined organic layer was dried in a phase separator and concentrated under vacuum to give (1-sideoxy-2-(1H-1,2,4-triazol-3-yl)tetrahydro- ^1λ6 -thiophene-1-ylidene)aminocarbamate. UPLC-MS-8: Rt = 0.42/0.48 min (two peaks, attributed to a non-mirror isomer mixture); MS m/z [M+H] ^⁺ = 321.0.

The following intermediates are prepared from commercially available intermediates or those obtained by the methods described herein using methods similar to those used in the synthesis of intermediates B-M1 to B-M20. intermediate Structure method Characteristic data B-T1 3-(1H-imidazol-4-yl)-3-methylphosphono-4-carboxylic acid tributyl ester Similar to intermediate B-M5, step 1 uses tributyl 3-methoxy-3-methylphosphono-4-carboxylate and 2-methylpropane-2-sulfinamide, and step 2 uses TosMIC and NaH in MeOH/DME (1/1) at 60°C. UPLC-MS-8: Rt 0.35 min; MS m/z [M+H] ⁺ 268.1. B-T2 2-(1H-imidazol-4-yl)tributyl 2-(1H-imidazol-4-yl)-O-lin-4-carboxylic acid Similar to intermediate B-M7, step 1 uses tributyl 3-methoxy-3-methylphosphono-4-carboxylate and 2-methylpropane-2-sulfinamide, and step 2 uses TosMIC and NaH in MeOH/DME (1/1) at 60°C. UPLC-MS-2: Rt 0.37 min; MS m/z [M+H] ⁺ 254.1. B-T3 3-(1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M6, step 1 uses 1-Boc-3-pyrrolidinecarboxaldehyde and 2-methylpropane-2-sulfinamide. UPLC-MS-2: Rt 0.42 min; MS m/z [M+H] ⁺ 238.2. B-T4 (2-(1H-1,2,4-triazol-3-yl)propyl-2-yl)aminocarbamate tributyl ester Similar to intermediate B-M2, it uses 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid. UPLC-MS-8: Rt 0.48 min; MS m/z [M+H] ⁺ 227.1. B-T5 4-(tetrahydrothiophene-2-yl)-1H-imidazole Similar to intermediate B-M5, step 1 uses tetrahydrothiophene-2-carboxaldehyde and 2-methylpropane-2-sulfinamide. UPLC-MS-2: Rt 0.17 min; MS m/z [M+H] ⁺ 155.0. B-T6 4-(tetrahydrothiophene-3-yl)-1H-imidazole Similar to intermediate B-M5, step 1 uses tetrahydrothiophene-3-carboxaldehyde and 2-methylpropane-2-sulfinamide. UPLC-MS-2: Rt 0.17 min; MS m/z [M+H] ⁺ 155.0. B-T7 5-(1H-imidazol-4-yl)-1-methylpyrrolidone-2-one Similar to intermediate B-M5, it uses 1-methyl-5-sideoxypyrrolidone-2-carboxaldehyde. UPLC-MS-2: Rt 0.12 min; MS m/z [M+H] ⁺ 166.0. B-T8 4-(2-(methylthio)propyl-2-yl)-1H-imidazolium Similar to intermediate B-M5, it uses 1-2-methyl-2-(methylthio)propanal. UPLC-MS-2: Rt 0.33 min; MS m/z [M+H] ⁺ 157.0. B-T9 4-(2-((tri-butyldimethylsilyl)oxy)cyclopentyl)-1H-imidazolium Similar to intermediate B-M5, it uses 2-((tri-butyldimethylsilyl)oxy)cyclopentane-1-carboxaldehyde (cis/trans mixture) [CAS No. 1243165-08-3] / [CAS No. 2170216-54-1] UPLC-MS-8: Rt 0.97 min; MS m/z [M+H] ⁺ 267.1. B-T10 (S)-5,5-difluoro-2-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid tributyl ester Similar to intermediate B-M2, it uses 1-(tertiary butoxycarbonyl)-5,5-difluoropiperidine-2-carboxylic acid [CAS No. 1255663-95-6]. UPLC-MS-8: Rt 0.87 min; MS m/z [MH] ^- 287.2. B-T11 (3,3-Difluoro-1-(1H-imidazol-4-yl)cyclobutyl)aminocarbamate tributyl ester Similar to intermediate B-M5, it uses tributyl (3,3-difluoro-1-methoxycyclobutyl)aminoformate [CAS No. 1232365-43-3]. UPLC-MS-2: Rt 0.36 min; MS m/z [M+H] ⁺ 274.0. B-T12 Tributyl 4,4-difluoro-2-(1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid Similar to intermediate B-M5, it uses (S)-4,4-difluoro-2-methylpyrrolidone-1-carboxylic acid tributyl ester [CAS No. 1194032-45-5]. UPLC-MS-8: Rt 0.44 min; MS m/z [M+H] ⁺ 274.0. B-T13 3-((tri-butyldimethylsilyl)oxy)-2-(1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M5, it uses (2S,3R)-3-((tri-butyldimethylsilyl)oxy)-2-methylpyrrolidone-1-carboxylic acid tributyl ester [CAS No. 627531-58-2]. UPLC-MS-8: Rt 1.00 min; MS m/z [M+H] ⁺ 368.2. B-T14 4-(1H-imidazol-4-yl)tetrahydro-2H-piperan-4-ol Similar to steps 1 and 3 of intermediate B-M13, 4-iodo-1-triphenylmethyl-1H-imidazole [CAS No. 96797-15-8] and tetrahydro-4H-piperan-4-one [CAS No. 29943-42-8]. UPLC-MS-2: Rt 0.13 min; MS m/z [M+H] ⁺ 169.2. As a TFA salt B-T15 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)methyl) acetazole Similar to intermediate B-M16, it uses 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentane-2-yl)-1H-pyrazole [CAS No. 269410-08-4] and 2-(chloromethyl) pyrazole [CAS No. 185246-17-7]. UPLC-MS-8: Rt 0.70 min; MS m/z [M+H] ⁺ 276.3. B-T16 (3-(1H-imidazol-4-yl)oxacyclobutane-3-yl)tributylaminoformate Similar to intermediate B-M5, it uses tributyl (3-methoxycyclobutane-3-yl)aminoformate [CAS No. 885669-84-1]. UPLC-MS-8: Rt 0.23 min; MS m/z [M+H] ⁺ 240.2. B-T17 2-(1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M10, it uses tributyl 2-methylpyrrolidone-1-carboxylate. UPLC-MS-2: Rt 0.71 min; MS m/z [M+H] ⁺ 238.3. B-T18 2-(1H-imidazol-4-yl)-2-methylpyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M5, it uses tributyl 2-methoxy-2-methylpyrrolidone-1-carboxylate [CAS No. 946484-82-8]. UPLC-MS-8: Rt 0.38 min; MS m/z [M+H] ⁺ 252.2 B-T19 4-(tetrahydrofuran-2-yl)-1H-imidazole Similar to intermediate B-M10, tetrahydrofuran-2-carbaldehyde is used. UPLC-MS-2: Rt 0.28 min; MS m/z [M+H] ⁺ 139.1 B-T20 2-Methyl-2-(1H-1,2,4-triazol-3-yl)tetrahydrothiophene 1,1-dioxide Similar to intermediate B-M2, it uses 1,1-dioxide of 2-methyltetrahydrothiophene-2-carboxylic acid [CAS No. 18458-95-2]. UPLC-MS-2: Rt 0.13-0.17 min; MS m/z [M+H] ⁺ 202.2 B-T21 3-(1H-1,2,4-triazol-3-yl)tributyl 4-carboxylate Similar to intermediate B-M2, it uses 4-(tertiary butoxycarbonyl)oline-3-carboxylic acid [CAS No. 212650-43-6]. UPLC-MS-8: Rt 0.54 min; MS m/z [M+H] ⁺ 255.2 B-T22 (3,3-Difluoro-1-(1H-1,2,4-triazol-3-yl)cyclobutyl)aminocarbamate tributyl ester Similar to intermediate B-M2, it uses 1-((tertiary butoxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid [CAS No. 1363380-83-9]. UPLC-MS-8: Rt 0.63 min; MS m/z [M+H] ⁺ 275.1 B-T23 3-Methyl-3-(1H-1,2,4-triazol-3-yl)tributyl-4-carboxylate Similar to the intermediate B-M2, it uses N-Boc-3-methylphosphono-3-carboxylic acid [CAS No. 1052680-53-1]. UPLC-MS-8: Rt 0.50 min; MS m/z [M+H] ⁺ 269.3 B-T24 3,3-Difluoro-2-(1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M2, it uses 1-(tertiary butoxycarbonyl)-3,3-difluoropyrrolidone-2-carboxylic acid [CAS No. 1822567-84-9]. UPLC-MS-8: Rt 0.62 min; MS m/z [M+H] ⁺ 275.1 B-T25 (S)-4,4-difluoro-2-methyl-2-(1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M2, (S)-1-(tertiary butoxycarbonyl)-4,4-difluoro-2-methylpyrrolidone-2-carboxylic acid [CAS No. 1194032-23-9] is used. UPLC-MS-8: Rt 0.73 min; MS m/z [MH] ^- 287.1 B-T26 4,4-Difluoro-2-(1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate B-M2, 4,4-difluoro-1-Boc-2-pyrrolidone carboxylic acid [CAS No. 1000313-01-8] is used. UPLC-MS-8: Rt 0.63 min; MS m/z [M+H] ⁺ 275.1 B-T27 3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentane-2-yl)-1H-pyrazol-1-yl)propyl-2-yl)-1H-1,2,4-triazole Similar to intermediate B-M2/step 2, 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)propionic acid [CAS No. 1282518-81-3] is used. HPLC-MS: Rt 1.99 min; MS m/z [M+H] ⁺ 304.3 B-T28 2-(1H-imidazol-4-yl)thiocarbamate-4-carboxylic acid tributyl ester Similar to intermediate B-M9, the corresponding N-methoxy-N-methyl-methylamine is prepared using 4-(tert-butoxycarbonyl)thiocarbamate-2-carboxylic acid [CAS No. 134676-67-8] first following the procedure described in WO 2014/23258. UPLC-MS-8: Rt 0.39 min; MS m/z [M+H] ⁺ 270 B-T29 3-(1H-imidazol-4-yl)thiocarbamate-4-carboxylic acid tributyl ester Similar to intermediate B-M9, the corresponding N-methoxy-N-methyl-methylamine is prepared using 4-(tert-butoxycarbonyl)thiocarboxylin-3-carboxylic acid [CAS No. 128453-98-5] first following the procedure described in WO 2014/23258. UPLC-MS-2: Rt 0.37 min; MS m/z [M+H] ⁺ 270.1 B-T30 (1R,3S,5R)-3-(1H-imidazol-4-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tributyl ester Similar to intermediate B-M9, the corresponding N-methoxy-N-methyl-methylamine is prepared using (1R,3S,5R)-2-(tertiary butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid [CAS No. 197142-34-0] first following the procedure described in WO 2014/23258. UPLC-MS-2: Rt 0.37 min; MS m/z [M+H] ⁺ 250.3 B-T31 Tributyl 6-(1H-imidazol-4-yl)-5-azaspiro[2,4]heptane-5-carboxylic acid Similar to intermediate B-M5, tributyl (S)-6-methoxy-5-azaspiro[2,4]heptane-5-carboxylate [CAS No. 1262397-14-7] is used. UPLC-MS-2: Rt 0.47 min; MS m/z [M+H] ⁺ 264.2 B-T32 (1S,3R,4R)-3-(1H-imidazol-4-yl)-2-azabicyclic[2.2.1]heptan-2-carboxylic acid tributyl ester Similar to intermediate B-M9, the corresponding N-methoxy-N-methyl-methylamine is prepared using (1S,3R,4R)-2-[(tertiary butoxy)carbonyl]-2-azabicyclic [2.2.1]heptane-3-carboxylic acid [CAS No. 291775-53-6] first following the procedure described in WO 2014/23258. UPLC-MS-2: Rt 0.45 min; MS m/z [M+H] ⁺ 264.3 B-T33 (1R,3S,4S)-3-(1H-imidazol-4-yl)-2-azabicyclic[2.2.1]heptan-2-carboxylic acid tributyl ester Similar to intermediate B-M9, the corresponding N-methoxy-N-methyl-methylamine is prepared using (1R,3S,4S)-2-[(tertiary butoxy)carbonyl]-2-azabicyclic [2.2.1]heptane-3-carboxylic acid [CAS No. 291775-59-2] first following the procedure described in WO 2014/23258. UPLC-MS-2: Rt 0.49 min; MS m/z [M+H] ⁺ 264.3 B-T34 1-Methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentane-2-yl)-1H-pyrazol-1-yl)methyl)-1H-tetrazole Similar to intermediate B-M16, it uses 5-(chloromethyl)-1-methyl-1H-tetrazole [CAS No. 57235-84-4]. UPLC-MS-2: Rt 0.59 min; MS m/z [M+H] ⁺ 291.1 B-T35 2-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentan-2-yl)-1H-pyrazol-1-yl)methyl propionate Similar to intermediate B-M16, methyl 2-bromo-2-methylpropionate [CAS No. 23426-63-3] is used. HPLC-MS-9: Rt 1.42 min; MS m/z [M+H] ⁺ 295.4 B-T36 2-(1H-imidazol-4-yl)-2-methylazacyclobutane-1-carboxylic acid tributyl ester Similar to intermediate B-M9, 1-(tert-butoxycarbonyl)-2-methylazacyclobutane-2-carboxylic acid [CAS No. 449758-77-4] is used first, following the procedure described in WO 2014/23258, to prepare the corresponding N-methoxy-N-methylmethylamine. UPLC-MS-8: Rt 0.38 min; MS m/z [M+H] ⁺ 238.2 B-T37 Dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)methyl)phosphine oxide Similar to intermediate B-M16, (chloromethyl)dimethylphosphine oxide [CAS No. 1638-75-1] and _K₂CO₃ are used in DMF _. UPLC-MS-2: Rt 0.57 min; MS m/z [M+H] ⁺ 285.2 B-T38 (3-((1H-imidazol-4-yl)methyl)oxocyclobutane-3-yl)benzyl aminocarbamate Similar to intermediate B-M10, the corresponding aldehyde was prepared using ethyl acetate 2-(3-(((benzyloxy)carbonyl)amino)oxadiazon-3-yl)ethyl acetate [CAS No. 1207175-05-0], first using DIBAL-H/DCM/-78°C. UPLC-MS-2: Rt 0.25 min; MS m/z [M+H] ⁺ 288.2 B-T39 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-carboxylic acid tributyl ester Similar to intermediate B-M8, it uses tributyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate [CAS No. 1147557-97-8]. HPLC-MS-7: Rt 1.58 min; MS m/z [M+H] ⁺ 390.1 B-T40 1-(2-oxospiro[3.3]hept-6-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronocyclopentane-2-yl)-1H-pyrazole Similar to intermediate B-M8, it uses 2-oxazaspiro[3.3]hepta-6-ol [CAS No. 1363381-08-1] and TsCl HPLC-MS-7: Rt 1.46 min; MS m/z [M+H] ⁺ 290.8 B-T41 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)piperidin-2-one Similar to intermediate B-M4, it uses 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole [CAS No. 269410-08-4] and 4-hydroxypiperidin-2-one [CAS No. 476014-76-3] HPLC-MS-4: Rt 0.80 min; MS m/z [M+H] ⁺ 292.3 B-T42 2,2-Dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester Similar to intermediate B-M4, it uses 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 269410-08-4] and tributyl 4-hydroxy-2,2-dimethylpiperidin-1-carboxylate [CAS No. 1502162-73-3]. HPLC-MS-4: Rt 1.06 min; MS m/z [M+H] ⁺ 406.4 B-T43 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)piperidin-2-one Similar to intermediate B-M4, it uses 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole [CAS No. 269410-08-4] and 5-hydroxypiperidin-2-one [CAS No. 19365-07-2] HPLC-MS-4: Rt 0.79 min; MS m/z [M+H] ⁺ 292.3 B-T44 4-Hydroxyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylic acid tributyl ester Similar to intermediate B-M3/step 1, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-1H-pyrazole [CAS No. 269410-08-4] and 1-oxa-6-azaspiro[2,5]octane-6-carboxylic acid tributyl ester [CAS No. 147804-30-6] with NaH/DMF HPLC-MS-4: Rt 0.95 min; MS m/z [M+H] ⁺ 408.3 B-T45 1-Methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboroniumcyclopentane-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine Similar to intermediate B-M16, it uses 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 269410-08-4] and 1-(2-chloroethyl)-4-methylpiperazine [CAS No. 39123-20-1] HPLC-MS: Rt 1.84 min; MS m/z [M+H] ⁺ 321.2

C -M1 intermediate : 5-fluoro-6-(4-(2 - methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-amine

Step 1: At 15°C, 31 g (193.9 mmol) of 2,3-difluoro-5-nitropyridine [CAS No. 954219-68-2] and 75.1 g (581.7 mmol) of DIPEA were added to a solution of intermediate B-M1 (34.2 g, 193.9 mmol) in ACN (684 ml). After stirring for 1 h, the reaction mixture was diluted with EtOAc and washed with brine. The organic phase was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was ground with 1:5 TBME/heptane to give 3-fluoro-2-(4-(2-methyltetrahydrothiophene _- 2-yl)-1H-imidazol-1-yl)-5-nitropyridine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.20 (d, 1H), 8.96 (dd, 1H), 8.42 (m, 1H), 7.73 (t, 1H), 3.00 (dd, 2H), 2.40 (dt, 1H), 2.09 (td, 2H), 1.92 (m, 1H), 1.72 (s, 3H).

Step 2: At 15°C, zinc powder (54.2 g, 829.5 mmol) and _NH₄Cl (44.4 g, 829.5 mmol) were added to a solution of 3-fluoro-2-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)-5-nitropyridine (Step 1, 53 g, 165.9 mmol) in a 5:1 MeOH/ _H₂O (318 ml) solution. After stirring for 16 h, the reaction mixture was diluted with MeOH and filtered. The filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc, and the mixture was washed with _H₂O and brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was ground with 1:5 TBME/heptane to give 5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridine-3-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.94 (t, 1H), 7.67 (dd, 1H), 7.37 (t, 1H), 6.98 (dd, 1H), 5.87 (s, 2H), 2.96 (t, 2H), 2.38 (m, 1H), 2.08 (m, 2H), 1.84 (m, 1H), 1.69 (s, 3H).

Intermediate C-M2 : 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropiperidine-1-carboxylic acid tributyl ester

Step 1: At room temperature, a solution of 2,3-difluoro-5-nitropyridine [CAS No. 954219-68-2] (610.8 mg, 3.815 mmol) in ACN (5 ml) was added to a solution of intermediate B-M2 (1.1 g, 3.815 mmol) and DIPEA (1.99 ml, 11.45 mmol) in ACN (30 ml). After stirring for 1 week, the reaction mixture was diluted with EtOAc and washed with _H2O , saturated _NH4Cl aqueous solution and saturated _NaHCO3 aqueous solution. The organic layer was dried (in a phase separator) and concentrated under reduced pressure. The residue was purified by normal phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 53:47) to give tert-butyl 4,4-difluoro-2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 9.25 (d, 1H), 9.01 (dd, 1H), 5.62 (br s, 1H), 4.14 (m, 1H), 2.73 (m, 1H), 2.51 (m, 1H), 1.96-2.09 (m, 2H), 1.39 (br s, 9H). UPLC-MS-8: Rt = 1.06 min; MS m/z [M+Na] ⁺ 451.2.

Step 2: A mixture of 4,4-difluoro-2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-1,2,4-triazol-3-yl)piperidin-1-carboxylic acid tributyl ester (Step 1, 280 mg, 0.654 mmol) and Pd/C (34.8 mg) in MeOH (15 ml) was stirred at room temperature under 1 atm hydrogen. After 2 h, the reaction mixture was filtered through ^Celite® and the filtrate was concentrated under reduced pressure to give 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropiperidin-1-carboxylic acid tributyl ester, which was used without further purification. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 7.70 (d, 1H), 6.98 (dd, 1H), 6.13 (s, 2H), 5.54 (br s, 1H), 4.06-4.13 (m, 2H), 2.69 (m, 1H), 2.42 (m, 1H), 1.91-2.05 (m, 2H), 1.37 (br s, 9H). UPLC-MS-8: Rt = 0.85 min; MS m/z [M+H] ⁺ 399.1.

Intermediate C-M3 : 5-amino-3-fluoro-2-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)benzonitrile

Step 1: Under nitrogen atmosphere and at room temperature, NBS (13.07 g, 73.5 mmol) was added to a solution of 10 g, 73.5 mmol, of 3-amino-5-fluorobenzonitrile [CAS No. 210992-28-2] in DMF (100 ml). After 1 h, the reaction mixture was poured into ice/ _H₂O , and the resulting solid was filtered and dried under vacuum to give 5-amino-2-bromo-3-fluorobenzonitrile. HPLC-MS-9: Rt 1.27 min; MS m/z [MH] ^- 213.2/215.2.

Step 2: Add 2 M _{Na₂CO₃ aqueous} solution (0.581 ml, 1.163 mmol) to 1-(tetrahydro-2H-piperan-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 1040377-03-4] (380 mg, 1.366 mmol), 5-amino-2-bromo-3-fluorobenzonitrile (Step 1, 250 mg, 1.163 mmol), and _PdCl₂ (dppf).DCM (95 mg, 0.116 mmol) in a suspension in DME (6 ml). After degassing with Ar for 5 min, seal the reaction vial and warm to 120°C. After 15 min, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with _H₂O and brine. The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure, and the residue was purified by normal-phase chromatography (eluent: DCM/(MeOH + ₂ % v/v 7 M _NH₃ /MeOH) 99:1 to 90:10) to give 5-amino-3-fluoro-2-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)benzonitrile. UPLC-MS-2: Rt = 0.55 min; MS m/z [M+H] ⁺ 287.2.

Intermediate C-M4 : (2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)prop-2-yl)tributyl carbamate

Step 1: At room temperature, 2,3-difluoro-5-nitropyridine [CAS No. 954219-68-2] (882.9 mg, 5.516 mmol) and DIPEA (2.88 ml, 16.55 mmol) were added to a solution of intermediate B-M6 (2.18 g, 5.516 mmol) in ACN (20 ml). After stirring for 6 h, the reaction mixture was diluted with EtOAc and washed with saturated _NaHCO3 aqueous solution. The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 1:0 ₎ to give tributyl (2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)prop-2-yl)aminocarbamate. UPLC-MS-2: Rt = 0.99 min; MS m/z [M+H] ⁺ 366.2.

Step 2: At room temperature, zinc (5.712 g, 87.36 mmol) and _NH₄Cl (4.673 g, 87.36 mmol) were added to a mixture of (2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)prop-2-yl)aminocarbamate tributyl ester (Step 1, 798 mg, 2.184 mmol) in MeOH (24 ml) and _H₂O (8 ml). After 30 min, the reaction mixture was diluted with 1:1 DCM/MeOH and filtered through ^Hyflo® . The filtrate was concentrated under reduced pressure. The residue was diluted with DCM and washed with _H₂O (2x). The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give _tributyl (2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)propyl-2-yl)aminocarbamate, which was used directly without purification. ^¹H NMR (600 MHz, DMSO- _d₃ ) δ 7.93 (s, 1H), 7.68 (m, 1H), 7.25 (s, 1H), 7.00 (dd, 1H), 6.72 (br s, 1H), 5.88 (s, 2H), 1.51 (s, 6H), 1.29–1.39 (m, 9H). UPLC-MS-2: Rt = 0.63 min; MS m/z [M+H] ⁺ 336.2.

Intermediate C-M5 : 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)tributyl 2-oxo-2-carboxylate

Step 1: Add 2,3-difluoro-5-nitropyridine [CAS No. 954219-68-2] (0.095 ml, 0.929 mmol) and DIPEA (0.487 ml, 2.79 mmol) to a solution of crude intermediate B-T2 (235 mg, 0.929 mmol) in ACN (8 ml), and stir the reaction mixture at room temperature for 1 h. Dilute the reaction mixture with EtOAc and quench with a _saturated aqueous solution of _H₂O and NaHCO₃. Separate the phases and extract the aqueous layer with EtOAc (2x). Wash the combined organic layer with brine, _dry ( _Na₂SO₄ ) and evaporate. The crude product was purified by silica gel column chromatography (using a gradient elution of EtOAc (0-100%) in cyclohexane). Fractions containing the desired product were combined and evaporated to give tributyl 2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl) α-lino-4-carboxylic acid. UPLC-MS-2: Rt = 0.90 min; MS m/z [M+H] ⁺ 394.1.

Step 2: Add iron (68.8 mg, 1.232 mmol) to a suspension of 2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)tributyl 2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)tributyl 2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)carboxylate (2 ml) in HOAc, and stir the resulting suspension at 60°C for 1 h. Dilute the reaction mixture with DCM/MeOH (9/1, 20 ml), filter through a ^Celite® mat, wash with DCM/MeOH (9/1), and evaporate the filtrate. Purify the crude product by silica gel column chromatography (using a gradient elution of MeOH (0-20%) in DCM). The fractions containing the desired product were combined and evaporated to give tributyl 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl) urinate-4-carboxylic acid. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 7.99 (d, 1H), 7.69–7.66 (m, 1H), 7.47 (s, 1H), 7.00 (dd, 1H), 5.93 (s, 2H), 4.37 (dd, 1H), 4.00 (d, 1H), 3.87 (d, 1H), 3.76 (s, 1H), 3.53 (t, 1H), 2.97 (s, 1H), 1.42 (s, 9H). UPLC-MS-2: Rt = 0.71 min; MS m/z [M+H] ⁺ 342.2.

Intermediate C-M6 : 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)tributyl 3-oxoline-4-carboxylate

Step 1: Add 5-bromo-2,3-difluoropyridine (1.117 ml, 10.41 mmol) and DIPEA (7.27 ml, 41.6 mmol) to a solution of 1H-imidazol-4-carboxaldehyde (1 g, 10.41 mmol) in DMSO (40 ml). Stir the reaction mixture at 100°C for 24 h, dilute with EtOAc, and quench with _a saturated aqueous solution of _H₂O and NaHCO₃. Separate the phases and extract the aqueous layer with EtOAc (2x). Wash the combined organic layer with brine, dry and evaporate using a phase separator. The crude product was purified by RP-HPLC (using gradient elution of ACN (10% to 100%) in _H₂O + 0.1% HCOOH). Fractions containing the desired product were combined, saturated aqueous solution _{of NaHCO₃} was added, and the aqueous solution was extracted with DCM (3x). The combined organic layers were dried and evaporated using a phase separator to give 1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-carboxaldehyde. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 9.87 (d, 1H), 8.62 (m, 3H), 8.49 (d, 1H). UPLC-MS-2: Rt = 0.47 min; MS m/z [M+H] ⁺ 270.0, 272.0.

Step 2: Under an inert atmosphere, add 1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-carboxaldehyde (Step 1, 1.1 g, 3.83 mmol) to an oven-dried flask containing molecular sieve 4A (1 g), followed by a solution of 2-((trimethylsilyl)methoxy)ethyl-1-amine (SLAP M) (0.677 g, 4.59 mmol) in anhydrous DCM (20 ml), and stir the reaction mixture at room temperature for 3 h. The reaction mixture was filtered through a ^Celite® mat, and the filtrate was concentrated to give (E)-1-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-N-(2-((trimethylsilyl)methoxy)ethyl)methylimine. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 8.59–8.58 (m, 1H), 8.56 (dd, 1H), 8.36 (t, 1H), 8.23 (d, 1H), 8.09 (t, 1H), 3.68–3.63 (m, 2H), 3.58 (t, 2H), 3.11 (s, 2H), -0.02 (s, 9H).

Step 3: Add (E)-1-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-N-(2-((trimethylsilyl)methoxy)ethyl)methylimino (Step 2, 1.672 g, 3.35 mmol) dissolved in ACN (18 ml) and HFIP (2 ml) to a vial containing a molecular sieve and a magnetic rod. Add 2,4,6-triphenylpiperonium tetrafluoroborate (0.303 g, 0.766 mmol) and TMSOTf (0.830 ml, 4.59 mmol), and stir the reaction mixture and irradiate it with a blue LED lamp at room temperature under argon for 60 h. The reaction mixture was concentrated and purified by RP-HPLC (using gradient elution of ACN (0% to 100%) in _H₂O + 0.1% HCOOH). Fractions containing the product were combined, frozen, and lyophilized to give 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl) thioline, which was then further purified by RP-HPLC (using gradient elution of ACN (0% to 100%) in _H₂O + 7.3 mM _NH₄OH ). Fractions containing the desired product were combined, frozen, and lyophilized to give 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl) thioline. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.55 (d, 1H), 8.52 (dd, 1H), 8.25 (t, 1H), 7.61 (q, 1H), 7.46 - 7.32 (m, 1H), 3.89 (dd, 1H), 3.80 (dd, 1H), 3.70 (dt, 1H), 3.44 - 3.39 (m, 1H), 3.28 (d, 1H), 2.85 - 2.80 (m, 2H). UPLC-MS-2: Rt = 0.25 min; MS m/z [M+H] ⁺ 327.1, 329.1.

Step 4: Add _Boc₂O (0.222 ml, 0.957 mmol), Et₃N (0.199 ml, 1.435 mmol), and DMAP (5.84 mg, 0.048 mmol) to a solution of 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol- ₄ -yl) α-line (Step 3, 163 mg, 0.478 mmol) in DCM (4 ml). Stir the reaction mixture at room temperature for 24 h. Dilute the reaction mixture with a saturated aqueous solution _{of NaHCO₃} and extract with DCM (2x). Dry and evaporate the combined organic layer using a phase separator. The crude product was purified by silica gel column chromatography (using gradient elution of EtOAc (0-100%) in cyclohexane). The fractions containing the desired product were combined and evaporated to give tributyl 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl) 3-oxoline-4-carboxylic acid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.55 (d, 1H), 8.52 (dd, 1H), 8.28 (t, 1H), 7.52 (s, 1H), 4.94 (s, 1H), 4.27 (d, 1H), 3.77 (d, 1H), 3.68 (dd, 1H), 3.64 (dd, 1H), 3.41 (td, 1H), 3.10 (s, 1H), 1.41 (s, 9H). UPLC-MS-2: Rt = 1.03 min; MS m/z [M+H] ⁺ 427.1, 429.1.

Intermediate C-M7 : 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-4-methylpyrroline

Paraformaldehyde (55.6 mg, 1.761 mmol) and HOAc (0.034 ml, 0.587 mmol) were added to a solution of 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl) α-line (see intermediate C-M6/step 3, 100 mg, 0.293 mmol) in DCM (3 ml), followed by fractional addition of NaBH(OAc) ₃ (385 mg, 1.761 mmol). The resulting suspension was stirred overnight at room temperature. Additional paraformaldehyde (55.6 mg, 1.761 mmol) and NaBH(OAc) ₃ (385 mg, 1.761 mmol) were added, and the reaction mixture was stirred again at room temperature for 24 h. The reaction mixture was diluted with saturated aqueous solutions of DCM and _NaHCO3 , the phases were separated, and the aqueous phase was extracted with DCM (2x). The combined organic layers were washed with brine, dried and evaporated using a phase separator. The crude product was purified by RP-HPLC (using a gradient elution of ACN (10%-100%) in _H2O + 7.3 mM _NH4OH ). The fractions containing the desired product were combined, saturated aqueous solutions of _NaHCO3 were added, and the aqueous phase was extracted with DCM (3x). The combined organic layers were dried and evaporated using a phase separator to give 3-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-4-methyltrimonium phosphate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.56 - 8.54 (m, 1H), 8.52 (dd, 1H), 8.25 (t, 1H), 7.65 (t, 1H), 3.78 (d, 1H), 3.70 - 3.66 (m, 1H), 3.60 (td, 1H), 3.46 (dd, 1H), 3.13 (dd, 1H), 2.77 - 2.73 (m, 1H), 2.23 (td, 1H), 2.07 (s, 3H). UPLC-MS-1: Rt = 0.71 min; MS m/z [M+H] ⁺ 341.0, 344.0.

Intermediate C-M8 : 6-(4-(5,6-dihydro-1,4-oxothiocyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-amine

Step 1: Add _K₂CO₃ (15.06 g, 10⁹ mmol) to a solution of 5-bromo-2,3-difluoropyridine (6 g, 30.9 mmol) and _1- (1H-imidazol-4-yl)ethyl-1-one (4.8 g, 43.6 mmol) in ACN (150 ml), and stir the resulting suspension at room temperature for 5 days. Remove the solvent and purify the crude product by silica gel column chromatography (eluting with a gradient of EtOAc (80%–100%) in cyclohexane). Concentrate the fraction containing the desired product to give 1-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)ethyl-1-one. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.65 - 8.59 (m, 2H), 8.40 (dt, 2H), 2.50 (s, 3H). UPLC-MS-1: Rt = 0.57 min; MS m/z [M+H] ⁺ 284.0, 286.0.

Step 2: Under argon atmosphere and at room temperature, 1-(1-(5-bromo-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)ethyl-1-one (Step 1, 2.9 g, 10.21 mmol) was dissolved in dimethyl ether (100 ml). Tributyl carbamate (2.392 g, 20.42 mmol), _K₃PO₄ (5.42 g, 25.5 mmol), and BrettPhos Pd G₃ (0.463 g, 0.510 mmol) were added, and the reaction mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with _H₂O and extracted with DCM (2x). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (using a gradient elution of EtOAc (0-100%) in cyclohexane). The fraction containing the desired product was concentrated to give tributyl (6-(4-acetylated-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)aminocarbamate and 1-(1-(3-fluoropyridin-2-yl)-1H-imidazol-4-yl)acet-1-one. UPLC-MS-1: Rt = 0.87 min; MS m/z [M+H] ⁺ 321.3, 286.0.

Step 3: Add Br₂ (8.04 µl, 0.156 mmol) to a mixture of (6-(4-acetylated-1H-imidazol- ₁ -yl)-5-fluoropyridin-3-yl)aminocarbamate tributyl ester (Step 2, 50 mg, 0.156 mmol) in HBr of HOAc (200 µl, 1.215 mmol). Stir the resulting mixture at room temperature for 45 min. Dilute the suspension with _Et₂O , centrifuge, and remove the liquid phase. Repeat the same procedure twice. Dry the remaining powder to give 1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-bromoethyl-1-one. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.50 - 8.48 (m, 1H), 8.44 - 8.41 (m, 1H), 7.74 (dd, 1H), 7.06 (dd, 1H), 4.73 (s, 2H). UPLC-MS-1: Rt = 0.44 min; MS m/z [M+H] ⁺ 299.1, 301.1.

Step 4: Add 1-(1-(5-amino-3-fluoropyridin- _2- yl)-1H-imidazol-4-yl)-2-bromoethane-1-one (Step 3, 335 mg, 0.799 mmol) to a solution of 2-aminoethanol (0.169 ml, 2.397 mmol) and Et3N (0.554 ml, 4.00 mmol) in DCM (8 ml). Stir the resulting mixture at room temperature for 2 h. Dilute the reaction mixture with DCM and wash with a saturated aqueous solution of _NaHCO3 . Extract the aqueous phase with DCM. The combined organic phase was dried ( _Na₂SO₄ ) and concentrated to give 1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl ₎ -2-((2-hydroxyethyl)thio)ethyl-1-one. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.30 - 8.28 (m, 1H), 8.19 - 8.17 (m, 1H), 7.73 - 7.71 (m, 1H), 7.04 - 7.00 (m, 1H), 6.07 (s, 2H), 4.81 (t, 1H), 3.83 (s, 2H), 3.56 - 3.51 (m, 2H), 2.64 (t, 2H). UPLC-MS-1: Rt = 0.24 min; MS m/z [M+H] ⁺ 279.0.

Step 5: Add TMSOTf (0.183 ml, 1.012 mmol) and triethylsilane (0.162 ml, 1.012 mmol) to a suspension of 1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-((2-hydroxyethyl)thio)ethyl-1-one (Step 4, 200 mg, 0.675 mmol) in THF (5 ml) cooled to 0°C, and allow the resulting solution to stir at room temperature for 20 h. Quench the reaction mixture with MeOH and add Et _3N (0.281 ml, 2.025 mmol). The solution was adsorbed onto an Isolute column, and the crude product was purified by silica gel column chromatography (eluting in DCM with a gradient of MeOH (NH3 _· 7N) (0-90%)). Fractions containing the desired compound were combined and concentrated to give 6-(4-(5,6-dihydro-1,4-oxothiacyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-amine). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.00 (t, 1H), 7.68 (dd, 1H), 7.35 (t, 1H), 6.99 (dd, 1H), 5.92 (s, 2H), 5.89 (s, 1H), 4.37 - 4.32 (m, 2H), 3.09 - 3.03 (m, 2H). UPLC-MS-1: Rt = 0.55 min; MS m/z [M+H] ⁺ 279.0.

Intermediate C-M9 : 6-(4-(3-((tri-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-amine

Step 1: At room temperature, add intermediate B-T13 (1.400 g, 70% wt, 2.666 mmol), 2,3-difluoro-5-nitropyridine [CAS No. 954219-68-2] (469.5 mg, 2.933 mmol), ACN (17.70 ml), and DIPEA (1.034 g, 1.39 ml, 7.999 mmol) to a vial. Stir the mixture at room temperature for 3 h. Alkalize the reaction mixture with a saturated _NaHCO3 aqueous solution and extract with EtOAc (2x). Wash the combined organic phase with brine and dry it using a phase separator. The solvent was removed under reduced pressure to give a residue, which was then purified by normal-phase chromatography (eluent: cyclohexane/EtOAc 100:0 to 70:30, over 45 min) to give the first eluted trans isomer and the second eluted cis isomer of 3-((tributyldimethylsilyl)oxy)-2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester.

Trans isomer: ^¹H NMR (700 MHz, DMSO- _d⁶ ) δ 9.21 (t, ¹H), 8.98 (dd, ¹H), 8.44 (d, ¹H), 7.63 (d, ¹H), 4.61 (d, ¹H), 4.40–4.37 (m, ¹H), 3.49 (dt, 2H), 2.14 (q, ¹H), 1.81–1.69 (m, ¹H), 1.41 (s, 4H), 1.28 (s, 5H), 0.88 (s, 9H), 0.18–0.03 (m, 6H). UPLC-MS-8: Rt = 1.61 min; MS m/z [M+H] ⁺ 508.3.

Step 2: At room temperature, add 3-((tributyldimethylsilyl)oxy)-2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester (Step 1, 309.0 mg, 608.7 µmol) and DCM (6 ml) to a vial and cool the mixture to 0°C. Then add TFA (1.388 g, 937.9 µl, 12.17 mmol) dropwise. After 2.5 h, add another 500 μl of TFA, and after another 2.5 h, add another 300 μl of TFA. After 6 h, alkalize the reaction mixture with saturated _NaHCO3 aqueous solution and extract with DCM (3x). The combined organic phase was eluted, dried, and evaporated using a phase separation column to give the trans isomer of 2-(4-(3-((tri-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-1H-imidazol-1-yl)-3-fluoro-5-nitropyridine. UPLC-MS-8: Rt = 0.99 min; MS m/z [M+H] ⁺ 408.2.

Step 3: At room temperature, add 2-(4-(3-((tri-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-1H-imidazol-1-yl)-3-fluoro-5-nitropyridine (Step 2, 224.0 mg, 85% wt, 467.2 µmol), ACN (3.5 ml), and formaldehyde (192.2 mg, 176.3 µl, 36.5% wt, 2.336 mmol) to a vial. Then add sodium cyanoboronide (61.81 mg, 95% wt, 934.4 µmol) at room temperature. After 1.5 h at room temperature, additional formaldehyde (192.2 mg, 176.3 µl, 36.5% wt, 2.336 mmol) and sodium cyanoboronide (61.81 mg, 95% wt, 934.4 µmol) were added. After 19 h at room temperature, additional formaldehyde (192.2 mg, 176.3 µl, 36.5% wt, 2.336 mmol) and sodium cyanoboronide (61.81 mg, 95% wt, 934.4 µmol) were added. After 21 h, the reaction mixture was extracted with _H₂O and EtOAc (3x) and 2-Me-THF (4x). The combined organic phase was eluted, dried, and evaporated using a separating phase column to give the residue, which was then purified by normal-phase chromatography (eluent: cyclohexane/EtOAc 80:20 to 0:100, over 11 min) to give the trans isomer of 2-(4-(3-((tri-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-3-fluoro-5-nitropyridine. UPLC-MS-2: Rt = 0.94 min; MS m/z [M+H] ⁺ 422.2.

Step 4: 2-(4-(3-((tri-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-3-fluoro-5-nitropyridine (Step 3, 119.0 mg, 98% wt, 276.6 µmol) was dissolved in MeOH (5.840 ml) at room temperature, and zinc (180.9 mg, 2.766 mmol) and _NH₄Cl (148.0 mg, 2.766 mmol) were added. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was then extracted with _H₂O and EtOAc (3x) and 2-Me-THF (4x). The combined organic phase was eluted, dried, and evaporated using a phase separation column to give the trans isomer of 6-(4-(3-((tri-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-amine. UPLC-MS-2: Rt = 0.82 min; MS m/z [M+H] ⁺ 392.4.

Intermediate C-M10 : 5-amino-2-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-4-yl)nicotinonitrile

To a mixture of 5-amino-2-chloronaphthoonitrile [CAS No. 13600-46-9] (50 mg, 0.326 mmol) in dichloroisocyanurate/ _H₂O (v/v 10/1) (5 ml) _{, K₃PO₄} (276 mg, 1.302 mmol), potassium trifluoro[1-(chloroisocyanurate-2-yl)-1H-pyrazol-4-yl]borate [CAS No. 1423013-22-2] (168 mg, 0.651 mmol), and XPos Pd G₃ (28 mg, 33 µmol) were added. The reaction mixture was degassed and stirred at 120°C for 1 h. _H₂O was added, and the mixture was extracted with DCM. The combined organic phase was evaporated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: cyclohexane/EtOAc 94:6 to 0:100, over 18 min) to give 5-amino-2-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-4-yl)nicotinonitrile. UPLC-MS-2: Rt = 0.54 min; MS m/z [M+H] ⁺ 270.2.

The following intermediates are prepared using a method similar to that used for intermediates C-M1 to C-M10, from commercially available intermediates or intermediates obtained by the methods described herein. intermediate Structure method Characteristic data C-T1 6-(4-bromo-1H-imidazol-1-yl)-5-fluoropyridine-3-amine Similar to intermediate C-M1, 4-bromo-1H-imidazole [CAS No. 2302-25-2] is used in step 1 and Fe/HOAc/60°C is used in step 2. UPLC-MS-2: Rt 0.66 min; MS m/z [M+H] ⁺ 287.1/289.1. C-T2 (racemic) C-T2 (peak 1 ) C-T2 (peak 2 ) 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)tributyl ... Similar to intermediate C-M1, intermediate B-M5 was used, followed by C-SFC (Daicel Chiralpak AD 10 µm, 250 x 50 mm) for the first and second eluted mirror isomers. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.00 (t, 1H), 7.69 (dd, 1H), 7.28 (d, 1H), 7.00 (dd, 1H), 5.91 (s, 2H), 4.92 (d, 1H), 4.25 (d, 1H), 3.76 (dd, 1H), 3.67 - 3.64 (m, 1H), 3.64 - 3.59 (m, 1H), 3.41 - 3.36 (m, 1H), 3.11 (s, 1H), 1.40 (s, 9H). UPLC-MS-2: Rt 0.68 min; MS m/z [M+H] ⁺ 364.2. Peak 1 : C-SFC-24 (mobile phase: CO ₂ / EtOH + 0.05% NH ₃ (60:40)): Rt = 0.56 min. Peak 2 : C-SFC-24 (mobile phase: CO ₂ / EtOH + 0.05% NH ₃ (60:40)): Rt = 1.39 min. C-T3 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-3-methylphosphono-4-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T1 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.95 (d, 1H), 7.68 (d, 1H), 7.26 (d, 1H), 7.00 (dd, 1H), 5.89 (s, 2H), 3.79 (d, 1H), 3.76 (q, 1H), 3.69 (ddd, 1H), 3.55 - 3.48 (m, 1H), 3.40 - 3.35 (m, 2H), 1.61 (s, 3H), 1.20 (s, 9H). UPLC-MS-8: Rt 0.67 min; MS m/z [M+H] ⁺ 378.1. C-T4 6-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl) 3-oxo-lin-3-one Similar to intermediate C-M5, intermediate B-M7 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.10 (d, 1H), 8.01 (d, 1H), 7.68 (d, 1H), 7.55 (s, 1H), 7.00 (dd, 1H), 5.94 (s, 2H), 4.77 (dd, 1H), 4.15 (d, 1H), 4.08 (d, 1H), 3.58 (dd, 1H), 3.42 - 3.39 (m, 1H). UPLC-MS-1: Rt 0.31 min; MS m/z [M+H] ⁺ 276.0. C-T5 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M5, it uses intermediate B-T3. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.97 (d, 1H), 7.68 (dd, 1H), 7.37 (s, 1H), 6.99 (dd, 1H), 5.90 (s, 2H), 3.59 (td, 1H), 3.43 - 3.37 (m, 1H), 3.37 - 3.34 (m, 1H), 3.31 - 3.22 (m, 2H), 2.19 - 2.10 (m, 1H), 2.05 - 1.96 (m, 1H), 1.40 (s, 9H). UPLC-MS-1: Rt 0.75 min; MS m/z [M+H] ⁺ 348.2. C-T6 ((3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxycyclobutyl)methyl)tributyl carbamate Similar to intermediate C-M1, intermediate B-M9 is used. UPLC-MS-2: Rt 0.95 min; MS m/z [M+H] ⁺ 390.2. C-T7 (2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)tributyl carbamate Similar to the intermediate C-M4, the intermediate B-T4 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 7.75 - 7.67 (m, 1H), 6.98 (dd, 2H), 6.07 (s, 2H), 1.60 - 1.57 (m, 1H), 1.54 (s, 7H), 1.32 (s, 11H). UPLC-MS-8: Rt 0.67 min; MS m/z [M+H] ⁺ 337.3. C-T8 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-4,4-difluoropiperidine-1-carboxylic acid tributyl ester Similar to intermediate C-M5, intermediate B-M10 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.99 (t, 1H), 7.68 (dd, 1H), 7.23 (d, 1H), 6.99 (dd, 1H), 5.91 (s, 2H), 5.44 (d, 1H), 4.07 (d, 1H), 3.08 (t, 1H), 2.79 - 2.70 (m, 1H), 2.28 (ddt, 1H), 2.01 - 1.93 (m, 2H), 1.41 (d, 9H). UPLC-MS-2: Rt 0.85 min; MS m/z [M+H] ⁺ 398.2. C-T9 5-Fluoro-6-(4-(tetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-amine Similar to intermediate C-M1, intermediate B-T5 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.80 (t, 1H), 7.66 (dd, 1H), 6.98 (dd, 1H), 6.80 - 6.76 (m, 1H), 5.84 (s, 2H), 3.75 - 3.64 (m, 4H), 3.02 - 2.96 (m, 4H). UPLC-MS-2: Rt 0.85 min; MS m/z [M+H] ⁺ 398.2. C-T10 5-Fluoro-6-(4-O-lino-1H-imidazol-1-yl)pyridin-3-amine Similar to intermediate C-M5, intermediate B-M11 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.80 (t, 1H), 7.66 (dd, 1H), 6.98 (dd, 1H), 6.80 - 6.76 (m, 1H), 5.84 (s, 2H), 3.75 - 3.64 (m, 4H), 3.02 - 2.96 (m, 4H). UPLC-MS-2: Rt 0.32 min; MS m/z [M+H] ⁺ 264.1. C-T11 5-Fluoro-6-(4-(tetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-amine Similar to intermediate C-M5, intermediate B-T6 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.95 (t, 1H), 7.68 (dd, 1H), 7.40 (d, 1H), 6.99 (dd, 1H), 5.89 (s, 2H), 3.33 - 3.28 (m, 1H), 3.07 (dd, 1H), 2.91 (dd, 1H), 2.88 - 2.85 (m, 2H), 2.32 - 2.23 (m, 1H), 2.10 - 2.02 (m, 1H). UPLC-MS-2: Rt 0.38 min; MS m/z [M+H] ⁺ 265.3. C-T12 5-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-1-methylpyrrolidin-2-one Similar to intermediate C-M5, intermediate B-T7 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.03 (t, 1H), 7.69 (dd, 1H), 7.57 - 7.53 (m, 1H), 7.00 (dd, 1H), 5.93 (s, 2H), 4.58 (dd, 1H), 2.54 (s, 3H), 2.45 - 2.40 (m, 1H), 2.32 - 2.23 (m, 2H), 2.09 - 2.03 (m, 1H). UPLC-MS-2: Rt 0.25 min; MS m/z [M+H] ⁺ 276.1. C-T13 3-(4-(4-amino-2-cyano-6-fluorophenyl)-1H-pyrazole-1-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M3/step ₂ , using 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)pyrrolidone-1-carboxylic acid tributyl ester [CAS No. 1359974-18-7] with _Cs₂CO₃ HPLC-MS-2: Rt 1.53 min; MS m/z [M+H] ⁺ 372.3. C-T14 (Trans) 6-(4-(2-((tri-butyldimethylsilyl)oxy)cyclopentyl)-1H-imidazol-1-yl)-5-fluoropyridine-3-amine (trans isomer) Similar to intermediate C-M4, it uses intermediate B-T9. UPLC-MS-8: Rt 1.29 min; MS m/z [M+H] ⁺ 377.3. C-T15 (racemic) 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-5,5-difluoropiperidine-1-carboxylic acid tributyl ester Similar to intermediate C-M2, intermediate B-T10 is used. UPLC-MS-8: Rt 0.96 min; MS m/z [M+H] ⁺ 399.3. C-T16 (1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-3,3-difluorocyclobutyl)tributylaminocarbamate Similar to intermediate C-M4, using intermediate B-T11 UPLC-MS-8: Rt 0.86 min; MS m/z [M+H] ⁺ 384.2. C-T17 1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)cyclohexyl-1-ol Similar to the intermediate C-M4, 1-(1H-imidazol-4-yl)cyclohexane-1-ol [CAS No. 123914-25-0] is used. UPLC-MS-2: Rt 0.17 min; MS m/z [M+H] ⁺ 277.3. C-T18 (racemic) 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M4, intermediate B-T12 is used. UPLC-MS-8: Rt 0.89 min; MS m/z [MH] ^- 382.1. C-T19 1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)cyclopentan-1-ol Similar to the intermediate C-M2, 1-(1H-imidazol-4-yl)cyclopentane-1-ol [CAS No. 123914-22-7] is used. UPLC-MS-8: Rt 0.32 min; MS m/z [M+H] ⁺ 263.3. C-T20 (racemic) 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxytetrahydrothiophene 1,1-dioxide Similar to intermediate C-M2, intermediate B-M13 is used. UPLC-MS-2: Rt 0.14 min; MS m/z [M+H] ⁺ 313.2. C-T21 (racemic) 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-methylazacyclobutane-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T36 is used. UPLC-MS-8: Rt 0.73 min; MS m/z [M+H] ⁺ 348.3. C-T22 6-(4-(3,9-dioxane-7-azabicyclo[3.3.1]nonane-7-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-amine Similar to intermediate C-M2, intermediate B-M14 is used. UPLC-MS-2: Rt 0.25 min; MS m/z [M+H] ⁺ 306.2. C-T23 (racemic) 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)piperidine-1-carboxylic acid tributyl ester Similar to intermediate C-M2, intermediate B-M15 is used. UPLC-MS-2: Rt 0.87 min; MS m/z [M+H] ⁺ 362.1. C-T24 5-amino-2-(1-((1-benzyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-fluorobenzonitrile Similar to intermediate C-M3/Step 2, use intermediate B-M16. UPLC-MS-2: Rt 0.54 min; MS m/z [M+H] ⁺ 373.3. C-T25 Ethyl 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-methylpropionate Similar to the intermediate C-M2, ethyl 2-(1H-imidazol-4-yl)-2-methylpropionate [CAS No. 21149-99-5] is used. UPLC-MS-2: Rt 0.55 min; MS m/z [M+H] ⁺ 293.2. C-T26 4-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)piperidine-1-carboxylic acid tributyl ester Similar to the intermediate C-M2, it uses tributyl 4-(1H-imidazol-4-yl)piperidin-1-carboxylate [CAS No. 152241-38-8]. UPLC-MS-2: Rt 0.74 min; MS m/z [M+H] ⁺ 362.3. C-T27 4-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)tetrahydro-2H-piperan-4-ol Similar to intermediate C-M4, intermediate B-T14 is used. UPLC-MS-2: Rt 0.20 min; MS m/z [M+H] ⁺ 279.1. C-T28 5-Amino-3-fluoro-2-(1-(acezo-2-ylmethyl)-1H-pyrazol-4-yl)benzonitrile Similar to intermediate C-M3/Step 2, use intermediate B-T15. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.16 - 8.09 (m, 2H), 7.74 (s, 1H), 7.23 (s, 1H), 6.81 (d, 1H), 6.73 (dd, 1H), 5.94 (s, 2H), 5.60 (s, 2H). UPLC-MS-2: Rt 0.45 min; MS m/z [M+H] ⁺ 284.1. C-T29 (3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)oxacyclobutane-3-yl)tributyl carbamate Similar to intermediate C-M4, intermediate B-T16 is used. UPLC-MS-8: Rt 0.65 min; MS m/z [M+H] ⁺ 350.1. C-T30 5-Fluoro-6-(4-(tetrahydrofuran-2-yl)-1H-imidazol-1-yl)pyridin-3-amine Similar to intermediate C-M1, intermediate B-T19 is used. UPLC-MS-2: Rt 0.31 min; MS m/z [M+H] ⁺ 249.3. C-T31 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-4,4-difluoro-2-methylpyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-M17 is used. UPLC-MS-8: Rt 0.96 min; MS m/z [M+H] ⁺ 398.3. C-T32 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)pyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T17 is used. UPLC-MS-2: Rt 0.71 min; MS m/z [M+H] ⁺ 348.3. C-T33 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-2-methyltetrahydrothiophene 1,1-dioxide Similar to intermediate C-M1, intermediate B-T20 is used. UPLC-MS-2: Rt 0.27 min; MS m/z [M+H] ⁺ 312.2. C-T34 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)tributyl tert-butyl 4-carboxylate Similar to intermediate C-M1, intermediate B-T21 is used. UPLC-MS-8: Rt 0.67 min; MS m/z [M+H] ⁺ 365.3. C-T35 (1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-3,3-difluorocyclobutyl)tributylaminocarbamate Similar to intermediate C-M1, intermediate B-T22 is used. UPLC-MS-8: Rt 0.78 min; MS m/z [M+H] ⁺ 385.3. C-T36 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-3-methylphosphono-4-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T23 is used. UPLC-MS-8: Rt 0.66 min; MS m/z [M+H] ⁺ 379.3. C-T37 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-3,3-difluoropyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T24 is used. UPLC-MS-8: Rt 0.78 min; MS m/z [M+H]+ 385.1 C-T38 (S)-2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoro-2-methylpyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T25 is used. UPLC-MS-8: Rt 0.89 min; MS m/z [M+H]+ 399.1 C-T39 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T26 is used. UPLC-MS-8: Rt 0.81 min; MS m/z [M+H] ⁺ 385.3. C-T40 (S)-2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-M18 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 7.70 (dd, 1H), 6.98 (dd, 1H), 6.14 (s, 2H), 5.16 (d, 1H), 3.91 (s, 1H), 3.86 - 3.77 (m, 1H), 3.03 (td, 1H), 2.57 - 2.51 (m, 1H), 1.29 (d, 9H). UPLC-MS-8: Rt 0.80 min; MS m/z [M+H] ⁺ 385.3. C-T41 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)thiocarbamate-4-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T28 is used. UPLC-MS-8: Rt 0.85 min; MS m/z [M+H] ⁺ 380. C-T42 3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)thiocarbamate-4-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T29 is used. UPLC-MS-2: Rt 0.79 min; MS m/z [M+H] ⁺ 380.3. C-T43 5-Fluoro-6-(4-(tetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-amine Similar to the intermediate C-M1, it uses 4-(tetrahydro-2H-piperan-4-yl)-1H-imidazole [CAS No. 1935037-79-8]. UPLC-MS-2: Rt 0.21 min; MS m/z [M+H] ⁺ 263.3. C-T44 (1R,3S,5R)-3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T30 is used. UPLC-MS-2: Rt 0.74 min; MS m/z [M+H] ⁺ 360.3. C-T45 6-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-5-azaspiro[2,4]heptane-5-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T31 is used. UPLC-MS-2: Rt 0.82 min; MS m/z [M+H] ⁺ 374.4. C-T46 (1S,3R,4R)-3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-azabicyclic[2.2.1]heptan-2-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T32 is used. UPLC-MS-2: Rt 0.81 min; MS m/z [M+H] ⁺ 374.3. C-T47 (1R,3S,4S)-3-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-azabicyclic[2.2.1]heptan-2-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T33 is used. UPLC-MS-2: Rt 0.82 min; MS m/z [M+H] ⁺ 374.3. C-T48 1-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2,2,2-trifluoroethane-1-one Similar to intermediate C-M1, intermediate B-M19 is used. UPLC-MS-2: Rt 0.46 min; MS m/z [M+H] ⁺ 275.2. C-T49 4-(4-(4-amino-2-cyano-6-fluorophenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester Similar to intermediate C-M3/step 2, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester [CAS No. 877399-74-1] is used. UPLC-MS-2: Rt 0.95 min; MS m/z [M-Boc+H] ⁺ 286.4 C-T50 (2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-1-sideoxytetrahydro- ^1λ6 -thiophene-1-yl)benzyl aminocarboxylate Similar to intermediate C-M1, intermediate B-M20 is used. UPLC-MS-8: Rt 0.54/0.60 min (2 peaks, attributed to non-mirror isomer mixture); MS m/z [M+H] ⁺ 431. C-T51 5-Amino-3-fluoro-2-(1-((1-methyl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-4-yl)benzonitrile Similar to intermediate C-M3/Step 2, use intermediate B-T34. UPLC-MS-2: Rt 0.33 min; MS m/z [M+H] ⁺ 299.2. C-T52 2-(4-(4-amino-2-cyano-6-fluorophenyl)-1H-pyrazole-1-yl)-2-methylpropionate Similar to intermediate C-M3/Step 2, use intermediate B-T35. UPLC-MS-2: Rt 0.68 min; MS m/z [M+H] ⁺ 303. C-T53 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)acetonitrile Similar to C-M1, it uses 2-(1H-imidazol-4-yl)acetonitrile [CAS No. 18502-05-1] UPLC-MS-2: Rt 0.28 min; MS m/z [M+H] ⁺ 218.2. C-T54 5-Amino-3-fluoro-2-(1-(tetrahydro-2H-piperan-3-yl)-1H-pyrazol-4-yl)benzonitrile Similar to intermediate C-M3/step 2, 1-(tetrahydro-2H-piperan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 2223009-52-5] is used. UPLC-MS-2: Rt 0.62 min; MS m/z [M+H] ⁺ 287.2. C-T55 3-(4-(4-amino-2-cyano-6-fluorophenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester Similar to intermediate C-M3/step 2, tributyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [CAS No. 1092563-74-0] is used. UPLC-MS-2: Rt 0.94 min; MS m/z [M-Boc+H] ⁺ 287.2. C-T56 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)-2-methylpyrrolidone-1-carboxylic acid tributyl ester Similar to intermediate C-M1, intermediate B-T18 is used. UPLC-MS-2: Rt 0.77 min; MS m/z [M+H] ⁺ 362.4. C-T57 ethyl 1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-carboxylate Similar to the intermediate C-M2, ethyl 1H-imidazolium-4-carboxylate [CAS No. 23785-21-9] is used. HPLC-MS-3: Rt 0.47 min; MS m/z [M+H] ⁺ 251.4. C-T58 (3-((1-(5-amino-3-fluoropyridin-2-yl)-1H-imidazol-4-yl)methyl)oxocyclobutane-3-yl)benzyl carbamate Similar to intermediate C-M1, intermediate B-T38 is used. UPLC-MS-2: Rt 0.53 min; MS m/z [M+H] ⁺ 398.8.

D- intermediate D -M1 : N-(6-chloro-5-cyanopyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide

Step 1: A mixture of 2-chloro-5-nitroniconitrile [CAS No. 31309-08-7] (400 mg, 1.114 mmol) and Fe (1.18 g, 21.14 mmol) in HOAc (6 ml) was stirred at 100°C. After 2.5 h, the reaction mixture was filtered through ^Hyflo® . The filtrate was alkalized with a saturated _NaHCO3 aqueous solution and extracted with DCM (2x). The combined organic layers were dried (phase separator) and concentrated under reduced pressure to give 5-amino-2-chloroniconitrile. UPLC-MS-1: Rt = 0.49 min; MS m/z [M+H] ⁺ 154.1/156.2.

Step 2: A solution of 5-amino-2-chloronicotinonitrile (Step 1, 214 mg, 1.003 mmol), 2-(3-(trifluoromethyl)phenoxy)acetic acid [CAS No. 349-82-6] (265 mg, 1.204 mmol), DIPEA (0.35 ml, 2.007 mmol), and HATU (763 mg, 2.007 mmol) in DMF (10 ml) was stirred at room temperature. After 5 h, the reaction mixture was alkalized with saturated _NaHCO3 aqueous solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (using a phase separator), concentrated under reduced pressure, and the residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:1 to 30:70) to give N-(6-chloro-5-cyanopyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetylamine. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 10.74 (br s, ¹H), 8.89 (d, ¹H), 8.64 (d, ¹H), 7.57 (m, ¹H), 7.32–7.39 (m, ³H), 4.90 (s, ²H). UPLC-MS-2: Rt = 1.09 min; MS m/z [M+H] ⁺ 356.2/358.1.

Intermediate D-M2 : N-(4-ethynyl-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

Step 1: Under _N2 at room temperature, CuI (67 mg, 0.352 mmol), Pd( _PPh3 ) ₄ (271 mg, 0.235 mmol), and then _Et3N (7.1 g, 70.584 mmol) were added to a solution of 3,5-difluoro-4-iodoaniline [CAS No. 1542-34-3] (3 g, 11.764 mmol) in DMF (30 ml). The reaction mixture was warmed to 75°C and then treated with ethynyltrimethylsilane (1.7 g, 17.647 mmol). After 12 h, the mixture was diluted with _H2O and extracted with EtOAc (2x). The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give 3,5-difluoro-4-((trimethylsilyl ₎ ethynyl)aniline, which was then used without further purification.

Step 2: _K₂CO₃ (737 mg, 5.333 mmol) was added to _a solution of 3,5-difluoro-4-((trimethylsilyl)ethynyl)aniline (Step 1, 1 g, 4.444 mmol) in MeOH (10 ml) at room temperature. After stirring for 12 h, the reaction mixture was diluted with _H₂O and extracted with EtOAc ( _2x ). The combined organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/hexane 20:80 to 30:70) to give 4-ethynyl-3,5-difluoroaniline. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.15-6.18 (m, 2H), 4.05 (br s, 2H), 3.36 (s, 1H).

Step 3: At room temperature, DIPEA (0.7 ml, 3.921 mmol) and T3P (831 mg, 2.614 mmol) were added to a solution of 4-ethynyl-3,5-difluoroaniline (Step 2, 200 mg, 1.307 mmol) and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] (377 mg, 1.699 mmol). After stirring for 12 h, the reaction mixture was diluted with _H2O and extracted with EtOAc (2x). The combined organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give N-(4-ethynyl-3,5-difluorophenyl)-2-(2 _- fluoro-3-(trifluoromethyl)phenyl)acetamide, without further purification.

Intermediate D-M3 : N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

Step 1: Add DIPEA (10.69 ml, 61.2 mmol) and then HATU (13.97 g, 36.7 mmol) to a mixture of 2-(3-(trifluoromethyl)phenyl)acetic acid [CAS No. 351-35-9] (5.0 g, 24.49 mmol) and 4-bromo-3-fluoroaniline [CAS No. 656-65-5] (5.58 g, 29.4 mmol) in DCM (50 ml). After stirring overnight, dilute the reaction mixture with _H₂O and extract with EtOAc. Wash the organic layer with brine, _dry ( _Na₂SO₄ ), and concentrate under reduced pressure. The residue was purified by normal-phase chromatography (eluent: 20% EtOAc/hexane) to yield N-(4-bromo-3-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)acetamide. HPLC-MS: Rt 2.58 min; MS m/z [M+H] ⁺ 375.9/377.9.

Step 2: B2Pin2 [CAS No. 73183-34-3] (149 mg, 0.585 mmol), _PdCl2 (dppf)-DCM adduct (19.91 mg, 0.024 mmol), and KOAc (115 mg, 1.170 mmol) were added to a solution of N-(4-bromo-3-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (Step 1, 73 mg, 0.194 mmol) in dimethyl ether (3 ml). The reaction mixture was stirred at 90°C under argon for 18 h. The reaction mixture was diluted with EtOAc and then extracted with 25 ml _H2O . The organic phase was dried ( _Na₂SO₄ ) and concentrated under vacuum to give N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl ₎ phenyl)-2-(3-(trifluoromethyl)phenyl)acetylamine, which was used without further purification. HPLC-MS: Rt 2.57 min; MS m/z [M+H] ⁺ 424.2.

Intermediate D-M4 : N-(6-(4-bromo-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

At room temperature, DIPEA (2.03 ml, 11.67 mmol) and then T3P (50% in EtOAc) (6.9 ml, 11.67 mmol) were added to a solution of 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] and intermediate C-T1 (1 g, 3.89 mmol) in THF (30 ml). After 1.5 h, the reaction mixture was quenched with _H2O and extracted with DCM (2x). The combined organic layers were washed with saturated _NaHCO3 aqueous solution and brine, dried (phase separator), and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: DCM/(9:1 DCM/MeOH) 100:0 to 30:70) to give N-(6-(4-bromo-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. UPLC-MS-2: Rt = 1.02 min; MS m/z [M+H] ⁺ 447.1/449.2.

Intermediate D-M5 : N-(3,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

_PdCl₂ (dtbpf) (6.48 mg, 9.95 μmol) was added to a mixture of intermediate D-T1 (20 _mg , 0.050 mmol), 1-(methanesulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 944994-03-0] (16.24 mg, 0.060 mmol), and _Na₂CO₃ (10.54 mg, 0.099 mmol) in a 2:1 dimethyl sulfoxide/ _H₂O mixture (3 ml). The mixture was degassed and stirred at 40°C. After 1 h, the reaction mixture was diluted with MeOH and purified by RP-HPLC to N-(3,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide. HPLC-MS: Rt 2.46 min; MS m/z [M+H] ⁺ 382.0

The following intermediates are prepared using a method similar to that used for intermediates D-M1 to D-M5, from commercially available intermediates or intermediates obtained by the methods described herein. intermediate Structure method Characteristic data D-T1 N-(4-bromo-3,5-difluorophenyl)-2-(3-(trifluoromethyl)phenyl)acetamide Similar to D-M3/Step 1, except for 4-bromo-3,5-difluoroaniline [CAS No. 203302-95-8] ES/MS m/z [M+H] ⁺ 394.0/396.0 D-T2 N-(6-(4-bromo-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to D-M4, except for 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] UPLC-MS-2: Rt 1.18 min; MS m/z [M+H] ⁺ 461.2/463.2 D-T3 N-(6-(4-bromo-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to D-M4, it uses 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] UPLC-MS-2: Rt 1.03 min; MS m/z [M+H] ⁺ 444.3/446.3 D-T4 N-(4-bromo-3-cyano-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to D-M4, it uses 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] and 5-amino-2-bromo-3-fluorobenzonitrile. UPLC-MS-2: Rt 1.13 min; MS m/z [M+H] ⁺ 402.4/404.2 D-T5 N-(6-chloro-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to D-M4, it uses 6-chloro-5-fluoropyridine-3-amine and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4]. UPLC-MS-2: Rt 1.18 min; MS m/z [M+H] ⁺ 351.2 D-T6 N-(6-chloro-5-cyanopyridin-3-yl)-7-fluorosem-2-methylamine Similar to D-M1, step 2 uses 7-fluorochromo-2-carboxylic acid [CAS No. 944904-25-0], T3P, and THF. UPLC-MS-2: Rt 1.02 min; MS m/z [MH] ^- 330.1/332.1 D-T7 N-(6-chloro-5-cyanopyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to D-M1, step 2 uses 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] and T3P as well as EtOAc. HPLC-MS-6: Rt 1.60 min; MS m/z [M+H] ⁺ 358.1/360.1 D-T8 N-(4-bromo-3-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to intermediate D-M3/step 1, 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] is used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.09 (m, 1H), 7.82 (d, 1H), 7.72-7.78 (m, 2H), 7.64 (t, 1H), 7.30 (m, 1H), 4.01 (s, 2H). HPLC-MS: Rt 2.49 min; MS m/z [M+H] ⁺ 378.9 D-T9 N-(5,6-Difluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to intermediate D-M3/step 1, 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] and 5,6-difluoropyridine-3-amine [1214344-65-6] with T3P (50% in EtOAc) are used. UPLC-MS-2: Rt 1.12 min; MS m/z [MH] ^- 333.1

Example 1 of the preparation of the final compound : N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)throm-3-methylamine and (R or S)-N-(5-fluoro-6-(4-((R or S)-2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)throm-3-methylamine

Step 1: At room temperature, 7-(trifluoromethyl)chromo-3-carboxylic acid [CAS No. 1956332-20-9] (132.7 mg, 0.539 mmol), T3P (50% in EtOAc) (0.481 ml, 0.808 mmol), and DIPEA (0.282 ml, 1.617 mmol) were added to a solution of intermediate C-M1 (150 mg, 0.539 mmol) in THF (3 ml). After 30 min, the reaction mixture was diluted with EtOAc and washed with saturated _NaHCO3 aqueous solution and saturated _NH4Cl aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal phase chromatography (eluent: EtOAc/cyclohexane 0:100 to 100:0) to give N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)chromium-3-methylamine. UPLC-MS-8: Rt = 0.74–0.81 min (multiplets); MS m/z [M+H] ⁺ 507.3.

Step 2: Add mCPBA (156.7 mg, 0.908 mmol) to an ice-cold solution of N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)chromium-3-methamide (Step 1, 200 mg, 0.395 mmol) in DCM (5 ml). Allow the reaction to warm to room temperature. After ₁₈ h, dilute the reaction mixture with DCM and wash with 0.5 M _{Na₂S₂O₃ aqueous} solution. The organic layer was dried (phase separator) and concentrated under reduced pressure, and the residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:100 to 100:0) to give N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)chromium-3-methamide (a mixture of non-mirror isomers). UPLC-MS-8: Rt = 1.13 min; MS m/z [M+H] ⁺ 539.3.

Step 3: The non-mirror isomers of N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)chromium-3-methylamine (a mixture of non-mirror isomers) (Step 2, 140 mg, 0.26 mmol) were first separated by C-SFC-1 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 70/30 (to give the 3rd and 4th eluted isomers), and then (for a mixture of the 1st and 2nd eluted isomers) by C-SFC-3 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 70/30) separation to give a single isomer of N-(5-fluoro-6-(4-(2-methyl-1,1-di-oxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)som-3-methamide.

Example 1a : (R or S)-N-(5-fluoro-6-(4-(((R or S)-2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)som-3-methamide: First eluted isomer: C-SFC-2 (mobile phase: CO ₂ /(MeOH + 0.05% NH ₃ ) 75/25): Rt = 1.5 min.

Example 1b : (R or S)-N-(5-fluoro-6-(4-(((R or S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)som-3-methamide: Second eluted isomer: C-SFC-2 (mobile phase: CO ₂ /(MeOH + 0.05% NH ₃ ) 75/25): Rt = 1.6 min.

Example 1c : (R or S)-N-(5-fluoro-6-(4-((R or S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)somn-3-methylamine: Third eluted isomer: ^¹H NMR (600 MHz, DMSO -d6 ) δ 10.91 (s, _1H ), 8.51 (d, 1H), 8.33 (dd, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.41 (d, 1H), 7.22 (d, 1H), 7.12 (s, 1H), 4.53 (m, 1H), 4.20 (m, 1H), 3.21-3.27 (m, 1H), 3.13-3.21 (m, 2H), 3.06-3.13 (m, 2H), 2.72 (m, 1H), 2.23 (m, 1H), 2.08-2.17 (m, 2H), 1.65 (s, 3H). UPLC-MS-8: Rt = 1.11 min; MS m/z [M+H] ⁺ 539.2. C-SFC-2 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 75/25): Rt = 2.3 min.

Example 1d : (R or S)-N-(5-fluoro-6-(4-(((R or S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)som-3-methylamine: fourth eluted isomer: C-SFC-2 (mobile phase: CO ₂ /(MeOH + 0.05% NH ₃ ) 75/25): Rt = 3.4 min.

Example 2 : N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and (R or S)-N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: At room temperature, 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (41.8 mg, 0.201 mmol), DIPEA (0.105 ml, 0.602 mmol) and T3P (50% in EtOAc) (0.179 ml, 0.301 mmol) were added to a solution of intermediate C-M2 (80 mg, 0.201 mmol) in THF (3 ml). After 18 h, additional 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (41.8 mg, 0.201 mmol), DIPEA (0.105 ml, 0.602 mmol), and T3P (50% in EtOAc) (0.179 ml, 0.301 mmol) were added. After another 1 h, the reaction mixture was diluted with EtOAc and washed with saturated _NH4Cl aqueous solution and saturated _NaHCO3 aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:100 to 100:0) to give tributyl 4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid (racemic mixture). UPLC-MS-8: Rt = 1.22 min; MS m/z [M+H] ⁺ 589.4.

Step 2: The mirror isomers (racemic mixtures) of 4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid tributyl ester (Step 1, 110 mg, 0.187 mmol) were separated by C-SFC-4 (mobile phase: _CO2 /(IPA + 0.05% _NH3 ) 65/35).

First eluted isomer: UPLC-MS-8: Rt = 1.25 min; MS m/z [M+H] ⁺ 589.1. C-SFC-5 (mobile phase: CO ₂ / (IPA + 0.05% NH ₃ ) 75/25): Rt = 0.96 min.

Second eluted isomer: C-SFC-5 (mobile phase: CO ₂ / (IPA + 0.05% NH ₃ ) 75/25): Rt = 1.56 min.

Step 3: At room temperature, TFA (0.065 ml, 0.850 mmol) was added to a solution of tributyl 4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)piperidin-1-carboxylate (the second eluted isomer) (Step 2, 50 mg, 0.085 mmol) in DCM (0.4 ml). After 2.5 h, the reaction mixture was loaded onto a Pora Pack column, and TFA was removed by elution with MeOH. The column was then eluted with 7 M _NH3 /MeOH. Add _H₂O to the eluent and freeze the solution to give Example 2 : (R or S)-N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.13 (br s,1H), 9.07 (s, 1H), 8.53 (d, 1H), 8.30 (dd, 1H), 6.56 (s, 1H), 5.19 (s, 2H), 3.94 (m, 1H), 3.13 (m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.34 (m, 1H), 2.32 (s, 3H), 1.96-2.12 (m, 2H), 1.88 (m, 1H). UPLC-MS-8: Rt = 0.69 min; MS m/z [M+H] ⁺ 489.2.

Treat 4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetaminoyl)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)piperidin-1-carboxylic acid tributyl ester (first eluted isomer) (step 2, 47 mg, 0.080 mmol) to give Example 2b : (R or S)-N-(6-(3-(4,4-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetaminoyl. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.18 (s,1H), 9.07 (s, 1H), 8.53 (d, 1H), 8.30 (dd, 1H), 6.56 (s, 1H), 5.20 (s, 2H), 3.97 (m, 1H), 3.14 (m, 1H), 2.76 (m, 1H), 2.34 (m, 1H), 2.32 (s, 3H), 1.97-2.14 (m, 2H), 1.89 (m, 1H). UPLC-MS-8: Rt = 0.75 min; MS m/z [M+H] ⁺ 489.1.

Example 3 : N-(5-cyano-6-(1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide

Step 1: At room temperature, Ar was bubbled through _a mixture of intermediates B-M3 (130 mg, 0.315 mmol), D-M1 (112 mg, 0.315 mmol), and _K₃PO₄ (200 mg, 0.944 mmol) in dimethyl ether (5.1 ml) and _H₂O (1.7 ml). XPhos-Pd-G3 (40.0 mg, 0.0047 mmol) was added, the vial was sealed, and the mixture was microwaved at 100°C. After 1 h, the reaction mixture was diluted with _H₂O and extracted with EtOAc (2x). The combined organic layer was washed with brine, dried (phase separator), and concentrated under reduced pressure. The residue was dissolved in EtOAc and the solution was treated with Si-thiol resin (200 mg). After stirring for 1 h, the mixture was filtered and concentrated under reduced pressure, and the residue was purified by normal phase chromatography (eluent: EtOAc/cyclohexane 0:100 to 50:50) to give tributyl 4-(4-(3-cyano-5-(2-(3-(trifluoromethyl)phenoxy)acetamino)pyridin-2-yl)-1H-pyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylic acid. UPLC-MS-2: Rt = 1.27 min; MS m/z [MH] ^- 605.3.

Step 2: At room temperature, TFA (0.145 ml, 1.879 mmol) was added to a solution of 4-(4-(3-cyano-5-(2-(3-(trifluoromethyl)phenoxy)acetaminopheno)pyridin-2-yl)-1H-pyrazol-1-yl)-3,3-difluoropiperidin-1-carboxylic acid tributyl ester (Step 1, 114 mg, 0.188 mmol) in DCM (0.47 ml). After 1.5 h, the reaction mixture was alkalized with saturated _NaHCO3 aqueous solution, stirred for 15 min, and then extracted with DCM (3x). The combined organic layers were dried (phase separator) and concentrated under reduced pressure, and the residues were purified by RP-HPLC-1 (mobile phase: _H2O /ACN 90:10 to 50:50) to give N-(5-cyano-6-(1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s,1H), 8.99 (d, 1H), 8.53 (d, 1H), 8.43 (s, 1H), 8.19 (s, 1H), 7.58 (m, 1H), 7.36-7.40 (m, 2H), 7.35 (m, 1H), 5.02 (m, 1H), 4.90 (s, 2H), 3.19 (m, 1H), 3.06 (m, 1H), 2.92 (m, 1H), 2.57-2.75 (m, 2H), 2.29 (m, 1H), 2.08 (m, 1H). UPLC-MS-2: Rt = 0.79 min; MS m/z [M+H] ⁺ 507.3.

Example 4 : N-(3-fluoro-4-(1-(2-side-oxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide and (R or S)-N-(3-fluoro-4-(1-(2-side-oxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

Step 1: The mixture of intermediate D-M3 (170 mg, 0.197 mmol), intermediate B-M4 (54.3 mg, 0.236 mmol), _Na₂CO₃ ( _41.7 mg, 0.394 mmol), and _PdCl₂ (dtbpf) (12.8 mg, 0.020 mmol) in disulfide (1.5 ml) and _H₂O (1.5 ml) was degassed and then heated in a microwave at 100°C. After 1 h, the reaction mixture was diluted with EtOAc and washed with _H₂O . The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was purified by alkaline RP _- preparative HPLC to yield N-(3-fluoro-4-(1-(2-sideoxypyrrolidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (racemic mixture). HPLC-MS: Rt 2.32 min; MS m/z [M+H] ⁺ 447.0.

Step 2: The mirror isomers (racemic mixtures) of N-(3-fluoro-4-(1-(2-side-oxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (Step 1, 37 mg, 0.083 mmol) were separated by SFC to give a single mirror isomer (R or S)-N-(3-fluoro-4-(1-(2-side-oxypyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide.

Example 4a : First eluted isomer: ^¹H NMR (400 MHz, DMSO _-d6 ) δ 10.45 (s, 1H), 8.14 (m, 2H), 7.90 (d, 1H), 7.55–7.71 (m, 6H), 7.32 (dd, 1H), 5.10 (t, 1H), 3.81 (s, 2H), 3.39 (m, 1H), 3.29 (m, 1H), 2.42–2.58 (m, 2H). HPLC-MS: Rt 2.32 min; MS m/z [M+H] ⁺ 447.0.

Example 4b : Second eluted isomer: HPLC-MS: Rt 2.32 min; MS m/z [M+H] ⁺ 447.0.

Example 5 : N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro- ^λ6 -hydrothio)phenyl)acetamide

At room temperature, DIPEA (0.052 ml, 0.299 mmol) and T3P (50% in EtOAc) (0.089 ml, 0.149 mmol) were added to a suspension of 2-(3-(pentafluoro- ^λ6 -hydrothio)phenyl)acetic acid [CAS No. 1211578-68-5] (39.1 mg, 0.149 mmol) and intermediate C-M3 (50 mg, 0.100 mmol). After 30 min, the reaction mixture was diluted with EtOAc and washed with _H2O (3x) and brine, _dried ( _Na2SO4 ), and concentrated under reduced pressure. The residue was purified by RP-HPLC-2 (mobile phase: ( _H₂O + 7.3 mM _NH₄OH )/(ACN + 7.3 mM _NH₄OH ) 70:30 to 30:70) to give N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro- ^λ6 -hydrothio)phenyl)acetamide. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.75 (s,1H), 8.24 (s, 1H), 7.84-7.90 (m, 4H), 7.82 (m, 1H), 7.57-7.64 (m, 2H), 4.53 (m, 1H), 3.93-4.02 (m, 2H), 3.88 (s, 2H), 3.45-3.51 (m, 2H), 1.94-2.03 (m, 4H). UPLC-MS-2: Rt = 1.13 min; MS m/z [M+H] ⁺ 531.2.

Example 6 : N-(3,5-difluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

Step 1: At room temperature, _PdCl₂ (dtbpf) (6.8 mg, 0.0105 mmol) was added to a mixture of intermediate D-T1 (140 mg, 0.210 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tributyl ester [CAS No. 877399-74-1 _] (119 mg, 0.314 mmol), and _Na₂CO₃ (67 mg, 0.629 mmol) in dimethyl ether (2 ml) and _H₂O (1 ml). After degassing, the mixture was stirred overnight at 60°C. The reaction mixture was cooled to room temperature, diluted with _H₂O , and extracted with EtOAc ( _3x ). The combined organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give tributyl 4-(4-(2,6-difluoro-4-(2-(3-(trifluoromethyl)phenyl)acetaminophen)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid, which was used directly in the next step without purification. HPLC-MS: Rt 2.67 min; MS m/z [M+H] ⁺ 565.1.

Step 2: At room temperature, add TFA (1 ml) to a solution of tributyl 4-(4-(2,6-difluoro-4-(2-(3-(trifluoromethyl)phenyl)acetaminophen)phenyl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid (Step 1, 118 mg, 0.180 mmol) in DCM (1 ml). After stirring for 1 h, concentrate the reaction mixture under reduced pressure. Dilute the residue with MeOH and filter. Purify the filtrate by alkaline RP-preparative HPLC to give N-(3,5-difluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetaminophen. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.07 (d, 1H), 7.78 (t, 1H), 7.70 (d, 1H), 7.62-7.66 (m, 2H), 7.58 (m, 1H), 7.37-7.45 (m, 2H), 4.28 (m, 1H), 3.82 (s, 2H), 3.04 (m, 2H), 2.58 (m, 2H), 1.89-1.97 (m, 2H), 1.75-1.86 (m, 2H). HPLC-MS: Rt 2.19 min; MS m/z [M+H] ⁺ 465.1.

Example 7 : N-(3,5-difluoro-4-(1-((1R,2R)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide (racemic mixture)

At room temperature, intermediate D-M2 (50 mg, 0.140 mmol), CuSO4 _{· 5H2O} (70 mg, 0.280 mmol), and sodium ascorbate (83 mg, 0.419 mmol) were added to a solution of racemic-(1R,2R)-2-azidocyclopentanol-1-ol (39.4 mg, 0.280 mmol) in DMSO (2 ml) and _H2O (1 ml). After stirring overnight at 40°C, the reaction mixture was diluted with EtOAc and washed with _H2O . The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was purified by preparative HPLC using RP to yield N-( _3,5 -difluoro-4-(1-((1R,2R)-2-hydroxycyclopentyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.75 (s,1H), 8.41 (s, 1H), 7.68-7.79 (m, 2H), 7.37-7.48 (m, 3H), 5.26 (d, 1H), 4.69 (m, 1H), 4.32 (m, 1H), 3.89 (s, 2H), 2.26 (m, 1H), 1.96-2.07 (m, 2H), 1.76-1.85 (m, 2H), 1.60 (m, 1H). HPLC-MS-8: Rt 1.29 min; MS m/z [M+H] ⁺ 485.1.

Example 8 : 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea and (R or S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea

Step 1: At room temperature, CDI (233 mg, 1.437 mmol) was added to a mixture of intermediate C-M1 (100 mg, 0.359 mmol), 2-fluoro-N-methyl-3-(trifluoromethyl)aniline [CAS No. 1261808-48-3] (260 mg, 0.539 mmol), and DIPEA (0.188 ml, 1.078 mmol) in DMSO (4 ml). After 18 h, the reaction mixture was diluted with _H2O and extracted with DCM. The organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal phase chromatography (eluent: EtOAc/cyclohexane 0:100 to 100:0) to give 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea. UPLC-MS-8: Rt = 1.22 min; MS m/z [M+H] ⁺ 498.0.

Step 2: At 0°C, a solution of mCPBA (66 mg, 0.295 mmol) in DCM (5 ml) was added dropwise to a solution of 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea (Step 1, 79 mg, 0.134 mmol) in DCM (10 ml). After 30 min, the reaction mixture was diluted with DCM and washed with saturated _NaHCO3 aqueous solution and brine. The organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: EtOAc/cyclohexane 0:100 to 60:40) to give 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea (racemic mixture). UPLC-MS-8: Rt = 0.93 min; MS m/z [M+H] ⁺ 530.2.

Step 3: The mirror isomers (racemic mixtures) of 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea (Step 2, 60 mg, 0.114 mmol) were prepared by C-SFC-6 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 60/40) separation to give (R or S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea.

Example 8a : First eluted isomer: C-SFC-5 (mobile phase: CO ₂ / (IPA + 0.05% NH ₃ ) 60/40): Rt = 1.27 min.

Example 8b : Second eluted isomer: ^¹H NMR (600 MHz, DMSO _- d⁶ ) δ 9.16 (s, ¹H), 8.43 (d, ¹H), 8.22 (s, ¹H), 8.16 (dd, ¹H), 7.88 (m, ¹H), 7.75–7.80 (m, 2H), 7.50 (m, ¹H), 3.31 (s, 3H), 3.14–3.27 (m, 2H), 2.71 (m, 1H), 2.23 (m, 1H), 2.07–2.17 (m, 2H), 1.64 (s, 3H). UPLC-MS-8: Rt = 0.93 min; MS m/z [M+H] ⁺ 530.3. C-SFC-5 (mobile phase: CO ₂ / (IPA + 0.05% NH ₃ ) 60/40): Rt = 1.76 min.

Example 9 : N-(6-(4-(1,1-di-dioxythio-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Under Ar and at room temperature, 1,1-dioxide of thiocyanate [CAS No. 39093-93-1] (136 mg, 1.01 mmol) was added to a mixture of intermediate D-M4 (150 mg, 0.335 mmol), NaOtBu (97 mg, 1.01 mmol), and Pd-PEPPSI-Ipent (27 mg, 0.034 mmol) in DMA (3 ml). After rinsing with Ar, the reaction vial was sealed and warmed to 60°C. After 18 h, the reaction mixture was diluted with EtOAc and washed with a saturated _NaHCO3 aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure, and the residue was purified by RP-HPLC-2 (mobile phase: ( _H2O + 7.3 mM _NH4OH )/ACN 95:5 to 30:70) to give N-(6-(4-(1,1-di-dioxythio-lino)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.14 (br,1H), 8.45 (s, 1H), 8.25 (d, 1H), 8.08 (s, 1H), 7.19 (s, 1H), 6.56 (s, 1H), 5.16 (s, 2H), 3.66-3.74 (m, 4H), 3.10-3.17 (m, 4H), 2.31 (s, 3H). UPLC-MS-2: Rt = 0.78 min; MS m/z [M+H] ⁺ 502.3.

Example 10 : N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

A solution of intermediate D-T2 (50 mg, 0.108 mmol), 2-(3,6-dihydro-2H-piperan-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentane [CAS No. 287944-16-5] (25 mg, 0.119 mmol), NaHCO3 (27 mg, 0.325 mmol), and ( _Ph3P ) _4Pd (6 mg, 0.0054 mmol) in DME (2.3 ml) and _H2O (0.78 ml) was stirred overnight at room temperature under Ar conditions at 100°C. After 18 h, the reaction mixture was diluted with EtOAc and saturated _NaHCO3 aqueous solution. The separated organic layer was washed with brine, dried ( _MgSO4 ), concentrated under reduced pressure, and the residue was purified by RP-HPLC-21 (mobile phase: ( _H2O + 0.1% TFA)/(ACN + 0.1% TFA) 80:20 to 0:100) to give N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.94 (br s,1H), 8.48 (d, 1H), 8.29 (dd, 1H), 8.23 (m, 1H), 7.69-7.80 (m, 2H), 7.69 (s, 1H), 7.41 (m, 1H), 6.40 (s, 1H), 4.19-4.26 (m, 2H), 3.95 (s, 2H), 3.76-3.84 (m, 2H), 2.35-2.42 (m, 2H). UPLC-MS-2: Rt = 1.07 min; MS m/z [M+H] ⁺ 465.1.

Example 11 : N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Add 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (126.0 mg, 605.4 µmol), DIPEA (213.4 mg, 288 µl, 1.651 mmol) and T3P (50% in EtOAc) (700.5 mg, 651.0 µl, 1.101 mmol) to a solution of intermediate C-T2 (200.0 mg, 1 equivalent, 550.4 µmol) in ACN (5 ml) and stir the reaction mixture overnight at room temperature. Add additional T3P (50% in EtOAc) (700.5 mg, 651.0 µl, 1.101 mmol) and DIPEA (213.4 mg, 288 µl, 1.651 mmol), and continue stirring the reaction mixture at room temperature for 2 h until complete conversion. Dilute the reaction mixture with DCM and wash with a saturated aqueous solution of _NaHCO3 . Separate the phases and extract the aqueous layer with DCM (2x). Wash the combined organic layer with brine, dry and evaporate using a phase separator. Purify the crude product by silica gel column chromatography (eluting with a gradient of MeOH (0-20%) in DCM). The fractions containing the product are combined and evaporated to give 3-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)pyridin-2-yl)-1H-imidazol-4-yl)tributyl ... ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.47 (d, 1H), 8.27 (dd, 1H), 8.23 (d, 1H), 7.49 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 4.94 (s, 1H), 4.26 (d, 1H), 3.79 - 3.74 (m, 1H), 3.67 (dd, 1H), 3.66 - 3.62 (m, 1H), 3.40 (td, 1H), 3.11 (s, 1H), 2.31 (s, 3H), 1.41 (s, 9H). UPLC-MS-2: Rt = 1.16 min; MS m/z [M+H] ⁺ 554.2.

Step 2: Add TFA (1.248 g, 10.94 mmol) to a solution of tributyl 3-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)pyridin-2-yl)-1H-imidazol-4-yl)tributyl 3-oxoline-4-carboxylate (Step 1, 309.0 mg, 547.1 µmol) in DCM (3 ml), and stir the reaction mixture at room temperature for 2 h. Co-evaporate the reaction mixture with DCM (3x), dissolve it in DCM (10 ml), neutralize to pH 8 with ammonia/MeOH, and concentrate. The crude product was purified by reversed-phase column chromatography (RediSep Rf 50 g GOLD C18 column) (eluting with a gradient of ACN (0% to 100%) in _H₂O (containing 7.3 mM _NH₄OH ). Fractions containing the desired product were combined, frozen, and lyophilized to yield N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 8.47 (d, 1H), 8.26 (dd, 1H), 8.19 (t, 1H), 7.58 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 3.89 (dd, 1H), 3.80 (dd, 1H), 3.71 (dt, 1H), 3.44 - 3.41 (m, 1H), 3.30 - 3.27 (m, 1H), 2.86 - 2.80 (m, 2H), 2.31 (s, 3H). UPLC-MS-8: Rt = 0.62 min; MS m/z [M+H] ⁺ 454.2.

Example 12 : N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and (R or S)-N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Add acetic acid (58.17 mg, 968.7 µmol), DIPEA (250.4 mg, 1.937 mmol), and T3P (50% in EtOAc) (616.4 mg, 968.7 µmol) to a solution of N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl) in ACN (2 ml), and stir the reaction mixture overnight at room temperature. Dilute the reaction mixture with EtOAc, wash with a saturated aqueous solution of _NaHCO3 , separate the phases, and extract the aqueous layer with EtOAc. The combined organic layers were washed with brine, dried and evaporated using a phase separator. The crude product was purified by silica gel column chromatography (using a gradient elution of MeOH (0-20%) in DCM). The fractions containing the product were combined and evaporated to give N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. 1H NMR (600 MHz, DMSO-d ₆ ) δ 8.00 - 7.83 (m, 1H), 4.40 - 4.23 (m, 1H), 3.83 - 3.75 (m, 1H), 3.69 (t, 1H), 3.66 - 3.56 (m, 1H), 3.49 (ddd, 1H), 3.32 - 3.28 (m, 1H), 3.19 - 2.97 (m, 1H), 2.94 (ddd, 1H), 2.87 - 2.78 (m, 1H), 1.38 (d, 9H), 1.10 (d, 9H). UPLC-MS-8: Rt = 0.80 min; MS m/z [M+H] ⁺ 496.1.

Step 2: The mirror isomers (racemic mixtures) of N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 1, 233 mg, 0.47 mmol) were prepared by C-SFC-10 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 )). 63/37) Separation to give (R or S)-N-(6-(4-(4-acetylbrin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide: first (Example 12a) and second (Example 12b).

Example 12a : First eluted isomer: ^¹H NMR (600 MHz, DMSO- _d₆ ) δ 11.10 (s, ¹H), 8.47 (d, ¹H), 8.31 - 8.18 (m, 2H), 7.59 (d, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 4.95+5.37 (d, ¹H), 4.31 (dd, ¹H), 4.05 (d, ¹H), 3.85 - 3.77 (m, ¹H), 3.77 - 3.69 (m, ¹H), 3.64 - 3.57 (m, ¹H), 3.46 - 3.35 (m, 2H), 2.75 (td, 1H), 2.31 (s, 3H), 2.16 (d, 3H). UPLC-MS-8: Rt = 0.78 min; MS m/z [M+H] ⁺ 496.2. C-SFC-8 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 70/30): Rt = 3.01 min.

Example 12b : Second eluted isomer: ^¹H NMR (600 MHz, DMSO- _d₆ ) δ 11.10 (s, ¹H), 8.47 (d, ¹H), 8.31 - 8.18 (m, 2H), 7.59 (d, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 5.4+4.95 (s, 1H), 4.31 (dd, ¹H), 4.05 (d, 1H), 3.86 - 3.77 (m, 1H), 3.74 (dd, 1H), 3.61 (t, 1H), 3.46 - 3.37 (m, 2H), 2.78 - 2.71 (m, 1H), 2.31 (s, 3H), 2.17 (d, 3H). UPLC-MS-8: Rt = 0.78 min; MS m/z [M+H] ⁺ 496.2. C-SFC-8 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 70/30): Rt = 3.62 min.

Example 13 : N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide

Step 1: In a microwave-safe vial, pack intermediates C-M6 (127 mg, 0.297 mmol), A- _M4 (91 mg, 0.446 mmol), _K₃PO₄ (158 mg, 0.743 mmol), BrettPhos Pd G₃ (53.9 mg, 0.059 mmol), and anhydrous dimethyl ether (2 ml). Stir the reaction mixture at 10°C for 1.5 h. Cool the mixture to room temperature, dilute with EtOAc, and wash with _H₂O and brine. Dry and evaporate the organic layer using a phase separator. Purify the crude product using silica gel column chromatography (eluting with a gradient of MeOH (0-20%) in DCM). The fractions containing the desired product were combined and evaporated to give tributyl 3-(1-(3-fluoro-5-(2-(6-(trifluoromethyl)pyridin-2-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)tributyl 3-oxoline-4-carboxylate. UPLC-MS-2: Rt = 1.05 min; MS m/z [M+H] ⁺ 551.3.

Step 2: Add TFA (0.317 ml, 4.12 mmol) to a solution of 3-(1-(3-fluoro-5-(2-(6-(trifluoromethyl)pyridin-2-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)tributyl 3-oxoline-4-carboxylate (Step 1, 157.5 mg, 0.206 mmol) in DCM (1 ml), and stir the reaction mixture overnight at room temperature. Co-evaporate the reaction mixture with DCM (3x) to give a crude product, which is purified by RP-HPLC-2 (mobile phase: _H₂O + 7.3 mM _NH₄OH /ACN, 5% to 100%, over 20 min). The fractions containing the desired product were combined, frozen, and freeze-dried to give N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (racemic mixture). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.48 (d, 1H), 8.28 (dd, 1H), 8.18 (t, 1H), 8.10 (t, 1H), 7.83 (dd, 1H), 7.77 (d, 1H), 7.56 (q, 1H), 4.06 (d, 2H), 3.89 (dd, 1H), 3.79 (dd, 1H), 3.70 (dt, 1H), 3.41 (ddd, 1H), 3.30 - 3.26 (m, 1H), 2.83 (p, 2H). UPLC-MS-2: Rt = 0.50 min; MS m/z [M+H] ⁺ 451.1.

Step 3: A racemic mixture of N-(5-fluoro-6-(4-(olyolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (Step 2, 35.4 mg, 0.078 mmol) was separated by chiral preparative HPLC using C-HPLC-3 (mobile phase: n-heptane/EtOH/MeOH + 0.05% DEA (84:8:8)) to give the first (Example 13a) and second (Example 13b) eluted isomers. The received mirror isomers were then subjected to preparative HPLC using RP-HPLC-2 (mobile phase: ( _H₂O + 7.3 mM _NH₄OH /ACN 95:5 to 0:1)). 100) Repurification.

Example 13a : (R or S)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide: First eluted isomer: ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 10.98 (s, ¹H), 8.48 (d, ¹H), 8.29 (dd, ¹H), 8.18 (t, ¹H), 8.10 (t, ¹H), 7.83 (d, ¹H), 7.77 (d, ¹H), 7.56 (q, ¹H), 4.07 (s, 2H), 3.89 (dd, ¹H), 3.81 - 3.76 (m, 1H), 3.72 - 3.68 (m, 1H), 3.41 (ddd, 1H), 3.28 (m, 1H), 2.83 (m, 2H), 2.67 (s, 1H). UPLC-MS-2: Rt = 0.50 min; MS m/z [M+H] ⁺ 451.1. C-HPLC-4 (mobile phase: heptane + DEA : EtOH/MeOH (50 : 50) + DEA 84/16): Rt = 8.20 min.

Example 13b : (R or S)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide: Second eluted isomer: ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 10.97 (s, ¹H), 8.48 (d, ¹H), 8.28 (dd, ¹H), 8.18 (t, ¹H), 8.10 (t, ¹H), 7.83 (d, ¹H), 7.77 (d, ¹H), 7.58-7.55 (m, ¹H), 4.07 (s, 2H), 3.89 (dd, 1H), 3.79 (dd, 1H), 3.70 (dt, 1H), 3.41 (ddd, 1H), 3.31 - 3.25 (m, 1H), 2.85 - 2.80 (m, 2H), 2.72 - 2.63 (s, 1H). UPLC-MS-2: Rt = 0.50 min; MS m/z [M+H] ⁺ 451.1. HPLC-4 (mobile phase: heptane + DEA : EtOH/MeOH (50 : 50) + DEA 84/16): Rt = 10.99 min.

Example 14 : N-(3-cyano-5-fluoro-4-(1-(isoazolidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide

Step 1: Add intermediate B-M8 (102 mg, 0.210 mmol), 1.8 MK _2CO3 aqueous solution (0.318 ml, 0.573 mmol), and PdCl2 (dppf).DCM (7.8 mg, 0.010 mmol) to a solution _of intermediate D-T4 (80 mg, 0.191 mmol) in DME ( ₂ ml), and stir the reaction mixture at 90°C. After 3 days _, add another intermediate B-M8 (102 mg, 0.210 mmol), _PdCl2 (dppf).DCM (7.8 mg, 0.010 mmol), and _K2CO3 (79 mg, 0.573 mmol). After 4 days, add another _PdCl2 (dppf).DCM (31.2 mg, 0.038 mmol). The reaction mixture was partitioned between DCM and _H₂O . The organic layer was dried and evaporated using a phase separator. The crude product was purified by silica gel column chromatography (eluent: EtOAc/cyclohexane 0:100 to 100:0 and then changed to MeOH (0-20%) in DCM) to give 4-(4-(2-cyano-6-fluoro-4-(2-(6-(trifluoromethyl)pyridin-2-yl)acetamino)phenyl)-1H-pyrazol-1-yl)isoazolidine-2-carboxylic acid tributyl ester. UPLC-MS-2: Rt = 1.08 min; MS m/z [M+Na] ⁺ 583.4.

Step 2: Add TFA (0.162 ml, 2.098 mmol) to a solution of 4-(4-(2-cyano-6-fluoro-4-(2-(6-(trifluoromethyl)pyridin-2-yl)acetaminophen)phenyl)-1H-pyrazol-1-yl)isoazolidine-2-carboxylic acid tributyl ester (Step 1, 84 mg, 0.105 mmol) in DCM (1 ml). Stir the reaction mixture overnight at room temperature. Evaporate the mixture to dryness, filter using a syringe filter, and purify the crude product by RP-HPLC-2 (mobile phase: _H₂O + 7.3 mM _NH₄OH /ACN 95:5 to 0:100). The fractions containing the desired product are combined, frozen, and freeze-dried to give N-(3-cyano-5-fluoro-4-(1-(isoazolidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 8.38 (s, 1H), 8.08 (t, 1H), 8.01 (s, 1H), 7.92 - 7.86 (m, 2H), 7.80 (d, 1H), 7.74 (d, 1H), 5.81 (ddt, 1H), 4.54 (dd, 1H), 4.43 (dd, 1H), 4.10-4.01 (m, 2H), 4.04 (s, 2H). UPLC-MS-2: Rt = 0.81 min; MS m/z [M+H] ⁺ 461.3.

Example 15 : N-(3-cyano-5-fluoro-4-(1-(2-methylisoazolidine-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide

Paraformaldehyde (7.91 mg, 0.250 mmol) and HOAc (4.77 µl, 0.083 mmol) were added in portions to a solution of N-(3-cyano-5-fluoro-4-(1-(isoazolidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (Example 14, 33 mg, 0.042 mmol) in DCM (500 µl), followed by the fractional addition of NaBH(OAc) ₃ (54.7 mg, 0.250 mmol). The resulting suspension was stirred at room temperature for 5 h. Additional paraformaldehyde (7.91 mg, 0.250 mmol) and NaBH(OAc) _₃ (54.7 mg, 0.250 mmol) were added, and the reaction mixture was stirred overnight at room temperature. More paraformaldehyde (7.91 mg, 0.250 mmol), HOAc (4.77 µl, 0.083 mmol), and NaBH(OAc) _₃ (54.7 mg, 0.250 mmol) were added, and the reaction was stirred at room temperature for 72 h. Additional paraformaldehyde (7.91 mg, 0.250 mmol), HOAc (4.77 µl, 0.083 mmol), and NaBH(OAc) _₃ (54.7 mg, 0.250 mmol) were added, and the mixture was stirred at room temperature for 4 h to complete the reaction. The reaction mixture was diluted with DCM and a saturated aqueous solution of _NaHCO3 was added. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried using a phase separator, and evaporated. The crude product was purified by RP-HPLC-2 (mobile phase: _H2O + 7.3 mM _NH4OH /ACN 95:5 to 0:100). The fractions containing the desired product were combined, frozen, and lyophilized to give N-(3-cyano-5-fluoro-4-(1-(2-methylisoazolidine-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 8.30 - 8.24 (m, 1H), 8.09 (t, 1H), 7.94 - 7.89 (m, 1H), 7.89 - 7.85 (m, 2H), 7.83 (d, 1H), 7.76 (d, 1H), 5.57 - 5.47 (m, 1H), 4.15 - 4.06 (m, 1H), 4.04 (s, 2H), 3.94 - 3.75 (m, 1H), 3.49 (d, 1H), 3.03 - 2.77 (m, 1H), 2.73 - 2.62 (m, 3H). UPLC-MS-2: Rt = 0.88 min; MS m/z [M+H] ⁺ 475.4.

Example 16 : N-(5-fluoro-6-(4-(2-(3-hydroxypyrrolidin-1-yl)propyl-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide

Step 1: Add 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (120.1 mg, 577.0 µmol), DIPEA (149.1 mg, 201 µl, 1.154 mmol), and T3P (50% in EtOAc) (489.5 mg, 455.0 µl, 769.3 µmol) to a solution of intermediate C-M4 (150.0 mg, 384.6 µmol) in ACN (2.5 ml), and stir the reaction mixture at room temperature for 2 h. Additional 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (120.1 mg, 577.0 µmol), DIPEA (149.1 mg, 201 µl, 1.154 mmol), and T3P (50% in EtOAc) (489.5 mg, 455.0 µl, 769.3 µmol) were added, and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of _NaHCO3 . The phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layer was washed with brine, dried using a phase separator, and evaporated. The crude product was purified by silica gel column chromatography (using gradient elution of EtOAc (0-100%) in cyclohexane). The fractions containing the desired product were combined and evaporated to give tributyl (2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)propyl-2-yl)aminocarbamate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.07 (bs, 1H), 8.47 (d, 1H), 8.26 (dd, 1H), 8.15 (d, 1H), 7.44 (s, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 5.16 (s, 2H), 2.31 (s, 3H), 1.52 (d, 6H), 1.34 (s, 9H). UPLC-MS-8: Rt = 1.19 min; MS m/z [M+H] ⁺ 526.2.

Step 2: A solution of tributyl (2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)propyl-2-yl)aminocarbamate (Step 1, 171.0 mg, 90% wt, 292.9 µmol) and 4 M HCl/dimethylamine (213.6 mg, 1.464 ml, 5.857 mmol) in DCM (1 ml) was stirred for 2 h at room temperature. The reaction mixture was evaporated to dryness. The residue was dissolved in _H₂O , and the aqueous layer was alkalized with a saturated aqueous solution _{of NaHCO₃} , followed by extraction with DCM (2x). The combined organic layer was dried and evaporated using a phase separator to give N-(6-(4-(2-aminopropyl-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 8.46 (d, 1H), 8.25 (dd, 1H), 8.16 (s, 1H), 7.51 (s, 1H), 6.56 (s, 1H), 5.17 (s, 2H), 2.31 (s, 3H), 1.35 (s, 6H). UPLC-MS-8: Rt = 0.65 min; MS m/z [M+H] ⁺ 426.2.

Step 3: Add 1,4-dichlorobut-2-ol (17.38 mg, 13.5 µl, 121.5 µmol) to a solution of N-(6-(4-(2-aminopropyl-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 2, 50.00 mg, 110.5 µmol) and Et ₃ N (55.90 mg, 77.0 µl, 5 equivalents, 552.4 µmol) in DMF (0.500 ml) and stir the reaction mixture at 100°C for 1 h using microwave irradiation. Add additional _Et3N (55.90 mg, 77.0 µl, 552.4 µmol) and 1,4-dichlorobut-2-ol (17.38 mg, 13.5 µl, 121.5 µmol), and continue stirring the reaction mixture at 100°C using microwave irradiation for 4 h. Add more _Et3N (55.90 mg, 77.0 µl, 552.4 µmol) and 1,4-dichlorobut-2-ol (17.38 mg, 13.5 µl, 121.5 µmol), and continue stirring overnight at 100°C using a heating block. Dilute the reaction mixture with EtOAc and wash with _H2O and brine. Dry and evaporate the combined organic layer using a phase separator. The crude product was purified by silica gel column chromatography (using gradient elution of MeOH (0-90%) in DCM + 0.2% 7N NH3 ₎ . Fractions containing the desired product were combined, evaporated, and further purified using a preparative RP-HPLC-3 (mobile phase: _H2O + 0.1% TFA/ACN 95:5 to 0:100). Fractions containing the desired compound were combined, and the aqueous solution was extracted with DCM (3x). The combined organic layers were dried and concentrated using a phase separator to give N-(5-fluoro-6-(4-(2-(3-hydroxypyrrolidin-1-yl)propyl-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.47 (dd, 1H), 8.27 (dd, 1H), 8.18 (s, 1H), 7.56 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 4.55 (s, 1H), 4.10 - 4.01 (m, 1H), 2.91 - 2.78 (m, 1H), 2.76 - 2.67 (m, 1H), 2.64 - 2.56 (m, 1H), 2.44 - 2.37 (m, 1H), 2.32 (s, 3H), 1.87 - 1.74 (m, 1H), 1.44 (m, 1H), 1.41 (s, 6H). UPLC-MS-8: Rt = 0.69 min; MS m/z [M+H] ⁺ 496.2.

Example 17 : N-(5-fluoro-6-(4-(2-(2-sideoxypyrrolidin-1-yl)propyl-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide

Step 1: A solution of N-(6-(4-(2-aminopropyl-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 16/Step 2, 150.0 mg, 292.0 µmol), methyl 4-sideoxybutyrate (67.81 mg, 61.15 µl, 584.0 µmol), and HOAc (17.53 mg, 16.71 µl, 292.0 µmol) in MeOH (3.0 ml) was stirred at room temperature for 20 min. NaBH(OAc) ₃ (123.8 mg, 584.0 µmol) was added, and the reaction mixture was stirred at room temperature for 72 h. Methyl 4-sideoxybutyrate (67.81 mg, 61.15 µl, 584.0 µmol) and HOAc (17.53 mg, 16.71 µl, 292.0 µmol) were added to the reaction mixture, followed by the addition of NaBH(OAc) _₃ (123.8 mg, 584.0 µmol). The reaction mixture was diluted with DCM and carefully quenched with _H₂O and washed with a saturated aqueous solution of _NaHCO₃ . The phases were separated and the aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried ( _Na₂SO₄ ), and evaporated. The crude product was purified by silica gel column chromatography (eluting with a gradient of MeOH (0-20%) in DCM ₎ . The fractions containing the product are combined and evaporated to give methyl 4-((2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)propyl-2-yl)amino)butyrate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.47 (d, 1H), 8.26 (dd, 1H), 8.18 (s, 1H), 7.49 (s, 1H), 6.56 (s, 1H), 5.17 (s, 2H), 3.54 (s, 3H), 2.34 - 2.29 (m, 7H), 1.58 (p, 2H), 1.33 (s, 6H). UPLC-MS-8: Rt = 0.66 min; MS m/z [M+H] ⁺ 526.2.

Step 2: A solution of methyl 4-((2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)propyl-2-yl)amino)butyrate (Step 1, 37.80 mg, 68.33 µmol) and 2-hydroxypyridine (13.00 mg, 136.7 µmol) in toluene (0.60 ml) was stirred under microwave irradiation at 120°C for 7 h. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with a saturated aqueous solution of _NaHCO3 and brine. The organic layer was dried and evaporated using a phase separator. The crude product was purified by silica gel column chromatography (using gradient elution of MeOH (0-20%) in DCM). Fractions containing the desired product were combined, evaporated, and further purified by RP-HPLC (using gradient elution of ACN (5%-100%) in _H₂O + 0.1% NH₄OH). Fractions containing the desired product were combined, _a saturated aqueous solution of NaHCO₃ was added, and the aqueous solution was extracted with DCM (3x). The combined organic layer was dried using a phase separator, evaporated, and further purified by RP-HPLC (using gradient elution of ACN (5%-100%) in _H₂O + 0.1% HCOOH). Fractions containing the desired product were combined, and the aqueous solution was extracted with DCM (3x). The combined organic layers were dried and concentrated using a phase separator. The residue was ground in ACN/ _H₂O (1/2), frozen, and freeze-dried to give N-(5-fluoro-6-(4-(2-(2-sideoxypyrrolidin-1-yl)prop-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 8.45 (d, 1H), 8.28 (dd, 1H), 8.17 (dd, 1H), 7.52 (t, 1H), 6.59 - 6.53 (m, 1H), 5.16 (s, 2H), 3.38 (t, 2H), 2.31 (d, 3H), 2.18 (dd, 2H), 1.89 - 1.78 (m, 2H), 1.69 (s, 6H). UPLC-MS-8: Rt = 0.93 min; MS m/z [M+H] ⁺ 494.1.

Example 18 : N-(5-fluoro-6-(4-(2-sideoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide

Under argon atmosphere _, intermediates D-M4 (150.0 mg, 332.1 µmol), CuI (94.87 mg, 1.5 equivalents, 498.1 µmol), and _K₂CO₃ (137.7 mg, 3 equivalents, 996.2 µmol) were charged into a sealed tube, followed by the addition of ACN (5 ml), pyrrolidone-2-one (56.53 mg, 50.5 µl, 664.1 µmol), and trans-(1r,2r)-N,N'-dimethyl-1,2-cyclohexanediamine (141.7 mg, 157 µl, 498.1 µmol). The reaction mixture was stirred overnight at 90°C. The reaction mixture was diluted with EtOAc and washed with _H₂O . The phases were separated, and the aqueous layer was extracted with EtOAc and DCM. The combined organic layers were washed with brine, dried and evaporated using a phase separator. The crude product was purified by RP-HPLC (using a gradient elution of 10%-100% ACN in _H₂O + 0.1% HCOOH). The fractions containing the desired product were combined, a saturated aqueous solution _{of NaHCO₃} was added, and the aqueous solution was extracted with DCM (3x). The combined organic layers were dried and evaporated using a phase separator. The residue was ground in 1.5 ml of ACN, centrifuged, and the supernatant was removed. The remaining solid was dried under high vacuum to produce N-(5-fluoro-6-(4-(2-sideoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 8.48 (d, 1H), 8.29 (dd, 1H), 8.18 (t, 1H), 7.98 (d, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 3.91 (t, 2H), 2.47 (d, 2H), 2.31 (s, 3H), 2.11 (p, 2H). UPLC-MS-2: Rt = 0.87 min; MS m/z [M+H] ⁺ 452.2.

Example 19 : N-(6-(4-(5,6-dihydro-1,4-oxothiacyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

T₃P (50% in EtOAc) (0.257 ml, 0.431 mmol) was added to a solution of 2-(5-methyl- _3- (trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (71.8 mg, 0.345 mmol), intermediate C-M8 (80 mg, 0.287 mmol), and DIPEA (0.151 ml, 0.862 mmol) in THF (2 ml), and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO_₃ (2x). The organic phase was dried (Na _₂SO_₄ ) and concentrated. The crude product was purified by RP-HPLC (using a gradient elution of ACN (0-70%) in _H₂O + 0.1% _NH₄OH ). Fractions containing the desired product were combined and freeze-dried to give N-(6-(4-(5,6-dihydro-1,4-oxothiacyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.46 (d, 1H), 8.26 (dd, 1H), 8.24 (t, 1H), 7.53 (t, J1H), 6.57 (s, 1H), 5.96 (d, 1H), 5.18 (s, 2H), 4.40 - 4.33 (m, 2H), 3.11 - 3.05 (m, 2H), 2.31 (d, 3H). UPLC-MS-2: Rt = 1.06 min; MS m/z [M+H] ⁺ 469.1.

Example 20 : N-(6-(4-(4,4-dioxy-5,6-dihydro-1,4-oxothiacyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

At 0°C, mCPBA (99 mg, 0.58 mmol) was added to a mixture of N-(6-(4-(5,6-dihydro-1,4-oxothiacyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 19, 90 mg, 0.19 mmol) in DCM (4 ml), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 10 ml of ₅ % _{Na₂S₂O₃} , stirred at room temperature for 30 min, diluted with _{H₂O ,} and extracted with DCM (3x). The combined organic phase was washed with a saturated aqueous solution _{of NaHCO3} , dried ( _{Na2SO4 )} , and concentrated to give N-(6-(4-(4,4-dioxy-5,6-dihydro-1,4-oxothiacyclohexadien-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.17 (s, 1H), 8.50 (d, 1H), 8.38 (t, 1H), 8.29 (dd, 1H), 8.06 (t, 1H), 6.57 (s, 1H), 6.43 - 6.39 (m, 1H), 5.20 (s, 2H), 4.84 - 4.77 (m, 2H), 3.66 - 3.59 (m, 2H), 2.33 - 2.28 (m, 3H). UPLC-MS-2: Rt = 0.76 min; MS m/z [M+H] ⁺ 501.3.

Example 21 : N-(6-(4-(4,4-dioxy-1,4-oxothiacyclohexane-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Pd/C (77 mg, 10% wt, 72 µmol) was added to a solution of Example 20 (72 mg, 0.14 mmol) and HOAc (43 mg, 41 µl, 0.72 mmol) in MeOH (5 ml) and THF (3 ml). The resulting suspension was stirred at room temperature under hydrogen atmosphere for 24 h. Additional Pd/C (77 mg, 10% wt, 72 µmol) was added and the suspension was stirred under hydrogen atmosphere for another 48 h. More Pd/C (77 mg, 10% wt, 72 µmol) was added and the suspension was stirred under hydrogen atmosphere for another 24 h. The reaction mixture was filtered through a ^Hyflo® mat and washed with MeOH and DCM. The filtrate was concentrated and purified by RP-HPLC (elution with a gradient of ACN (0-60%) in _H₂O + 0.1% _NH₄OH ). The fractions containing the desired product were combined and lyophilized to give: N-(6-(4-(4,4-dioxy-1,4-oxothiacyclohexane-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.42 (d, 1H), 8.28 (dd, 1H), 8.23 (s, 1H), 7.78 (s, 1H), 6.55 (s, 1H), 5.12 (s, 2H), 4.88 (dd, 1H), 4.32 (ddd, 1H), 3.96 (td, 1H), 3.56 - 3.51 (m, 1H), 3.44 (ddd, 1H), 3.36 - 3.29 (m, 1H), 3.26 - 3.21 (m, 1H), 2.30 (s, 3H). UPLC-MS-2: Rt = 0.71 min; MS m/z [M+H] ⁺ 503.1.

Example 22 : 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-methoxypyridin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide

Intermediates D-T2 (50 mg, 0.108 mmol), Pd(PPh3)4 (12.53 mg, 10.84 µmol), CuI (10.32 mg, 0.054 mmol), and LiCl (9.19 mg, 0.217 mmol) were mixed in a sealed flask under argon atmosphere. A solution of 3-methoxy-2-(tributylmethylenestanyl)pyridine (216 mg, 0.542 mmol) in anhydrous dimethyl ether (2 ml) was added, and the reaction mixture was stirred at 100°C for 23 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with a saturated aqueous solution of _NaHCO3 , dried ( _{Na2SO4 )} , and concentrated. The crude product was purified by RP-HPLC (using gradient elution of ACN (10%-70%) in _H₂O + 0.1% HCOOH). The fraction containing the desired product was collected, freeze-dried, and further purified by silica gel column chromatography (using gradient elution of MeOH 7N _NH₃ (0-100%) in DCM). The fraction containing the desired product was collected and concentrated to give 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-methoxypyridin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 8.52 (d, 1H), 8.36 - 8.30 (m, 2H), 8.27 (t, 1H), 8.23 (dd, 1H), 7.78 (t, 1H), 7.75 - 7.71 (m, 1H), 7.53 (dd, 1H), 7.42 (t, 1H), 7.29 (dd, 1H), 3.97 (s, 2H), 3.95 (s, 3H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ 490.4.

Example 23 : N-(5-fluoro-6-(4-(4-methyl-3-sideoxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide

Intermediate D-T3 (30 mg, 0.068 mmol), 1-methylpiperazine-2-one (12.21 mg, 0.081 mmol), NaOtBu (19.47 mg, 0.203 mmol), and tBuXPhos Pd G3 (5.37 mg, 6.75 µmol) were mixed in a sealed vial under argon atmosphere. Anhydrous DMA (0.5 ml) was added, and the reaction mixture was stirred at 100°C for 1.5 h. The reaction mixture was diluted with EtOAc and washed with a _saturated aqueous solution of _NaHCO3 . The organic phase was dried ( _Na2SO4 ) and concentrated. The crude material was purified by RP-HPLC (using a gradient elution of ACN in _H2O + 0.1% HCOOH). The fraction containing the desired product was collected, alkalized with _NaHCO3 , and extracted with EtOAc ( _2x ). The organic phase was dried ( _Na2SO4 ), concentrated, and purified by silica gel column chromatography (using a gradient elution of EtOAc/EtOH (3/1: 0-100%) in cyclohexane). The fraction containing the desired product was combined and concentrated to give N-(5-fluoro-6-(4-(4-methyl-3-sideoxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.45 (d, 1H), 8.33 (dd, 1H), 8.16 (d, 1H), 8.05 (t, 1H), 7.74 (dd, 2H), 7.17 (t, 1H), 4.08 (s, 2H), 3.76 (s, 2H), 3.58 - 3.47 (m, 4H), 3.03 (s, 3H). UPLC-MS-2: Rt = 0.77 min; MS m/z [M+H] ⁺ 478.5.

Example 24 : 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide

Step 1: Add intermediate D-T5 (40 mg, 0.114 mmol), tBuXPhos Pd G3 (18.12 mg, 0.023 mmol), _{and K3PO4} (72.6 mg, 0.342 mmol) to a microwave-safe vial, and add intermediate B-M12 (30 mg, 0.116 mmol) in anhydrous dimethyl ether (1 ml). Degas the reaction mixture with argon and stir overnight at 100°C under an inert atmosphere. Add the remaining tBuXPhos Pd G3 ( _18.12 mg, 0.023 mmol) and _K3PO4 (72.6 mg, 0.342 mmol), and continue stirring at 100°C for 1 h. The reaction mixture was diluted with _H₂O and DCM. The phases were separated and the aqueous layer was extracted with DCM (2x). The combined organic layer was dried and evaporated using a phase separator to give tributyl 3-(1-(3-fluoro-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaminophen)pyridin-2-yl)-1H-imidazol-4-yl)carboxylate, which was used for the next step without further purification. UPLC-MS-2: Rt = 1.20 min; MS m/z [M+H] ⁺ 568.5.

Step 2: Dissolve 3-(1-(3-fluoro-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaminophen)pyridin-2-yl)-1H-imidazol-4-yl)tributyl 3-oxoline-4-carboxylate (Step 1, 124.6 mg, 0.068 mmol) in DCM and add TFA (0.264 ml, 3.42 mmol). Stir the reaction mixture at room temperature for 1 h. Evaporate the reaction mixture and purify the product by RP-HPLC (using a gradient elution of ACN (1%-100%) in _H₂O + 7.3 mM _NH₄OH ). Fractions containing the desired product are combined, frozen, and freeze-dried to give 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 8.48 (d, 1H), 8.28 (dd, 1H), 8.20 (d, 1H), 7.77 (t, 1H), 7.74 - 7.70 (m, 1H), 7.60 (s, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 3.91 (dd, 1H), 3.86 (s, 1H), 3.73 (dt, 1H), 3.45 (ddd, 1H), 3.31 (s, 1H), 2.90 - 2.83 (m, 2H). UPLC-MS-2: Rt = 1.20 min; MS m/z [M+H] ⁺ 468.3.

Example 25 : N-(6-(4-(3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide, N-(6-(4-((1r,3r)-3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5 5-Fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and N-(6-(4-((1s,3s)-3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Add 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (99.1 mg, 1.5 equivalents, 476 µmol), DIPEA (123 mg, 166 µl, 3 equivalents, 952 µmol) and T3P (50% in EtOAc) (404 mg, 375 µl, 2 equivalents, 635 µmol) to a solution of intermediate C-T6 (121 mg, 317 µmol) in ACN (2.0 ml), and stir the reaction mixture at room temperature for 2 h. Add additional DIPEA (123 mg, 166 µl, 952 µmol) and T3P (50% in EtOAc) (404 mg, 375 µl, 635 µmol), and stir the reaction mixture overnight at room temperature. Dilute the reaction mixture with EtOAc and wash with a saturated aqueous solution of _NaHCO3 . Separate the phases and extract the aqueous layer with EtOAc (2x). Wash the combined organic layer with brine, dry and evaporate using a phase separator. Dissolve the crude material in THF (2 ml) and add a 1 M aqueous solution of NaOH (0.04 g, 1 ml, 1 mmol). Stir the clear orange solution at room temperature for 1.5 h. Dilute the reaction mixture with a saturated aqueous solution of EtOAc and _NH4Cl . The phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layer was washed with brine, dried using a phase separator, and evaporated. The crude product was purified by silica gel column chromatography (using a gradient elution of MeOH (0-20%) in DCM). The fractions containing the desired product were combined and evaporated to give a mixture of ((3-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxycyclobutyl)methyl)aminocarbamate tributyl ester and its isomers. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.47 (t, 1H), 8.26 (dt, 1H), 8.20 (q, 1H), 7.50 (dt, 1H), 6.85 (q, 1H), 6.57 (s, 1H), 5.39 (d, 1H), 5.18 (s, 2H), 3.04 - 2.97 (m, 2H), 2.45 - 2.40 (m, 1H), 2.31 (s, 3H), 2.26 - 2.06 (m, 2H), 1.94 - 1.88 (m, 1H), 1.37(d,9H). UPLC-MS-2: Rt = 1.04-1.05 min; MS m/z [M+H] ⁺ 568.2.

Step 2: Add TFA (630.4 mg, 426.0 µl, 5.529 mmol) to a solution of tributyl (3-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetaminophen)pyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxycyclobutyl)methyl)aminocarbamate (Step 1, 156.9 mg, 276.5 µmol) in DCM (1.50 ml). Stir the reaction mixture at room temperature for 3 h. Co-evaporate the reaction mixture with DCM (3x), dissolve it in DCM (10 ml), neutralize to pH 8 with ammonia/MeOH, and concentrate. The crude product was purified by reversed-phase RP-HPLC-3: (mobile phase: _H₂O + 0.1% _NH₄OH /ACN 05:95 to 0:100). Fractions containing the desired product were combined, frozen, and lyophilized to give N-(6-(4-(3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (racemic mixture). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.12 (Bs, 1H), 8.46 (d, 1H), 8.26 (dt, 1H), 8.22 - 8.17 (m, 1H), 7.55 - 7.44 (m, 1H), 6.73 (s, 0H), 6.57 (s, 1H), 5.42 - 5.36 (m, 1H), 5.18 (s, 2H), 3.03 (q, 1H), 2.63 (d, 1H), 2.57 - 2.53 (m, 1H), 2.46 - 2.41 (m, 1H), 2.31 (s, 3H), 2.24 - 2.09 (m, 2H), 1.96 - 1.86 (m, 1H). ). UPLC-MS-8: Rt = 0.53 min; MS m/z [M+H] ⁺ 468.1.

Step 3: N-(6-(4-((1r,3r)-3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and N-(6-(4-((1s,3s)-3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl) A mixture of N-(6-(4-(3-(aminomethyl)-1-hydroxycyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (step 2, 99.30 mg, 212 µmol) was separated by chiral C-SFC-13 (mobile phase: CO ₂ /(MeOH + 0.05% NH ₃ ) 50/50) to give the first (Example 25a) and second (Example 25b) eluted isomers.

Example 25a : First eluted isomer: ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 8.46 (d, ¹H), 8.26 (dd, ¹H), 8.21–8.17 (m, ¹H), 7.48–7.44 (m, ¹H), 6.56 (s, ¹H), 5.35 (d, ¹H), 5.17 (s, 2H), 3.04 (t, ¹H), 2.62 (d, 2H), 2.41–2.37 (m, ¹H), 2.31 (s, 3H), 2.24–2.12 (m, 4H). UPLC-MS-8: Rt = 0.51 min; MS m/z [M+H] ⁺ 468.4. C-SFC-5 CO ₂ /(MeOH + 0.05% NH ₃ ) 50/50): Rt = 1.05 min.

Example 25b : Second eluted isomer: ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 8.47 (d, ¹H), 8.26 (dd, ¹H), 8.19 (t, ¹H), 7.54 - 7.51 (m, ¹H), 6.56 (s, ¹H), 5.37 (s, OH), 5.17 (s, 2H), 3.03 (t, ¹H), 2.63 - 2.60 (m, 2H), 2.44 (d, ¹H), 2.31 (s, 3H), 2.13 - 2.06 (m, ¹H), 1.91 (dt, 2H). UPLC-MS-8: Rt = 0.51 min; MS m/z [M+H] ⁺ 468.4. C-SFC-5 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 50/50): Rt = 2.90 min.

Example 26 : N-(5-fluoro-6-(4-(2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide and N-(5-fluoro-6-(4-((1S,(2R or 2S))-2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyridin-1-yl)acetamide

Step 1: At room temperature, 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (121.6 mg, 0.584 mmol), T3P (50% in EtOAc) (0.474 ml, 0.797 mmol), and DIPEA (0.278 ml, 1.593 mmol) were added to a solution of intermediate C-T14 (200 mg, 0.531 mmol) in THF (6.8 ml). After 2.5 h, the reaction mixture was diluted with EtOAc and washed with saturated _NaHCO3 aqueous solution and saturated _NH4Cl aqueous solution. The organic layer was dried (phase separator) and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (eluent: DCM : MeOH 9 : 1/DCM 0 : 100 to 45 : 55) to give N-(6-(4-(2-((tributyldimethylsilyl)oxy)cyclopentyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. UPLC-MS-8: Rt = 1.64 min; MS m/z [M+H] ⁺ 567.4.

Step 2: A solution of N-(6-(4-(2-((tributyldimethylsilyl)oxy)cyclopentyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 1, 196 mg, 345.9 µmol) and HCl (1.25 M/MeOH) (30.3 mg, 0.664 ml, 830.1 µmol) in MeOH (3.3 ml) was stirred at 40°C for 7 h. A saturated aqueous solution _{of NaHCO3} was added to the reaction mixture, extracted with EtOAc (2x), and washed with brine. The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The residue was purified by normal phase chromatography (eluent: DCM : MeOH 9 : 1 / DCM 0 : 100 to 90 : 10) to give N-(5-fluoro-6-(4-(2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.05 (s, 1H), 8.49 - 8.44 (m, 1H), 8.25 (dd, 1H), 8.19 - 8.13 (m, 1H), 7.47 (s, 1H), 6.56 (s, 1H), 5.17 (s, 2H), 4.64 (d, 1H), 4.11 (q, 1H), 2.90 - 2.81 (m, 1H), 2.31 (s, 3H), 2.07 - 1.96 (m, 1H), 1.92 - 1.80 (m, 1H), 1.79 - 1.59 (m, 3H), 1.57 - 1.45 (m, 1H). UPLC-MS-8: Rt = 0.86 min; MS m/z [M+H] ⁺ 453.0.

Step 3: The mirror isomer of N-(5-fluoro-6-(4-(2-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (trans according to NMR) (Step 2, 140 mg) was separated by C-SFC-28 (mobile phase: CO ₂ /(MeOH + 0.05% NH ₃ ) 65/35).

Example 26a : First eluted isomer: ^¹H NMR (400 MHz, DMSO _-d⁶ ) δ 11.08 (s, ¹H), 8.48 - 8.43 (m, ¹H), 8.25 (dd, ¹H), 8.18 - 8.13 (m, ¹H), 7.47 (s, ¹H), 6.56 (s, ¹H), 5.17 (s, 2H), 4.63 (d, ¹H), 4.10 (q, ¹H), 2.90 - 2.81 (m, ¹H), 2.31 (s, 3H), 2.09 - 1.94 (m, ¹H), 1.93 - 1.80 (m, ¹H), 1.80 - 1.58 (m, d⁶) 3H), 1.58 - 1.45 (m, 1H). UPLC-MS-8: Rt = 0.87 min; MS m/z [M+H] ⁺ 453.3. C-SFC-15 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 75/25): Rt = 2.96 min.

Example 26b : Second eluted isomer: ^¹H NMR (400 MHz, DMSO _-d⁶ ) δ 11.07 (s, ¹H), 8.48–8.43 (m, ¹H), 8.25 (dd, ¹H), 8.18–8.13 (m, ¹H), 7.47 (s, ¹H), 6.56 (s, ¹H), 5.17 (s, 2H), 4.64 (d, ¹H), 4.10 (q, ¹H), 2.89–2.83 (m, ¹H), 2.31 (s, 3H), 2.09–1.96 (m, ¹H), 1.93–1.80 (m, ¹H), 1.80–1.58 (m, d⁶) 3H), 1.58 - 1.43 (m, 1H). UPLC-MS-8: Rt = 0.87 min; MS m/z [M+H] ⁺ 453.3. C-SFC-15 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 75/25): Rt = 4.05 min.

Example 27 : (S)-3-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-1-methylurea

Step 1: At room temperature, add intermediate C-T40 (150 mg, 0.390 mmol) to a solution of 2-fluoro-N-methyl-3-(trifluoromethyl)aniline [CAS No. 1261808-48-3] (226 mg, 40% wt, 0.468 mmol) and CDI (253 mg, 1.561 mmol) in DMSO (5 ml). After 5 days, dilute the reaction mixture with _H2O and extract with TBME. The organic layer was dried (phase separator) and concentrated under reduced pressure, and the residue was purified by normal phase chromatography (eluent: EtOAc/cyclohexane 15:85 to 100:0) to give (S)-4,4-difluoro-2-(1-(3-fluoro-5-(3-(2-fluoro-3-(trifluoromethyl)phenyl)-3-methylureido)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester. UPLC-MS-8: Rt = 1.23 min; MS m/z [M+H] ⁺ 604.2.

Step 2: A solution of (S)-4,4-difluoro-2-(1-(3-fluoro-5-(3-(2-fluoro-3-(trifluoromethyl)phenyl)-3-methylureido)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester (Step 1, 102 mg, 169 µmol) and HCl (4 M/dioxane) (61.6 mg, 0.422 ml, 1.69 mmol) in DCM (5 ml) was stirred at room temperature for 5 h. The reaction mixture was evaporated to dryness. The residue was dissolved in _H₂O and the aqueous layer was alkalized with a saturated _NaHCO₃ aqueous solution and then extracted with DCM (2×). The combined organic layer was dried and evaporated using a phase separator. The residue was purified by normal phase chromatography (eluent: DCM/MeOH 95:5 to 70:30) to give (S)-3-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-1-methylurea. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 1.40 (br s, 1 H) 2.53 - 2.59 (m, 1 H) 2.61 - 2.71 (m, 1 H) 3.12 - 3.20 (m, 1 H) 3.40 - 3.52 (m, 1 H) 4.51 (br t, 1 H) 7.50 (br t, 1 H) 7.78 (br s, 1 H) 7.88 (br s, 1 H) 8.18 (br d, 1 H) 8.47 (br s, 1 H) 9.03 (br s, 1 H) 9.23 (br s, 1 H). UPLC-MS-8: Rt = 0.92 min; MS m/z [M+H] ⁺ 504.0.

Example 28 : N-(4-(1-((1-benzyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

Add 1-chloro-N,N,2-trimethylprop-1-en-1-amine [CAS No. 26189-59-3] (0.219 ml, 1.658 mmol) to a solution of 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] (184 mg, 0.829 mmol) in THF (1.5 ml), and stir the reaction mixture at room temperature under argon for 30 min. Then add the mixture to a suspension of intermediate C-T24 (190 mg, 0.332 mmol) and DIPEA (0.174 ml, 0.995 mmol) in THF (1.5 ml) and continue stirring at room temperature under argon for 45 min. The reaction was quenched with _H₂O and extracted with EtOAc (2×), and the combined organic layer was washed with brine, dried and evaporated using an SPE phase separator column. The crude product was purified by RP-HPLC-2 (mobile phase: ACN/( _H₂O + 0.1% _NH₄OH )₅/95 to 100/0) to give N-(4-(1-((1-benzyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.12 (s, 1H), 7.87 - 7.82 (m, 3H), 7.78 - 7.69 (m, 2H), 7.40 (t, 1H), 7.32 - 7.26 (m, 2H), 7.26 - 7.21 (m, 1H), 7.19 (d, 1H), 7.11 - 7.06 (m, 2H), 6.92 (d, 1H), 5.52 (s, 2H), 5.33 (s, 2H), 3.92 (s, 2H). UPLC-MS-2: Rt = 1.08 min; MS m/z [M+H] ⁺ 577.3.

Example 29 : N-(6-(4-(2-(1,3,4-diazol-2-yl)propyl-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Add 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (94.0 mg, 452 µmol), T3P (196 mg, 182 µl, 616 µmol), and DIPEA (159 mg, 215 µl, 1.23 mmol) to a solution of intermediate C-T25 (120 mg, 411 µmol) in THF (1.5 ml). Stir the reaction mixture at room temperature for 84 h. Dilute the reaction mixture with 20 ml of DCM and then wash with 10 ml of saturated _NaHCO3 and _NH4Cl aqueous solution. Dry the organic phase (phase separator) and concentrate under vacuum. The residue was purified by normal-phase chromatography (elution buffer: cyclohexane/EtOAc 100:0 to 0:100, over 7 min, followed by 100% EtOAc, 10 min) to give ethyl 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)-2-methylpropionate. UPLC-MS-2: Rt = 1.12 min; MS m/z [M+H] ⁺ 483.3.

Step 2: Add LiOH·H₂O (78.3 mg, 1.87 mmol) to a solution of ethyl 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin- ₂ -yl)-1H-imidazol-4-yl)-2-methylpropionate (Step 1, 180 mg, 373 µmol) in THF (1 ml) and _H₂O (0.2 ml). Stir the reaction mixture at room temperature for 18 h. Dilute the reaction mixture with _H₂O and carefully neutralize it by adding dropwise 4 M HCl aqueous solution to adjust the pH to 5-6. Extract the crude reaction mixture twice with a DCM/MeOH (v/v 9:1) mixture. The combined organic phase was dried (using a phase separator) and concentrated under vacuum to give crude 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)-2-methylpropionic acid, which was used in the next step without further purification. UPLC-MS-2: Rt = 0.88 min; MS m/z [M+H] ⁺ 455.3.

Step 3: Add hydrazine (1 M/THF) (24.3 mg, 759 µl, 759 µmol), T3P (242 mg, 225 µl, 759 µmol), and DIPEA (164 mg, 220 µl, 1.27 mmol) to a solution of 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetaminophen) in THF (1 ml) to the solution. The reaction mixture was stirred at room temperature for 18 h. Add additional hydrazine (24.3 mg, 759 µl, 1 mol, 759 µmol), DIEA (164 mg, 220 µl, 1.27 mmol), and T3P (242 mg, 225 µl, 759 µmol) and continue stirring at room temperature for another 60 h. Repeat the addition of the last reagent and stir at room temperature for another 18 h to complete the reaction. Dilute the reaction mixture with 10 ml of DCM and then wash with 5 ml of _H2O . Dry the organic phase (phase separator) and concentrate under vacuum. The residue was purified by normal-phase chromatography (eluent: DCM/MeOH 100:0 to 90:10 over 12 min, then isocratic 90:10 for 10 min) to give N-(5-fluoro-6-(4-(1-hydrazino-2-methyl-1-sideoxyprop-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. UPLC-MS-2: Rt = 0.78 min; MS m/z [M+H] ⁺ 469.3.

Step 4: Add p-TsOH (0.91 mg, 4.8 µmol) to a solution of N-(5-fluoro-6-(4-(1-hydrazino-2-methyl-1-sideoxyprop-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 3, 15 mg, 32 µmol) in trimethyl orthoformate (0.34 g, 0.35 ml, 3.2 mmol). Stir the reaction mixture at 110°C for 6 h. Purify the crude mixture directly by RP-HPLC-2 (mobile phase: ACN/( _H₂O + 0.1% _NH₄OH ) 5/95 to 100/0). The pure fractions were combined and the volatiles were removed under reduced pressure, followed by freeze-drying overnight to give N-(6-(4-(2-(1,3,4-diazol-2-yl)propyl-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.12 (s, 1H), 8.47 (d, 1H), 8.27 (dd, 1H), 8.18 (s, 1H), 7.66 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 2.31 (s, 3H), 1.75 (s, 6H). UPLC-MS-2: Rt = 0.89 min; MS m/z [M+H] ⁺ 479.3.

Example 30 : N-(4-(1-((1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

Pd-C (10%) (31.4 mg, 0.295 mmol) was added to a solution of N-(4-(1-((1-benzyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide (Example 28, 170 mg, 0.295 mmol) in MeOH (2.5 ml) and DCM (2.5 ml). The reaction mixture was heated at 50°C for 18 h. The reaction mixture was filtered through ^Celite® and washed with MeOH. The solvent was removed under reduced pressure and the crude mixture was purified by RP-HPLC-2 (mobile phase: ACN/( _H₂O + 0.1% _NH₄OH ) 5/95 to 100/0). The pure fractions were combined and the volatiles were removed under reduced pressure, followed by freeze-drying overnight to give N-(4-(1-((1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 12.24 (s, 1H), 10.83 (s, 1H), 8.21 (s, 1H), 7.89 - 7.83 (m, 3H), 7.78 - 7.70 (m, 2H), 7.40 (t, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 5.41 (s, 2H), 3.92 (s, 2H). UPLC-MS-2: Rt = 0.85 min; MS m/z [M+H] ⁺ 487.2.

Example 31 : N-(3-cyano-5-fluoro-4-(1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

Add K₂CO₃ (35.8 mg, 0.259 mmol) and MeI (0.016 ml, 0.259 mmol) to a solution of N-(4-(1-((1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)-3-cyano- ₅ -fluorophenyl)-2-(2-fluoro- _3- (trifluoromethyl)phenyl)acetamide (Example 30, 70 mg, 0.130 mmol) in DMF (1 ml). Stir the reaction mixture at room temperature for 18 h. Dilute the reaction mixture with EtOAc and then wash with 3 ml _H₂O . Dry the organic phase (phase separator) and concentrate under vacuum. The residues were purified by normal-phase chromatography (eluent: DCM/MeOH 100:0 to 95:5 over 15 min, then isocratic 95:5 for 5 min) followed by RP-HPLC-4 (mobile phase: ( _H₂O + 0.1% TFA)/(ACN + 0.1% TFA) 73/27 to 53/47). The purified fractions were combined and the volatiles were removed under reduced pressure, followed by freeze-drying overnight to give N-(3-cyano-5-fluoro-4-(1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.91 - 7.86 (m, 2H), 7.78 - 7.70 (m, 2H), 7.63 (s, 1H), 7.55 (s, 1H), 7.41 (t, 1H), 5.82 (s, 2H), 3.93 (s, 2H), 3.84 (s, 3H). UPLC-MS-2: Rt = 0.85 min; MS m/z [M+H] ⁺ 501.4.

Example 32 : N-(6-(4-(1,1-dioxothiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Dissolve intermediate C-T41 (320.0 mg, 90% wt, 1 equivalent, 759.0 µmol) in 6 ml THF, and add 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (189.6 mg, 1.2 equivalent, 910.8 µmol), DIPEA (588.6 mg, 793 µl, 6.0 equivalent, 4.554 mmol) and T3P (50% in EtOAc) (1.207 g, 1.123 ml, 2.5 equivalent, 1.897 mmol) to the mixture and stir overnight at room temperature. T3P (50% in EtOAc) (241.5 mg, 224.6 µl, 0.5 equivalents, 379.5 µmol) was then added to the mixture and stirred for another 5 days. The reaction mixture was then quenched with a saturated aqueous solution _{of NaHCO3} and extracted with EtOAc (2X). The combined organic phase was washed with brine and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane/EtOAc) followed by RP-HPLC with a gradient elution of ACN (5%-100%) in _H₂O + 0.2% HCOOH to yield 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)thiocarboxylate-4-carboxylic acid tributyl ester. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.47 (d, 1H), 8.27 (dd, 2H), 7.68 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 4.20 (d, 1H), 3.96 (dd, 2H), 3.59 (s, 1H), 3.27 (s, 2H), 2.78 - 2.63 (m, 2H), 2.31 (s, 3H), 1.39 (s, 9H). UPLC-MS-8: Rt = 1.25 min; MS m/z [M+H] ⁺ = 570.3.

Step 2: Slowly add a solution of mCPBA (289.1 mg, 70% wt, 3.5 equivalents, 1.173 mmol) in 5 ml DCM to a cooled (to -78°C) solution of 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)thiocarboxylate-4-carboxylic acid tributyl ester (Step 1, 200.9 mg, 95% wt, 1 equivalent, 335.1 µmol) in 10 ml DCM. Stir the reaction mixture at -78°C for 30 min, then heat to 24°C and stir for 3 h. The reaction mixture was then quenched by adding _{Na₂S₂O₃} • _5H₂O ( _aqueous solution) and saturated _NaHCO₃ aqueous solution, followed by extraction with EtOAc (2×). The combined organic phase was washed with brine, filtered, dried _, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane/EtOAc) to give 1,1-dioxide of 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-imidazol-4-yl)thiocarboxylate-4-carboxylic acid tributyl ester. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.49 (d, 1H), 8.29 (d, 2H), 7.81 (s, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 4.56 (s, 1H), 4.20 (d, 2H), 3.73 (d, 4H), 2.31 (s, 3H), 1.39 (d, 9H). UPLC-MS-8: Rt = 1.04 min; MS m/z [M+H] ⁺ = 602.

Step 3: Dissolve 1,1-dioxide of tributyl thiocarbamate 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)pyridin-2-yl)-1H-imidazol-4-yl)thiocarbamate (Step 2, 150.2 mg, 99% wt, 1 equivalent, 247.2 μmol) in 5 mL of DCM and place under argon atmosphere, then treat with TFA (704.6 mg, 476.1 μl, 25 equivalent, 6.179 mmol). Stir the reaction mixture overnight at room temperature. Then add DCM, followed by saturated _NaHCO3 aqueous solution. Extract the mixture with DCM (2×). The combined organic layers were filtered, dried, and concentrated under vacuum to give N-(6-(4-(1,1-dioxothiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide as a racemic mixture. UPLC-MS-8: Rt = 0.60 min; MS m/z [M+H] ⁺ = 502.

Step 4: The mirror isomers (racemic mixtures) of N-(6-(4-(1,1-dioxothiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 3, 124 mg, 0.247 mmol) were separated by C-SFC-22 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) (65:35)). (R or S)-N-(6-(4-(1,1-dioxothio-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide.

Example 32a : (R or S)-N-(6-(4-(1,1-dioxothiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide, first eluted isomer: C-SFC-14 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 65 : 35): Rt = 2.29 min.

Example 32b : (R or S)-N-(6-(4-(1,1-dioxothiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide, second eluted isomer: ^¹H -NMR (600 MHz, DMSO- _d⁶ ) δ 11.16 (s, 1H), 8.49 (d, 1H), 8.32–8.18 (m, 2H), 7.78 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 4.30 (dd, 1H), 3.43 (d, 1H), 3.31–3.26 (m, 1H), 3.24 - 3.13 (m, 2H), 3.12 - 3.03 (m, 2H), 2.31 (s, 3H). UPLC-MS-8: Rt = 0.59 min; MS m/z [M+H] ⁺ = 502. C-SFC-14 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 65: 35): Rt = 3.12 min.

Example 33 : N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide, (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)- 5-Fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and (R)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide ; ;

Step 1: Under Ar conditions, sodium methoxide (25% in MeOH) (863.4 mg, 914 µl, 1.11 equivalents, 3.996 mmol) was diluted with MeOH (5 ml). A solution of 2-cyano-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (880.0 mg, 95% Wt, 1 equivalent, 3.600 mmol) in MeOH (5 ml) was added with stirring to produce a brown solution, which was then stirred at room temperature for 16 h. Then, 0.5 ml of saturated _NH₄Cl solution and DCM were added. The aqueous layer was brought to pH 6 by adding 1 N HCl and extracted with DCM (3×). The combined organic layer was washed with brine, dried ( _Na₂SO₄ ), and concentrated in a vacuum to give _tributyl 4,4-difluoro-2-(imino(methoxy)methyl)pyrrolidone-1-carboxylic acid, which was then used in the next step without further purification.

Step 2: Under Ar, a solution of 2,3-difluoro-5-nitropyridine (1000 mg, 1 equivalent, 6.247 mmol) in EtOH (5 ml) was added to a solution of hydrazine hydrate (1.201 g, 1.167 ml, 50% Wt, 3 equivalent, 18.74 mmol) in EtOH (15 ml), immediately turning into a brown solution. After stirring at room temperature for 30 min, the reaction mixture was diluted with DCM, _dried ( _Na₂SO₄ ), and concentrated under vacuum to give a brown solid, to which 3 ml of IPA was added. The mixture was ultrasonicated until a fine dark brown precipitate had formed, which was then filtered and washed with a very small amount of IPA. The precipitate was dried under high vacuum to give 3-fluoro-2-hydrazino-5-nitropyridine. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.84 (d, 1H), 8.12 - 8.03 (m, 1H), 4.81 (s, 2H). UPLC-MS-2: [M+H] ⁺ = 173.2 , Rt = 0.25 min.

Step 3: Add Et 3 N (1.093 g, 1.51 ml, 3 equivalents, 10.80 mmol) to a solution of 4,4-difluoro- _2- (imino(methoxy)methyl)pyrrolidone-1-carboxylic acid tributyl ester (Step 1) (1.001 g, 95% Wt, 1 equivalent, 3.600 mmol) in MeOH (30 ml), and then add 3-fluoro-2-hydrazino-5-nitropyridine (Step 2) (657.2 mg, 99% Wt, 1.05 equivalents, 3.780 mmol). Stir the resulting mixture for 4 days. At Rt = 0.55 min, LCMS showed the presence of a possible intermediate (4,4-difluoro-2-((2-(3-fluoro-5-nitropyridin-2-yl)hydrazino)(imino)methyl)pyrrolidone-1-carboxylic acid tributyl ester). The mixture was concentrated to dryness and then dissolved in pyridine (11.4 g, 11.6 ml, 40 equivalents, 144.0 mmol), and trimethyl orthoformate (7.641 g, 7.88 ml, 20 equivalents, 72.00 mmol) was added. The mixture was heated to 120°C and stirred for 3 h, then stirred again at 80°C for 16 h. The reaction mixture was concentrated under vacuum to give an oily residue, which was dissolved in DCM. The DCM solution was washed with _H₂O (3×) and brine. The organic phase was dried ( _Na₂SO₄ ) and concentrated under vacuum. The residue was purified by rapid column silica gel chromatography (cyclohexane/EtOAc) to give _tributyl 4,4-difluoro-2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid. UPLC-MS-2: [M+Na] ^⁺ = 437, Rt = 0.92 min.

Step 4: Add zinc powder (181.5 mg, 5 equivalents, 2.775 mmol) and ammonium chloride (148.5 mg, 5 equivalents, 2.775 mmol) to a solution of 4,4-difluoro-2-(1-(3-fluoro-5-nitropyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester (Step 3, 230.0 mg, 1 equivalent, 555.1 µmol) in MeOH (25 ml) and _H₂O (5 ml). Sonicate the mixture at room temperature for 5 min, then stir at room temperature for 3 h. Afterward, dilute the reaction mixture with MeOH and filter. Concentrate the filtrate under vacuum. The residue was dissolved in 95:5 DCM/MeOH and washed with brine. The organic layer was filtered through a phase separator SPE column and concentrated under vacuum to give tributyl 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid, which was used for the next step without further purification. UPLC-MS-2: [MH] ^⁻ = 383.4, Rt = 0.75 min.

Step 5: Dissolve 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (123.5 mg, 95% Wt, 1.2 equivalents, 563.5 µmol) and 2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (Step 4, 190.0 mg, 95% Wt, 1 equivalent, 469.6 µmol) in THF (20 ml). DIPEA (182.1 mg, 245 µl, 3 equivalents, 1.409 mmol) and T3P (50% in EtOAc) (448.3 mg, 419.3 µl, 1.5 equivalents, 704.4 µmol) were added to give a brown solution, which was stirred at room temperature for 4 days. The reaction was quenched by adding _H₂O , diluted with EtOAc, washed with saturated _NaHCO₃ , _H₂O (3×) and brine, dried ( _Na₂SO₄ ), and concentrated under _vacuum . The residue was purified on silicone [cyclohexane/(TBME/EtOH (3:1)] to give tributyl 4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid. UPLC-MS-2: [M+H] ⁺ = 575.4, Rt = 1.14 min.

Step 6: Dissolve tributyl 4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid (Step 5, 92.00 mg, 95% Wt, 1 equivalent, 152.1 µmol) in DCM (2 ml). Add TFA (1.480 g, 1 ml, 85.32 equivalent, 12.98 mmol) and stir the mixture at room temperature for 2 h. Then concentrate the reaction mixture and dry it under vacuum. Dissolve the residue in DCM and wash the solution with saturated _NaHCO3 solution. The organic layer was filtered through a phase separator SPE column and concentrated in a vacuum to give N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (racemic mixture).

The mirror isomers (racemic mixture) of N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide (72 mg, 0.15 mmol) were separated by C-SFC-36 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (70:30)).

Example 33a : (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide, first eluted isomer: ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 11.18 (s, 1H), 9.08 (s, 1H), 8.52 (d, 1H), 8.30 (dd, 1H), 6.57 (s, 1H), 5.20 (s, 2H), 4.51 (t, 1H), 3.33 (s, 1H), 3.16 (q, 1H), 2.66 (ddt, 1H), 2.58 - 2.53 (m, 1H), 2.32 (s, 3H). UPLC-MS-2: [M+H] ⁺ = 475.2, Rt = 0.69 min. C-SFC-15 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 70:30): Rt = 1.89 min. (99.5% ee).

X-ray analysis of a single compound crystal confirmed the S-configuration at the chiral center, i.e., Example 33a = (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide.

Example 33b : (R)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide, second eluted isomer: ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 11.18 (s, 1H), 9.08 (s, 1H), 8.52 (d, 1H), 8.31 (dd, 1H), 6.57 (s, 1H), 5.20 (s, 2H), 4.51 (q, 1H), 3.33 (s, 1H), 3.23 - 3.09 (m, 1H), 2.75 - 2.57 (m, 2H), 2.32 (s, 3H). UPLC-MS-2: [M+H] ⁺ = 475.2, Rt = 0.70 min. C-SFC-15 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 70: 30): Rt = 2.80 min.

Alternatively, (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 33a) is prepared from chiral starting material, intermediate C-T40, as described below:

Step 1: Dissolve 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (2.111 g, 95% wt, 1.10 equivalent, 9.633 mmol) and (S)-2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (intermediate C-T40, 3.400 g, 99% wt, 1 equivalent, 8.757 mmol) in 100 ml THF. The solution was cooled in an ice bath, and DIPEA (3.396 g, 4.58 ml, 3 equivalents, 26.27 mmol) was added, followed by the slow addition of T3P (50% in EtOAc) (8.359 g, 7.820 ml, 1.5 equivalents, 13.14 mmol). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with EtOAc (400 ml), and _H₂O (50 ml) was added with stirring. The phases were separated, and the organic phase was washed with 10% citric acid (2×), _H₂O , saturated _NaHCO₃ , and brine, _dried ( _Na₂SO₄ ), and concentrated under vacuum to produce foam. The material was dissolved in TBME (15 ml) and the solution was added dropwise to heptane (200 ml) while being ultrasonically treated. The precipitate formed during the procedure was filtered out, washed with heptane, and dried at HV to give tributyl (S)-4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 9.08 (s, 1H), 8.53 (d, 1H), 8.30 (dd, 1H), 6.57 (s, 1H), 5.20 (s, 2H), 5.17 (s, 1H), 3.92 (s, 1H), 3.90 - 3.79 (m, 1H), 3.09 - 2.98 (m, 1H), 2.53 (s, 1H), 2.32 (d, 3H), 1.44 - 1.14 (m, 9H). UPLC-MS-8: Rt = 1.19 min; MS m/z [M+H] ⁺ = 575.3.

Step 2: Dissolve (S)-4,4-difluoro-2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyrrolidone-1-carboxylic acid tributyl ester (Step 1, 4.890 g, 95% wt, 1 equivalent, 8.086 mmol) in 20 ml DCM, and add TFA (8.880 g, 6.0 ml, 9.631 equivalent, 77.88 mmol) with stirring. Stir the solution at room temperature for 3 h, then add more TFA (4.440 g, 3.0 ml, 4.816 equivalent, 38.94 mmol). The reaction mixture was stirred for 1 h at room temperature. The mixture was then concentrated under vacuum by adding toluene, followed by further concentration under vacuum, then by adding EtOAc/toluene at a 3:1 ratio, followed by further concentration under vacuum. The residue was dissolved in EtOAc (400 ml) and saturated _NaHCO3 solution (100 ml) was added with stirring. The phases were separated, and the organic phase was washed with saturated _NaHCO3 solution and brine, _dried ( _Na2SO4 ), filtered through an SPE column and concentrated under vacuum. The resulting solid was dissolved in EtOAc (20 ml) at 40°C and ultrasonically treated until precipitation began. At this point, add 1:2 TBME/heptane (150 ml) and continue ultrasonic treatment. Filter out the precipitate and wash with heptane (2×), then dry at 35°C for 18 h at HV to give (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 9.08 (s, 1H), 8.53 (d, 1H), 8.31 (dd, 1H), 6.57 (s, 1H), 5.20 (s, 2H), 4.52 (t, 1H), 3.33 (d, 2H), 3.16 (q, 1H), 2.66 (ddt, 1H), 2.55 (d, 1H), 2.32 (s, 3H). UPLC-MS-8: Rt = 0.73 min; MS m/z [M+H] ⁺ = 475.1.

Example 34 : N-(5-fluoro-6-(4-(2-(trifluoromethyl)oxacyclobutane-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Dissolve 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (62 mg, 1.3 equivalents, 0.30 mmol) and intermediate C-T48 (70 mg, 90% wt, 1 equivalent, 0.23 mmol) in 1 ml THF, add DIPEA (89 mg, 0.12 ml, 3 equivalents, 0.69 mmol) and T3P (50% in EtOAc) (0.22 g, 0.21 ml, 1.5 equivalents, 0.34 mmol) and stir the solution at room temperature for 16 h. The reaction mixture was then diluted with EtOAc, washed with water (3×) and brine, dried ( _Na₂SO₄ ), and concentrated under vacuum to give N-(5-fluoro-6-(4-(2,2,2-trifluoroacetyl) _-1H -imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. UPLC-MS-2: Rt = 0.96 min (very broad peak); MS m/z [M+H] ^⁺ = 465.3 and [M+ _H₃O ] ^⁺ = 483.3.

Step 2: Dissolve KOtBu (56 mg, 2.4 equivalences, 0.50 mmol) in 1 ml DMSO, add trimethyl iodide (110 mg, 2.4 equivalences, 500 µmol) and stir the reaction mixture at room temperature for 30 min. Add dropwise a solution of N-(5-fluoro-6-(4-(2,2,2-trifluoroacetyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 1, 95 mg, 1 equivalence, 0.20 mmol) in 1 ml DMSO and stir for 16 h. The reaction mixture was then diluted with EtOAc, washed with brine ( _Na₂SO₄ ) _, and concentrated in a vacuum to give a crude product, which was then purified on silicone (hexane/TBME/EtOH) to give N-(5-fluoro-6-(4-(2-(trifluoromethyl)oxadiazon-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.49 (d, 1H), 8.36 (d, 1H), 8.30 (dd, 1H), 7.83 (s, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 4.70 - 4.55 (m, 2H), 3.30 - 3.27 (m, 1H), 3.04 (ddd, 1H), 2.31 (s, 3H). UPLC-MS-2: Rt = 1.08 min; MS m/z [M+H] ⁺ = 493.3.

Example 35 : 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(1-imino-1-oxotetrahydro-1H- ^1λ6 -thiophen-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide (a mixture of isomers)

Step 1: Add DIPEA (668.8 mg, 901 μl, 4.5 equivalents, 5.175 mmol), 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] (332.1 mg, 1.3 equivalents, 1.495 mmol), and T3P (50% in EtOAc) (2.195 g, 2.042 ml, 3.0 equivalents, 3.450 mmol) to a solution of intermediate C-T50 (495.0 mg, 1.150 mmol) in 10.00 ml THF. Stir the resulting mixture at room temperature for 45 min. Then add _H2O and EtOAc to the reaction mixture and separate the phases. Extract the aqueous phase with EtOAc (2×). The combined organic phase was washed with brine and concentrated under vacuum. The residue was purified on silicone (cyclohexane/EtOAc) to give (2-(1-(3-fluoro-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaminopheno)pyridin-2-yl)-1H-1,2,4-triazol- ³ -yl)-1-oxotetrahydro-1λ6-thiophene-1-yl)aminobenzyl carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.26 - 9.08 (m, 1H), 8.63 - 8.46 (m, 1H), 8.45 - 8.25 (m, 1H), 7.84 - 7.64 (m, 2H), 7.53 - 7.06 (m, 7H), 5.28 - 4.72 (m, 3H), 3.97 (s, 2H), 3.95 - 3.81 (m, 1H), 3.75 - 3.59 (m, 1H), 3.47 - 3.39 (m, 3H), 2.75 - 2.57 (m, 2H), 2.49 - 2.45 (m, 2H), 2.49 - 2.36 (m, 1H), 2.26 - 2.06 (m, 1H). UPLC-MS-8: Rt = 1.08/1.12 min (2 peaks due to non-mirror isomer mixture); MS m/z [M+H] ⁺ = 634.

Step 2: Dissolve (2-(1-(3-fluoro-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaminophen)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-1-oxotetrahydro- ^1λ6 -thiophene-1-yl)carbamate (Step 1, 800.0 mg, 1 equivalent, 1.261 mmol) in 15.00 ml MeOH and add Pd/C (134.2 mg, 10% wt, 0.1 equivalent, 126.1 μmol). Place the mixture under hydrogen (balloon) and stir overnight. Replace the balloon with a freshly filled hydrogen balloon and continue stirring for 24 h. The reaction mixture was then diluted with MeOH/DCM (1:1) and filtered through a ^Celite® mat. The mat was washed several times with MeOH/DCM. The filtrate was concentrated to a lower volume and a precipitate was formed. After standing for a period of time, the precipitate was filtered off to give 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(1-imino-1-oxotetrahydro- ^1H -1λ6-thiophene-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide (a mixture of non-mirror isomers). The filtrate was purified on silicone (DCM/MeOH) to give additional products. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04 (s, 1H), 9.19 - 9.04 (m, 1H), 8.53 (d, 1H), 8.33 (dd, 1H), 7.77 (t, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 4.45 (dt, 1H), 4.17 (s, 1H), 3.97 (s, 2H), 3.41 (s, 1H), 3.27 - 2.96 (m, 2H), 2.68 - 2.52 (m, 2H), 2.35 (dd, 1H), 2.19 - 2.05 (m, 1H). UPLC-MS-8: Rt = 0.86 min; MS m/z [M+H] ⁺ = 501.2.

Step 3: The nonmirror isomers (mixture of nonmirror isomers) of 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(1-imino- ¹ -oxotetrahydro-1H-1λ6-thiophen-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide (Step 2, 251 mg, 0.476 mmol) were first separated by C-SFC-40 (mobile phase: _CO2 /IPA + 0.05% _NH3 (50:50)) (to give the first and third eluted isomers) and then (for the mixture of the second and fourth eluted isomers) by C-SFC-41 (mobile phase: _CO2 /MeOH) + 0.05% NH ₃ (60 : 40) to separate the title compound into solid form.

Example 35a : First eluted isomer: C-HPLC-7 (mobile phase: (heptane + Et ₂ NH)/((1 : 1 EtOH/MeOH) + Et ₂ NH) 65 : 35): Rt = 5.43 min.

Example 35b : Second eluted isomer: C-HPLC-7 (mobile phase: (heptane + Et ₂ NH)/((1 : 1 EtOH/MeOH) + Et ₂ NH) 65 : 35): Rt = 6.12 min.

Example 35c : Third eluted isomer: C-HPLC-7 (mobile phase: (heptane + Et ₂ NH)/((1 : 1 EtOH/MeOH) + Et ₂ NH) 65 : 35): Rt = 7.48 min.

Example 35d : Fourth eluted isomer: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 10.95 (d, ¹H), 9.10 (s, ¹H), 8.50 (d, ¹H), 8.34 (dd, ¹H), 7.83 - 7.64 (m, 2H), 7.40 (t, ¹H), 4.43 (t, ¹H), 4.16 (s, ¹H), 3.95 (s, 2H), 3.23 - 3.15 (m, ¹H), 3.11 - 2.99 (m, ¹H), 2.68 - 2.54 (m, 2H), 2.41 - 2.27 (m, 1H), 2.19 - 2.03 (m, 1H). UPLC-MS-8: Rt = 0.83 min; MS m/z [M+H] ⁺ 501.2. C-HPLC-7 (mobile phase: (heptane + Et ₂ NH)/((1 : 1 EtOH/MeOH) + Et ₂ NH) 65 : 35): Rt = 14.64 min.

Examples 36/37 : N-(3-cyano-5-fluoro-4-(1-(2-(5-methyl-4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide and N-(3-cyano-5-fluoro-4-(1-(2-(5-methyl-1,3,4-diazol-2-yl)propyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide

Step 1: Dissolve 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] (180 mg, 0.877 mmol) and intermediate C-T52 (190 mg, 0.628 mmol) in 5 ml THF, add DIPEA (0.329 ml, 1.885 mmol) and T3P (50% in EtOAc) (0.561 ml, 0.943 mmol) and stir the solution at room temperature for 1 h. The reaction mixture was then diluted with EtOAc, washed with _H₂O (3×) and brine, dried ( _Na₂SO₄ ) _, and concentrated under vacuum to give methyl 2-(4-(2-cyano-6-fluoro-4-(2-(6-(trifluoromethyl)pyridin-2-yl)acetaminophen)phenyl)-1H-pyrazol-1-yl)-2-methylpropionate. UPLC-MS-2: Rt = 1.03 min; MS m/z [M+H] ^⁺ = 490.2.

Step 2: Dissolve methyl 2-(4-(2-cyano-6-fluoro-4-(2-(6-(trifluoromethyl)pyridin-2-yl)acetamino)phenyl)-1H-pyrazol-1-yl)-2-methylpropionate (Step 1, 330 mg, 0.634 mmol) in 10 ml of hydrazine solution (1 M in EtOH) and stir at 80°C for 4 days, and then concentrate under vacuum. The residue was purified on silicone [DCM/MeOH (+ 2% 7 N NH ₃ )] to give N-(3-cyano-5-fluoro-4-(1-(1-hydrazyl-2-methyl-1-sideoxypropyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. UPLC-MS-2: Rt = 0.80 min; MS m/z [M+H] ⁺ = 490.5.

Step 3: Dissolve N-(3-cyano-5-fluoro-4-(1-(1-hydrazyl-2-methyl-1-sideoxypropyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (Step 2, 25 mg, 0.046 mmol) in 0.5 ml EtOH. Add ethyl acetilime hydrochloride (16 mg, 0.129 mmol) and NaOH (5 mg, 0.125 mmol) and stir the reaction mixture at 80°C for ₄ days. Afterward, dilute the reaction mixture with EtOAc and wash with _H₂O and brine, dry ( _Na₂SO₄ ), and concentrate under vacuum. The residue was purified by RP-HPLC-2 (eluent A: H2O + 7.3 mM _NH4OH , eluent B: ACN + 7.3 mM _NH4OH , gradient: 20% to 50% B, over 22.5 min, hold for 2.5 min) and freeze-drying the relevant fractions to give: Example 36 : N-(3-cyano-5-fluoro-4-(1-(2-(5-methyl-4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.82 (s, 1H), 8.09 (dd, 1H), 8.04 (s, 1H), 7.89 - 7.79 (m, 4H), 7.75 (d, 1H), 4.03 (d, 2H), 2.31 (s, 3H), 1.99 - 1.89 (m, 6H). UPLC-MS-2: Rt = 0.88 min; MS m/z [M+H] ⁺ = 513.2. Example 37 : N-(3-cyano-5-fluoro-4-(1-(2-(5-methyl-1,3,4-diazol-2-yl)propyl-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide. ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 10.85 (s, 1H), 8.39 (s, 1H), 8.09 (t, 1H), 7.90–7.85 (m, 3H), 7.83 (d, 1H), 7.76 (d, 1H), 4.04 (s, 2H), 2.47 (s, 3H), 2.03 (s, 6H). MS-2: Rt = 0.91 min; MS m/z [M+H] ⁺ = 514.3.

Example 38 : N-(6-(4-((1H-tetrazol-5-yl)methyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide

Step 1: Dissolve 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] (243 mg, 1.093 mmol) and intermediate C-T53 (254 mg, 0.994 mmol) in 8 ml THF, add DIPEA (0.521 ml, 2.98 mmol) and T3P (50% in EtOAc) (0.888 ml, 1.491 mmol). Stir the mixture at room temperature for 30 min. Then dilute the reaction mixture with EtOAc, wash with _H2O (3×) and brine, dry ( _Na2SO4 ) and concentrate under _vacuum . Grind the residue in an ultrasonic bath with EtOAc/petroleum ether (1:9). The precipitate was filtered and washed with petroleum ether, then dried to give N-(6-(4-(cyanomethyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. UPLC-MS-2: Rt = 0.93 min; MS m/z [M+H] ⁺ = 422.3.

Step 2: N-(6-(4-(cyanomethyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide (Step 1, 100 mg, 0.237 mmol), _NaN₃ (30.9 mg, 0.475 mmol), and _ZnBr₂ (53.4 mg, 0.237 mmol) were suspended in 3 ml of 2:1 THF/water and stirred at 80°C for 20 h. The reaction mixture was then extracted with EtOAc (3×). The combined organic layer was washed with brine, dried ( _Na₂SO₄ ) _, and concentrated under vacuum. The residue was suspended in 5:1 DCM/IPA and then treated with 5% citric acid aqueous solution. The organic phase was filtered through a phase separator _packed with _Na₂SO₄ and concentrated under vacuum to give a crude product, which was purified by RP-HPLC 3 (eluent A: _H₂O + 0.1% HCOOH, B: ACN + 0.1% HCOOH 98:2 to 0:100) to give N-(6-(4-((1H-tetrazol-5-yl)methyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.48 (d, 1H), 8.37 (s, 1H), 8.30 (dd, 1H), 7.77 (t, 1H), 7.72 (d, 2H), 7.41 (t, 1H), 4.29 (s, 2H), 3.95 (s, 2H). UPLC-MS-2: Rt = 0.85/0.86 min; MS m/z [M+H] ⁺ = 465.2.

Example 39 : 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-((3-sideoxypiperazol-1-yl)methyl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide

Step 1: T3P (50% in EtOAc) (3.42 ml, 5.40 mmol) and DIPEA (1.25 ml, 7.20 mmol) were added to a solution of 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] (0.80 g, 3.60 mmol) and intermediate C-T57 (0.90 g, 3.60 mmol) in DMF (15 ml). After stirring at room temperature for 12 h, the reaction mixture was diluted with ice-cold _H2O and stirred for 10 min. The resulting precipitate was filtered, washed with _H₂O , and dried under vacuum to yield ethyl 1-(3-fluoro-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaminophen)pyridin-2-yl)-1H-imidazolium-4-carboxylate. HPLC-MS-3: Rt = 1.66 min; MS m/z [M+H] ^⁺ = 455.1.

Step 2: DIBAL-H (25% in _PhCH3 ) (0.56 ml, 0.99 mmol) was added dropwise to a solution of ethyl 1-(3-fluoro-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaminophen)pyridin-2-yl)-1H-imidazolium-4-carboxylate (Step 1, 0.15 g, 0.33 mmol) in THF (10 ml) at -78°C. After 1 h, the reaction mixture was diluted with saturated _NH4Cl aqueous solution and EtOAc. The separated organic layer was washed with brine (2×), _dried ( _Na₂SO₄ ), and concentrated under reduced pressure to give 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-methoxy-1H-imidazol-1-yl)pyridin-3-yl)acetamide. HPLC-MS-3: Rt = 0.40 min; MS m/z [M+H] ^⁺ = 411.1.

Step 3: HOAc (0.216 g, 0.36 mmol) was added dropwise to a solution of 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-methoxy-1H-imidazol-1-yl)pyridin- _{3-yl)acetamide (Step 2, 0.15 g, 0.36 mmol) and piperidine-2-one (0.548 g, 0.54 mmol) in DCM/MeOH (10 ml). After stirring at room temperature for 30 min, NaBH(OAc)3} (0.152 g, 0.72 mmol) was added and the mixture was stirred again for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and _H2O . The organic layer was washed with brine (2×), _dried ( _Na₂SO₄ ), concentrated under reduced pressure, and the residue was purified by RP-HPLC-5 (eluent A: _H₂O + 0.1% HCOOH, B: ACN) to give 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-((3-sideoxypiperazol-1-yl)methyl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.45 (d, 1H), 8.36 (dd, 1H), 8.34 (m, 1H), 7.77 (s, 1H), 7.61-7.73 (m, 2H), 7.35 (t, 1H), 3.93 (s, 2H), 3.68 (s, 2H), 3.18 (s, 2H), 2.72-2.84 (m, 2H). HPLC-MS-1: Rt = 1.32 min; MS m/z [M+H] ⁺ 495.0.

Example 40 : (2R,4R)-2-cyano-4-(4-(3-cyano-5-(2-(3-(trifluoromethyl)phenoxy)acetamino)pyridin-2-yl)-1H-pyrazole-1-yl)pyrrolidone-1-carboxylic acid tributyl ester

Step 1: _PdCl₂ (dppf) (309 mg, 0.422 mmol) was added to a solution of intermediate D-M1 (1.5 g, 4.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H- _pyrazole [CAS No. 269410-08-4] (1.23 g, 6.33 mmol), and _K₂CO₃ (1.75 g, 12.65 mmol) in a 5:1 dioxane/ _H₂O (12 ml) solution and the mixture was stirred at 100°C under _N₂ atmosphere. After 6 h, the reaction mixture was poured into _H₂O and extracted with DCM (4×). The combined organic layer was washed with brine (2×), dried ( _Na₂SO₄ ) _, and concentrated under reduced pressure. The residue was ground and filtered in 4:1 EtOAc/petroleum ether. The filter cake was dried under vacuum to give N-(5-cyano-6-(1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide. HPLC-MS-4: Rt = 0.91 min; MS m/z [M+H] ^⁺ = 388.0.

Step 2: _Cs₂CO₃ (421 mg, 1.29 mmol) was added to a _solution of N-(5-cyano-6-(1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide (Step 1, 250 mg, 0.645 mmol) and (2R,4S)-2-cyano-4-(toluenesulfonyloxy)pyrrolidone-1-carboxylic acid tributyl ester (284 mg, 0.775 mmol) in ACN (10 ml), and the mixture was heated to 80°C. After 16 h, the reaction mixture was concentrated. The residue was diluted with _H₂O and extracted with EtOAc (3×). The combined organic layer was washed with brine (2×), _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified first by RP-HPLC (alkaline conditions) and then by preparative TLC (1:2 petroleum ether/EtOAc) to give tributyl (2R,4R)-2-cyano-4-(4-(3-cyano-5-(2-(3-(trifluoromethyl)phenoxy)acetamino)pyridin-2-yl)-1H-pyrazol-1-yl)pyrrolidone-1-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, 1H), 8.63 (d, 1H), 8.46 (s, 1H), 8.42 (s, 2H), 7.57-7.51 (m, 1H), 7.39 (d, 1H), 7.30 (br s, 1H), 7.22 (dd, 1H), 5.00 (m, 1H), 4.74 (s, 2H), 4.68 m(m, 1H), 4.17-3.93 (m, 2H), 3.06-2.85 (m, 2H), 1.56 (m, 9H). HPLC-MS-4: Rt = 1.01 min; MS m/z [M+H] ⁺ = 582.2.

Note: The following procedure was used to obtain (2R,4S)-2-cyano-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tributyl ester.

Et ₃ N (0.85 ml, 6.12 mmol) and TsCl (700 mg, 3.67 mmol) were added to a solution of (2R,4S)-2-cyano-4-hydroxypyrrolidone-1-carboxylic acid tributyl ester [CAS No. 1613482-42-0] (650 mg, 3.06 mmol) and DMAP (37 mg, 0.306 mmol) in DCM (10 ml) at room temperature. After 2 h, the reaction mixture was poured into H ₂ O and extracted with DCM (3×). The combined organic layer was washed with brine (2×), _dried ( _Na₂SO₄ ), and concentrated under reduced pressure to give tributyl (2R,4S)-2-cyano-4-(toluenesulfonyloxy)pyrrolidone-1-carboxylic acid. HPLC-MS-4: Rt = 0.91 min; MS m/z [M+H] ^⁺ = 367.1.

Example 41 : N-(5-fluoro-6-(4-(3-methyl-1-oxo-1,2-thiazolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

_NH₄OAc (37.8 mg, 491 μmol) and (diethoxyiodide)benzene (94.9 mg, 294.6 μmol) were added to a solution of Example 109 (46 mg, 98.19 μmol) in a 1:1 dioxane/MeOH solution (3 ml). After stirring for 10 min, the mixture was treated with Si-thiol resin (500 mg) and then stirred at 0°C for 30 min, followed by stirring at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by RP-HPLC-3 (mobile phase: _H2O + 0.2% HCOOH/ACN 95:5 to 0:100) to give a non-mirror isomer of N-(5-fluoro-6-(4-(3-methyl-1-oxo-1,2-thiazolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide.

Example 41a : First eluted isomer: ^¹H NMR (600 MHz, DMSO _-d⁶ ) δ 11.09 (br s, 1H), 8.47 (d, 1H), 8.28 (dd, 1H), 8.15 (m, 1H), 7.96 (m, 1H), 6.57 (s, 1H), 6.56 (s, 1H), 5.18 (s, 2H), 2.69 (m, 1H), 2.42 (m, 1H), 2.33 (m, 1H), 2.31 (s, 3H), 2.15 (m, 1H), 1.60–1.71 (m, 2H), 1.35 (s, 3H). UPLC-MS-8: Rt = 0.79 min; MS m/z [M+H] ⁺ 500.2.

Example 41b : Second eluted isomer: ^¹H NMR (600 MHz, DMSO _-d⁶ ) δ 11.08 (br s, 1H), 8.47 (d, 1H), 8.26 (dd, 1H), 8.20 (m, 1H), 7.55 (s, 1H), 6.57 (s, 1H), 6.17 (s, 1H), 5.18 (s, 2H), 2.72 (m, 1H), 2.55-2.59 (m, 2H), 2.31 (s, 3H), 1.96-2.08 (m, 2H), 1.81 (m, 1H), 1.77 (s, 3H). UPLC-MS-8: Rt = 0.85 min; MS m/z [M+H] ⁺ 500.2.

Example 42 : N-(5-fluoro-6-(3-(2-(2-sideoxypyrrolidin-1-yl)propyl-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

Step 1: Add 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (315.1 mg, 1.514 mmol), DIPEA (391.4 mg, 527 µL, 3.028 mmol), and T3P (50% in EtOAc) (1.285 g, 1.194 ml, 2.019 mmol) to a solution of intermediate C-T7 (350.0 mg, 1.009 mmol) in ACN (6.00 ml) and stir the reaction mixture at room temperature for 2 h. Add additional DIPEA (391.4 mg, 527 µL, 3.028 mmol), T3P (50% in EtOAc) (1.285 g, 1.194 ml, 2.019 mmol), and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (315.1 mg, 1.514 mmol) and continue stirring the mixture at room temperature for 2.5 h. Dilute the reaction mixture with EtOAc, wash with saturated _NaHCO3 aqueous solution, separate the phases, and extract the aqueous layer with EtOAc (2×). Wash the combined organic layer with brine, dry using a phase separator, and evaporate. The crude product was purified by silica gel column chromatography using an EtOAc (0-100%) gradient elution in cyclohexane. The fractions containing the desired product were combined and evaporated to give tributyl (2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)aminocarbamate. ¹ H NMR (600 MHz, DMSO-d ₃ ) δ 11.14 (s, 1H), 8.95 (s, 1H), 8.51 (d, 1H), 8.29 (dd, 1H), 7.06 (s, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 2.32 (s, 3H), 1.55 (s, 6H), 1.32 (s, 9H). UPLC-MS-8: Rt = 1.11 min; MS m/z [M+H] ⁺ 527.3.

Step 2: A solution of tributyl 2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)aminocarbamate (Step 1, 486 mg, 0.775 mmol) and HCl (4 M/dioxane) (565.4 mg, 3.877 ml, 4.000 mol, 20 equivalents, 15.51 mmol) in DCM (3 ml) was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness. The residue was dissolved in _H₂O and the aqueous layer was alkalized with a saturated _NaHCO₃ aqueous solution and extracted with DCM (2×). The combined organic layer was dried and evaporated using a phase separator to give N-(6-(3-(2-aminopropyl-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ^¹H NMR (600 MHz, DMSO- _d³ ) δ 11.17 (s, 1H), 8.97 (s, 1H), 8.52 (d, 1H), 8.29 (dd, 1H), 6.56 (s, 1H), 5.19 (s, 2H), 2.32 (s, 3H), 1.43 (s, 6H). UPLC-MS-8: Rt = 0.59 min; MS m/z [M+H] ⁺ 427.1.

Step 3: A solution of N-(6-(3-(2-aminopropyl-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (Step 2, 100 mg, 0.213 mmol), _Et3N (149 μL, 1.067 mmol), and methyl 4-chlorobutyrate (28.6 μL, 0.235 mmol) in DMF (1.5 mL) was stirred at 100°C under microwave irradiation. After 1 h and 5 h, additional _Et3N (149 μL, 1.067 mmol) and methyl 4-chlorobutyrate (28.6 μL, 0.235 mmol) were added. After stirring overnight at 100°C (heating block), the reaction mixture was diluted with EtOAc and washed with _H₂O and brine. The organic layer was dried (phase separator) and concentrated under reduced pressure, and the residue was purified first by RP-HPLC-3 (mobile phase: _H₂O + 0.1% TFA/ACN 95:5 to 0:100) and then by RP-HPLC-3 (mobile phase: _H₂O + 0.1% _NH₄OH /ACN 95:5 to 0:100). The fractions containing the product were combined, diluted with saturated _NaHCO₃ aqueous solution, and extracted with DCM (3×). The combined organic layer was dried (phase separator) and concentrated under reduced pressure to give methyl 4-((2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)amino)butyrate. UPLC-MS-8: Rt = 0.66 min; MS m/z [M+H] ⁺ 527.3.

Step 4: A solution of methyl 4-((2-(1-(3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)amino)butyrate (Step 3, 52 mg, 97.78 μmol) and 2-hydroxypyridine (18.6 mg, 195.6 μmol) in toluene was stirred at 120°C for 72 h. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with saturated _NaHCO3 aqueous solution and brine. The organic layer was dried (phase separator) and concentrated under reduced pressure, and the residue was purified by RP-HPLC-3 (mobile phase: _H₂O + 0.1% TFA/ACN 95:5 to 0:100). Fractions containing the product were combined, diluted with saturated _NaHCO₃ aqueous solution, and extracted with DCM (3×). The combined organic layer is dried (phase separator) and concentrated under reduced pressure to give N-(5-fluoro-6-(3-(2-(2-sideoxypyrrolidin-1-yl)propyl-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.17 (br s, 1H), 8.96 (d, 1H), 8.51 (d, 1H), 8.30 (dd, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 3.53 (t, 2H), 2.32 (s, 3H), 2.14-2.21 (m, 2H), 1.86-1.96 (m, 2H), 1.69 (s, 6H). UPLC-MS-8: Rt = 0.88 min; MS m/z [M+H] ⁺ 495.1.

The following examples are prepared from intermediates using a method similar to that used in Examples 1-42. These intermediates are commercially available or obtainable using the methods described herein. Example Structure Methods, intermediates, and chiral separation conditions Characteristic data 43 N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 10, it is derived from the intermediate D-T3 and uses _PdCl2 (dppf). DCM/ _K3PO4 / ₆ : 1 dioxane/ _H2O ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (br s, 1H), 8.49 (d, 1H), 8.29 (dd, 1H), 8.23 (m, 1H), 8.10 (t, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.69 (s, 1H), 6.40 (m, 1H), 4.18-4.26 (m, 2H), 4.07 (s, 2H), 3.76-3.83 (m, 2H), 2.35-2.43 (m, 2H). UPLC-MS-2: Rt = 0.92 min; MS m/z [M+H] ⁺ 448.3. 44 - Racemic 44a - First eluted isomer 44b - Second eluted isomer 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 11, intermediate C-T3 and 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 922516-24-3] were produced using a first C-SFC-6 (mobile phase: _CO2 /(MeOH + 0.05% _NH3 ) 50%-70%). The first eluted isomer, ^¹H NMR (600 MHz, DMSO- _d⁶ ), δ 11.17 (s, ¹H), 8.47 (d, ¹H), 8.25 (dd, ¹H), 8.21 (t, ¹H), 7.62 (t, ¹H), 7.14 (s, ¹H), 5.30 (s, 2H), 3.90 (d, ¹H), 3.53 (dt, ¹H), 3.51–3.46 (m, ¹H), 3.40 (d, ¹H), 2.74 (ddd, ¹H), 2.69 (dt, ¹H), 1.24 (s, 3H). UPLC-MS-8: Rt = 0.71 min; MS m/z [M+H] ⁺ 488.0. C-SFC-5 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 50/50): Rt = 2.37 min. Second eluted isomer C-SFC-5 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 50/50): Rt = 4.47 min. 45 2-(3-chloro-5-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(3-methylpyrolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide The byproduct of Example 44, consisting of intermediate C-T3 and 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 922516-24-3] (containing some 2-(3-chloro-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid), uses a first C-SFC-6 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 50%-70%) and then C-SFC-6 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 40%-44%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.45 (d, 1H), 8.24 (dd, 1H), 8.20 (t, 1H), 7.61 (t, 1H), 7.25 (s, 1H), 5.26 (s, 2H), 3.90 (d, 1H), 3.55 - 3.51 (m, 1H), 3.51 - 3.46 (m, 1H), 3.40 (d, 1H), 2.74 (ddd, 1H), 2.71 - 2.65 (m, 1H), 1.24 (s, 3H). UPLC-MS-8: Rt = 0.71 min; MS m/z [M+H] ⁺ 488.0. C-SFC-5 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 50/50): Rt = 0.99 min. 46 - Racemic 46a - First eluted isomer 46b - Second eluted isomer N-(5-fluoro-6-(4-(3-methylpyrrolidone-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 11, intermediate C-T3 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were prepared using C-SFC-11 (mobile phase: _CO2 /(MeOH + 0.05% NH3) ₆₀ : 40). The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) with the following δ values: 10.95 (s, ¹H), 8.48 (d, ¹H), 8.29 (dd, ¹H), 8.19 (t, ¹H), 8.10 (t, ¹H), 7.83 (dd, ¹H), 7.77 (d, ¹H), 7.61 (t, ¹H), 4.07 (s, 2H), 3.90 (d, ¹H), 3.53 (dt, ¹H), 3.51–3.45 (m, ¹H), 3.40 (d, ¹H), 2.74 (ddd, ¹H), 2.71–2.66 (m, ¹H), and 1.24 (s, 3H). UPLC-MS-8: Rt = 0.58 min; MS m/z [M+H] ⁺ 465.1. C-SFC-5 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 55/45): Rt = 1.31 min. Second eluted isomer C-SFC-5 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 55/45): Rt = 1.81 min. 47 (racemic) 47a - first eluted isomer 47b - second eluted isomer 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(olin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 11, intermediate C-M5 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were prepared using C-SFC-12 (mobile phase: _CO2 /(MeOH + 0.05% NH3) ₆₀ : 40). The first eluted isomers showed the following ^¹H NMR values (600 MHz, DMSO- _d⁶ ): δ 10.95 (s, ¹H), 8.47 (d, ¹H), 8.28 (dd, ¹H), 8.17 (t, ¹H), 7.77 (t, ¹H), 7.72 (t, ¹H), 7.57 (s, ¹H), 7.41 (t, ¹H), 4.40 (d, ¹H), 3.95 (s, 2H), 3.81 (d, 1H), 3.58 (m, 1H), 3.03 (d, 1H), 2.79–2.68 (m, 3H). UPLC-MS-2: Rt = 0.72 min; MS m/z [M+H] ⁺ 468.1. C-SFC-5 (mobile phase: CO ₂ / (IPA + 0.05% NH ₃ ) 65/35): Rt = 2.79 min. Second eluted isomer C-SFC-5 (mobile phase: CO ₂ / (IPA + 0.05% NH ₃ ) 65/35): Rt = 4.48 min. 48 (racemic) 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(5-sideoxy-lin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 11, it is composed of intermediate C-T4 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4]. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.48 (d, 1H), 8.29 (dd, 1H), 8.23 (s, 1H), 8.12 (d, 1H), 7.77 (t, 1H), 7.74 (s, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 4.80 (dd, 1H), 4.17 (d, 1H), 4.10 (d, 1H), 3.95 (s, 2H), 3.58 (dd, 1H), 3.44 - 3.42 (m, 1H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ 482.1. 49 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-methyllin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 13, it consists of intermediates A-M5 and C-M7. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.48 (d, 1H), 8.29 (dd, 1H), 8.18 (t, 1H), 7.79 - 7.74 (m, 1H), 7.72 (t, 1H), 7.61 (d, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 3.78 (d, 1H), 3.70 - 3.66 (m, 1H), 3.60 (td, 1H), 3.46 (dd, 1H), 3.12 (dd, 1H), 2.75 (dt, 1H), 2.23 (td, 1H), 2.07 (s, 3H). UPLC-MS-2: Rt = 0.73 min; MS m/z [M+H] ⁺ 482.1. 50 N-(5-fluoro-6-(4-(pyrrolidin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 11, it is composed of intermediate C-T5 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0]. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.45 (d, 1H), 8.26 (dd, 1H), 8.16 (s, 1H), 7.50 (s, 1H), 6.57 (s, 1H), 5.17 (s, 2H), 3.17 - 3.07 (m, 2H), 2.93 - 2.81 (m, 2H), 2.73 (dd, 1H), 2.31 (s, 3H), 2.06 - 1.99 (m, 1H), 1.83 - 1.76 (m, 1H). UPLC-MS-2: Rt = 0.62 min; MS m/z [M+H] ⁺ 438.2 24 (racemic) 51a - first eluted isomer 51b - second eluted isomer 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 11, intermediate C-T2 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were prepared using C-HPLC-2 (mobile phase: n-heptane/DCM : EtOH + 0.05% _NH3 65 : 30 : 5). First eluted isomer C-HPLC-1 (mobile phase: n-heptane/DCM : EtOH + 0.05% NH ₃ (65 : 30 : 5)): Rt = 31.08 min. The second eluted isomer ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 10.97 (s, ¹H), 8.47 (d, ¹H), 8.28 (dd, ¹H), 8.18 (t, ¹H), 7.77 (t, ¹H), 7.72 (t, ¹H), 7.56 (s, ¹H), 7.41 (t, ¹H), 3.95 (s, 2H), 3.89 (dd, ¹H), 3.79 (dd, 1H), 3.70 (dt, 1H), 3.41 (ddd, 1H), 3.29 (dd, 1H), 2.86 - 2.79 (m, 2H), 2.68 (s, 1H). UPLC-MS-2: Rt = 0.74 min; MS m/z [M+H] ⁺ 468.1. C-HPLC-1 (mobile phase: n-heptane/DCM : EtOH + 0.05% NH ₃ (65 : 30 : 5)): Rt = 37.32 min. 52 - Racemic 52a - First eluted isomer 52b - Second eluted isomer N-(5-fluoro-6-(4-(3-methyllin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, intermediate C-T3 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were prepared using C-SFC-11 (mobile phase: _CO2 /MeOH + 0.05% NH3 ₅₀ : 50). The first eluted isomer, ^¹H NMR (600 MHz, DMSO- _d⁶ ), δ 11.08 (s, ¹H), 8.47 (d, ¹H), 8.27 (dd, ¹H), 8.21 (t, ¹H), 7.63 (s, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 3.90 (d, ¹H), 3.57–3.46 (m, 2H), 3.41 (d, 1H), 2.78–2.66 (m, 2H), 2.31 (d, 3H), 1.25 (s, 3H). UPLC-MS-8: Rt = 0.58 min; MS m/z [M+H] ⁺ 468.2. C-SFC-5 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (50:50)): Rt = 1.51 min. Second eluted isomer C-SFC-5 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (50:50)): Rt = 2.71 min. 11 - Racemic 53a - First eluted isomer 53b - Second eluted isomer N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, intermediate C-T2 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were prepared using C-SFC-13 (mobile phase: _CO2 /EtOH + 0.05% NH3 ₅₀ : 50). The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 11.09 (s, 1H), 8.47 (d, 1H), 8.26 (dd, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 3.89 (dd, 1H), 3.79 (dd, 1H), 3.73 - 3.66 (m, 1H), 3.44 - 3.39 (m, 1H), 3.31 - 3.27 (m, 1H), 2.89 - 2.80 (m, 2H), and 2.31 (s, 3H). UPLC-MS-2: Rt = 0.59 min; MS m/z [M+H] ⁺ 454.2. C-SFC-5 (mobile phase: CO ₂ /EtOH + 0.05% NH ₃ (65 : 35)): Rt = 2.71 min. Second eluted isomer UPLC-MS-2: Rt = 0.59 min; MS m/z [M+H] ⁺ 454.2. C-SFC-5 (mobile phase: CO ₂ /EtOH + 0.05% NH ₃ (65 : 35)): Rt = 2.71 min. 54 - Racemic 54a - First eluted isomer 54b - Second eluted isomer N-(5-fluoro-6-(4-(olin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, intermediate C-M5 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were prepared using C-SFC-10 (mobile phase: _CO2 /IPA + 0.05% _NH3 55:45). The first eluted isomer's ^¹H NMR (400 MHz, DMSO- _d₆ ) values were 11.10 (s, ¹H), 8.47 (d, ¹H), 8.26 (dd, ¹H), 8.18 (t, ¹H), 7.57 (s, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 4.38 (dd, ¹H), 3.79 (dt, ¹H), 3.59–3.52 (m, ¹H), 3.00 (dd, ¹H), 2.74–2.68 (m, 3H), and 2.31 (s, 3H). UPLC-MS-2: Rt = 0.60 min; MS m/z [M+H] ⁺ 454.2. C-SFC-5 (mobile phase: _CO₂ /IPA + 0.05% _NH₃ (60:40)): Rt = 1.53 min. Second eluted isomer UPLC-MS-2: Rt = 0.59 min; MS m/z [M+H] ⁺ 454.2. C-SFC-5 (mobile phase: _CO₂ /IPA + 0.05% _NH₃ (60:40)): Rt = 2.43 min. 55 - Racemic 55a - First eluted isomer 55b - Second eluted isomer 55c - Third eluted isomer 55d - Fourth eluted isomer N-(5-fluoro-6-(4-(2-methyl-1,1-dioxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid Similar to Example 1, intermediate C-M1 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid [CAS No. 1005566-34-6] were used with C-SFC-9 (mobile phase: _CO2 /MeOH + 0.05% _NH3 78:22). The first eluted isomers were analyzed by ^¹H NMR (400 MHz, DMSO- _d⁶ ) with the following δ values: 10.86 (s, ¹H), 8.50 (d, ¹H), 8.31 (dd, ¹H), 8.26 (t, ¹H), 7.82 (d, ¹H), 6.58 (s, ¹H), 5.33 (q, ¹H), 3.28–3.21 (m, ¹H), 3.21–3.13 (m, ¹H), 2.75–2.66 (m, ¹H), 2.31 (s, ³H), 2.27–2.18 (m, ¹H), 2.18–2.07 (m, 2H), 1.77 (d, ³H), and 1.65 (s, ³H). UPLC-MS-2: Rt = 0.82 min; MS m/z [M+H] ⁺ 515.3. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (78:22)): Rt = 1.73 min. The second eluted isomer's ^¹H NMR (400 MHz, DMSO- _d⁶ ) values are: δ 10.85 (s, ¹H), 8.50 (d, ¹H), 8.31 (dd, ¹H), 8.26 (t, ¹H), 7.82 (t, ¹H), 6.58 (s, ¹H), 5.33 (q, ¹H), 3.27 - 3.21 (m, ¹H), 3.21 - 3.13 (m, ¹H), 2.76 - 2.67 (m, ¹H), 2.31 (s, ³H), 2.27 - 2.19 (m, ¹H), 2.17 - 2.07 (m, 2H), 1.77 (d, ³H), 1.65 (s, ³H). UPLC-MS-2: Rt = 0.82 min; MS m/z [M+H] ⁺ 515.3. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (78:22)): Rt = 2.05 min. The third eluted isomer ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 10.86 (s, 1H), 8.50 (d, 1H), 8.31 (dd, 1H), 8.26 (t, 1H), 7.82 (t, 1H), 6.58 (s, 1H), 5.33 (q, 1H), 3.27 - 3.21 (m, 1H), 3.20 - 3.13 (m, 1H), 2.76 - 2.67 (m, 1H), 2.31 (s, 3H), 2.28 - 2.18 (m, 1H), 2.16 - 2.08 (m, 2H), 1.77 (d, 3H), 1.65 (s, 3H). UPLC-MS-2: Rt = 0.82 min; MS m/z [M+H] ⁺ 515.3. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (78:22)): Rt = 2.73 min. The fourth eluted isomer ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 10.86 (s, 1H), 8.50 (d, 1H), 8.31 (dd, 1H), 8.26 (t, 1H), 7.82 (t, 1H), 6.58 (s, 1H), 5.33 (q, 1H), 3.27 - 3.21 (m, 1H), 3.20 - 3.13 (m, 1H), 2.76 - 2.67 (m, 1H), 2.31 (s, 3H), 2.28 - 2.18 (m, 1H), 2.16 - 2.08 (m, 2H), 1.77 (d, 3H), 1.65 (s, 3H)). UPLC-MS-2: Rt = 0.82 min; MS m/z [M+H] ⁺ 515.3. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (78:22)): Rt = 5.01 min. 56 - Racemic 56a - First eluted isomer 56b - Second eluted isomer N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, using intermediate C-T8 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0], C-HPLC-6 was used (mobile phase: heptane + DEA/EtOH + 0.05% NH3 ₅₀ : 50). The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) with the following δ values: 11.09 (s, ¹H), 8.48 (d, ¹H), 8.26 (dd, ¹H), 8.22 (d, ¹H), 7.62 (s, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 3.78–3.72 (m, ¹H), 3.14–3.06 (m, ¹H), 2.72 (t, ¹H), 2.34–2.30 (m, 4H), 2.03–1.94 (m, ¹H), and 1.93–1.79 (m, 2H). UPLC-MS-2: Rt = 0.73 min; MS m/z [M+H] ⁺ 488.1. C-HPLC-5 (mobile phase: heptane + DEA/EtOH + DEA 50:50): Rt = 6.35 min. Second eluted isomer C-HPLC-5 (mobile phase: heptane + DEA/EtOH + DEA 50:50): Rt = 9.00 min. 57 - Racemic 57a - First eluted isomer 57b - Second eluted isomer N-(6-(4-(1,1-dioxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 1, intermediate C-T9 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were used, along with C-SFC-6 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)). The first eluted isomer C-SFC-14 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)): Rt = 1.56 min. The second eluted isomer's ^¹H NMR (400 MHz, DMSO- _d⁶ ) values are: δ 11.12 (s, ¹H), 8.49 (d, ¹H), 8.32–8.23 (m, 2H), 7.82 (d, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 4.36 (dd, ¹H), 3.27–3.21 (m, ¹H), 3.13–3.05 (m, ¹H), 2.49–2.45 (m, ¹H), 2.43–2.36 (m, ¹H), 2.31 (s, 3H), 2.28–2.22 (m, ¹H), and 2.14–2.05 (m, ¹H). UPLC-MS-2: Rt = 0.75 min; MS m/z [M+H] ⁺ 487.1. C-SFC-14 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)): Rt = 2.22 min. 58 N-(5-fluoro-6-(4-hydroxylino-1H-imidazol-1-yl)pyridin-3-yl)-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 5, the intermediate C-T10 and 2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 1823464-54-5] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 8.45 (d, 1H), 8.22 (dd, 1H), 8.06 (t, 1H), 7.81 (s, 1H), 6.98 (t, 1H), 5.15 (s, 2H), 3.76 - 3.66 (m, 4H), 3.08 - 2.98 (m, 4H), 2.16 - 2.10 (m, 3H). UPLC-MS-2: Rt = 0.91 min; MS m/z [M+H] ⁺ 454.2. 59 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(tetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 5, the intermediate C-T11 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H), 8.47 (d, 1H), 8.28 (dd, 1H), 8.18 (t, 1H), 7.79 - 7.75 (m, 1H), 7.74 - 7.70 (m, 1H), 7.60 (q, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 3.38 - 3.34 (m, 1H), 3.09 (dd, 1H), 2.93 (dd, 1H), 2.89 - 2.85 (m, 2H), 2.32 - 2.25 (m, 1H), 2.13 - 2.04 (m, 1H). UPLC-MS-2: Rt = 1.20 min; MS m/z [M+H] ⁺ 469.2. 60 N-(6-(4-(3,3-dimethylpiperazol-1-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 9, the intermediate D-M4 and 2,2-dimethylpiperazine were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.41 (d, 1H), 8.23 (dd, 1H), 8.01 (t, 1H), 6.88 (s, 1H), 6.55 (s, 1H), 5.14 (s, 2H), 2.90 (dd, 2H), 2.86 - 2.80 (m, 2H), 2.73 (s, 2H), 2.31 (s, 3H), 1.74 (d, 1H), 1.10 (s, 6H). UPLC-MS-2: Rt = 0.65 min; MS m/z [M+H] ⁺ 481.2. 61 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-hydroxylino-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 9, using the intermediate D-T2 and α-porphyrin ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 8.45 (d, 1H), 8.26 (dd, 1H), 8.05 (t, 1H), 7.76 (t, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 6.97 (t, 1H), 3.94 (s, 2H), 3.75 - 3.66 (m, 4H), 3.08 - 2.99 (m, 4H). UPLC-MS-2: Rt = 1.00 min; MS m/z [M+H] ⁺ 468.4. 62 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-methylpiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 9, intermediates D-T2 and 1-methylpiperazine were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 8.44 (d, 1H), 8.25 (dd, 1H), 8.03 (t, 1H), 7.76 (t, 1H), 7.74 - 7.70 (m, 1H), 7.41 (t, 1H), 6.93 (t, 1H), 3.94 (s, 2H), 3.05 (t, 4H), 2.42 (t, 4H), 2.21 (s, 3H). UPLC-MS-2: Rt = 0.78 min; MS m/z [M+H] ⁺ 481.5. 63 - Racemic 63a - First eluted isomer 63b - Second eluted isomer N-(6-(4-(1,1-dioxotetrahydrothiophene-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 1/Steps 2-3, use Example 59 and mCPBA, DCM at 0°C. C-SFC-6 (mobile phase: _CO2 /iPrOH + 0.05% _NH3 (50:50)) The first eluted isomer C-SFC-14 (mobile phase: _CO2 /iPrOH + 0.05% _NH3 (50:50)): Rt = 1.37 min. The second eluted isomer's ^¹H NMR (400 MHz, DMSO- _d⁶ ) values are: δ 10.97 (s, ¹H), 8.48 (d, ¹H), 8.29 (dd, ¹H), 8.23 (t, ¹H), 7.77 (t, ¹H), 7.74–7.70 (m, ¹H), 7.69 (q, ¹H), 7.41 (t, ¹H), 3.95 (s, 2H), 3.71–3.63 (m, ¹H), 3.49 (dd, ¹H), 3.30–3.26 (m, ¹H), 3.21–3.15 (m, 2H), 2.48–2.43 (m, ¹H), 2.30–2.19 (m, q). 1H). UPLC-MS-2: Rt = 0.92 min; MS m/z [M+H] ⁺ 501.1. C-SFC-14 (mobile phase: CO ₂ /iPrOH + 0.05% NH ₃ (50 : 50)): Rt = 2.45 min. 64 N-(5-fluoro-6-(4-(4-methyl-2-epoxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 18, the intermediate D-T3 and 4-methylpiperazine-2-one were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.49 (d, 1H), 8.31 (dd, 1H), 8.19 (t, 1H), 8.12 - 8.05 (m, 2H), 7.83 (d, 1H), 7.77 (d, 1H), 4.07 (s, 2H), 3.91 (t, 2H), 3.17 (d, 2H), 2.74 (t, 2H), 2.28 (s, 3H). UPLC-MS-2: Rt = 0.56 min; MS m/z [M+H] ⁺ 478.3. 65 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-sideoxypiperazol-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 18, intermediates D-T2 and tert-butyl 3-sideoxypiperazine-1-carboxylate were used, followed by Boc-deprotection at room temperature for 30 min using TFA and DCM. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.48 (d, 1H), 8.30 (dd, 1H), 8.18 (t, 1H), 8.09 (t, 1H), 7.77 (t, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 3.86 (t, 2H), 3.43 (s, 2H), 3.02 (t, 2H). UPLC-MS-2: Rt = 0.77 min; MS m/z [M+H] ⁺ 481.5. 66 - Racemic 66a - First eluted isomer 66b - Second eluted isomer N-(5-fluoro-6-(4-(1-methyl-5-sideoxypyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 1/Steps 1 and 3, intermediate C-T12 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] are used. C-SFC-16 (mobile phase: _CO2 /iPrOH + 0.05% _NH3 (63:37)) The first eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 11.17 (s, ¹H), 8.48 (d, ¹H), 8.30–8.25 (m, 2H), 7.76 (t, ¹H), 6.57 (s, ¹H), 5.19 (s, 2H), 4.64–4.59 (m, ¹H), 2.56 (s, 3H), 2.47–2.41 (m, ¹H), 2.31 (s, 3H), 2.30–2.25 (m, 2H), and 2.10–2.04 (m, ¹H). UPLC-MS-2: Rt = 0.77 min; MS m/z [M+H] ⁺ 466.1. C-SFC-15 (mobile phase: _CO₂ /iPrOH + 0.05% _NH₃ (60:40)): Rt = 1.81 min. Second eluted isomer C-SFC-15 (mobile phase: _CO₂ /iPrOH + 0.05% _NH₃ (60:40)): Rt = 2.47 min. 67 N-(5-fluoro-6-(4-(2-epoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 18, the intermediate D-T3 and pyrrolidone are used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.45 (d, 1H), 8.37 (dd, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.02 (t, 1H), 7.72 (t, 2H), 4.10 - 4.01 (m, 4H), 2.61 (t, 2H), 2.25 (p, 2H). UPLC-MS-2: Rt = 0.81 min; MS m/z [M+H] ⁺ 449.4. 68 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-hydroxy-2-sideoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 18, the intermediate D-T2 and 4-hydroxypyrrolidone-2-one are used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.48 (d, 1H), 8.31 (dd, 1H), 8.17 (t, 1H), 7.97 (t, 1H), 7.77 (t, 1H), 7.74 - 7.70 (m, 1H), 7.41 (t, 1H), 5.34 (d, 1H), 4.43 (td, 1H), 4.02 (dd, 1H), 3.95 (s, 2H), 3.81 (dd, 1H), 2.81 (dd, 1H), 2.27 (dd, 1H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ 482.3. 69 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 9, using the intermediate D-T2 and pyrrolidine ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.45 - 8.41 (m, 1H), 8.31 (dd, 1H), 8.10 (d, 1H), 7.73 - 7.68 (m, 1H), 7.66 (t, 1H), 7.37 (t, 1H), 6.90 (t, 1H), 3.94 (d, 2H), 3.25 (td, 4H), 2.03 - 1.97 (m, 4H). UPLC-MS-2: Rt = 0.74 min; MS m/z [M+H] ⁺ 470.5. 70 N-(5-fluoro-6-(4-hydroxylino-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 9, using intermediate D-M4 and α-porphyrin ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 8.44 (d, 1H), 8.24 (dd, 1H), 8.06 (t, 1H), 6.98 (t, 1H), 6.57 (s, 1H), 5.17 (s, 2H), 3.75 - 3.67 (m, 4H), 3.06 - 2.98 (m, 4H), 2.33 - 2.28 (m, 3H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ 454.2. 71 N-(6-(4-(5,6-dihydro-1,4-dichloro-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 10, 2-(5,6-dihydro-1,4-dichloro-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane [CAS No. 1046811-97-5] is used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.93 (s, 1H), 8.47 (d, 1H), 8.27 (dd, 1H), 8.23 - 8.18 (m, 1H), 7.81 - 7.68 (m, 2H), 7.52 - 7.47 (m, 1H), 7.41 (t, 1H), 6.76 (s, 1H), 4.22 - 4.15 (m, 2H), 4.15 - 4.06 (m, 2H), 3.95 (s, 2H). UPLC-MS-2: Rt = 1.06 min; MS m/z [M+H] ⁺ 467.2. 72 - Racemic 72a - First eluted isomer 72b - Second eluted isomer N-(6-(4-(1,4-dioxane-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 21, use Example 71, followed by C-SFC-19 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 80/20) The first eluted isomers showed the following ^¹H NMR values (400 MHz, DMSO- d⁶ ) _: δ 10.96 (s, ¹H), 8.50–8.45 (m, ¹H), 8.28 (dd, ¹H), 8.22–8.17 (m, ¹H), 7.81–7.68 (m, 2H), 7.67–7.62 (m, ¹H), 7.41 (t, ¹H), 4.57 (dd, ¹H), 3.94 (s, 2H), 3.87 (dd, 1H), 3.81 (dd, 1H), 3.77–3.67 (m, 2H), and 3.64–3.51 (m, 2H). UPLC-MS-2: Rt = 0.95 min; MS m/z [M+H] ⁺ 469.2. C-SFC-15 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 80/20): Rt = 3.72 min. Second eluted isomer C-SFC-15 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 80/20): Rt = 4.10 min. 73 - Racemic 73a - First eluted isomer 73b - Second eluted isomer N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 25, 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] and intermediate C-T18 were used with C-SFC-21 (mobile phase: CO ₂ / (EtOH + 0.05% NH ₃ ) 55/45). The first eluted isomers showed the following ^¹H NMR values (400 MHz, DMSO- d⁶ ) _: δ 10.93 (s, ¹H), 8.50–8.45 (m, ¹H), 8.28 (dd, ¹H), 8.23–8.18 (m, ¹H), 7.81–7.67 (m, 2H), 7.65 (s, ¹H), 7.41 (t, ¹H), 4.40–4.28 (m, ¹H), 3.95 (s, 2H), 3.33–3.28 (m, ¹H), 3.23–3.03 (m, 2H), 2.63–2.52 (m, ¹H), and 2.45–2.27 (m, ¹H). UPLC-MS-8: Rt = 0.88 min; MS m/z [M+H] ⁺ 488.1. C-SFC-5 (mobile phase: CO ₂ / (EtOH + 0.05% NH ₃ ) 70/30): Rt = 2.45 min. Second eluted isomer C-SFC-5 (mobile phase: CO ₂ / (EtOH + 0.05% NH ₃ ) 70/30): Rt = 3.71 min. 74 N-(5-cyano-6-(1-(3,3-difluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenoxy)acetamide Similar to Example 15, using Example 3 and NaCNBH ₃ ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 9.00 (d, 1H), 8.54 (d, 1H), 8.45 (s, 1H), 8.20 (s, 1H), 7.58 (t, 1H), 7.41 - 7.32 (m, 3H), 5.01 - 4.87 (m, 3H), 3.25 - 3.10 (m, 1H), 2.99 - 2.89 (m, 1H), 2.53 - 2.36 (m, 2H), 2.34 - 2.23 (m, 4H), 2.13 - 2.06 (m, 1H). UPLC-MS-2: Rt = 0.87 min; MS m/z [M+H] ⁺ 521.2. 75 - Racemic 75a - First eluted isomer 75b - Second eluted isomer N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 2, intermediate C-T8 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. After step 1 (Boc-protected racemic mixture), C-SFC-18 (mobile phase: _CO2 /iPrOH + 0.05% _NH3 (48:52)) was followed by Boc deprotection, giving the first eluted isomer and the second eluted isomer. The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) with the following δ values: 10.94 (s, ¹H), 8.49 (s, ¹H), 8.28 (dd, ¹H), 8.20 (s, ¹H), 8.09 (t, ¹H), 7.82 (d, ¹H), 7.76 (d, ¹H), 7.61 (s, ¹H), 4.07 (s, 2H), 3.77 (dd, ¹H), 3.14–3.06 (m, ¹H), 2.80–2.68 (m, ¹H), 2.38–2.27 (m, ¹H), 2.04–1.95 (m, ¹H), and 1.95–1.76 (m, 2H). UPLC-MS-8: Rt = 0.75 min; MS m/z [M+H] ⁺ 485.1. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values are: δ 10.94 (s, ¹H), 8.49 (s, ¹H), 8.28 (dd, ¹H), 8.20 (s, ¹H), 8.09 (t, ¹H), 7.82 (d, ¹H), 7.76 (d, ¹H), 7.62 (s, ¹H), 4.07 (s, 2H), 3.82–3.76 (m, ¹H), 3.15–3.06 (m, ¹H), 2.79–2.68 (m, ¹H), 2.36–2.26 (m, ¹H), 2.04–1.96 (m, ¹H), 1.95–1.77 (m, 2H). UPLC-MS-8: Rt = 0.66 min; MS m/z [M+H] ⁺ 485.1. 76 - Racemic 76a - First eluted isomer 76b - Second eluted isomer N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 2, intermediate C-T15 is used. After step 1 (the racemic form of the Boc-protected intermediate), C-SFC-6 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (85:15)) is followed by Boc deprotection, yielding the first eluted isomer and the second eluted isomer. The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) with the following δ values: 11.15 (s, 1H), 9.05 (s, 1H), 8.52 (d, 1H), 8.30 (dd, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 4.00 (d, 1H), 3.19 - 3.09 (m, 1H), 3.04 - 2.92 (m, 1H), 2.75 - 2.59 (m, 1H), 2.32 (s, 3H), 2.22 - 2.12 (m, 1H), 2.12 - 1.98 (m, 2H), and 1.93 - 1.82 (m, 1H). UPLC-MS-2: Rt = 0.74 min; MS m/z [M+H] ⁺ 489.2. The second eluted isomers showed the following ^¹H NMR values (600 MHz, DMSO- _d⁶ ): δ 11.15 (s, ¹H), 9.05 (s, ¹H), 8.52 (d, ¹H), 8.30 (dd, ¹H), 6.57 (s, ¹H), 5.19 (s, 2H), 4.00 (d, ¹H), 3.18–3.09 (m, ¹H), 3.05–2.91 (m, ¹H), 2.74–2.58 (m, ¹H), 2.32 (s, 3H), 2.21–2.12 (m, ¹H), 2.12–2.00 (m, 2H), and 1.93–1.82 (m, ¹H). UPLC-MS-8: Rt = 0.77 min; MS m/z [M+H] ⁺ 489.2. 77 (A mixture of non-mirror isomers) N-(5-fluoro-6-(4-(2-methyl-1,1-dioxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridin-2-methylamine Similar to Example 1, using intermediates C-M1 and A-M3, there is no chiral separation (a mixture of non-mirror isomers). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.65 - 8.60 (m, 1H), 8.38 (dd, 1H), 8.30 - 8.25 (m, 1H), 7.88 - 7.81 (m, 2H), 7.48 (d, 1H), 5.15 (dd, 1H), 3.29 - 3.12 (m, 2H), 3.04 - 2.94 (m, 1H), 2.94 - 2.83 (m, 1H), 2.78 - 2.68 (m, 1H), 2.38 - 2.28 (m, 1H), 2.28 - 2.04 (m, 4H), 1.65 (s, 3H). UPLC-MS-2: Rt = 0.83 min; MS m/z [M+H] ⁺ 540.3. 78 - Racemic 78a - First eluted isomer 78b - Second eluted isomer N-(5-fluoro-6-(4-(2-methyl-1,1-dioxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 1, intermediate C-M1 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. C-SFC-6 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (57:43)) The first eluted isomer C-SFC-14 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 55/45): Rt = 1.56 min. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values are: δ 10.99 (s, ¹H), 8.50 (d, ¹H), 8.31 (dd, ¹H), 8.27–8.24 (m, ¹H), 8.10 (t, ¹H), 7.85–7.80 (m, 2H), 7.77 (d, ¹H), 4.07 (s, 2H), 3.28–3.13 (m, 2H), 2.76–2.65 (m, ¹H), 2.28–2.19 (m, ¹H), 2.16–2.07 (m, 2H), 1.65 (s, 3H). UPLC-MS-8: Rt = 0.79 min; MS m/z [M+H] ⁺ 498.2. C-SFC-14 (mobile phase: CO ₂ / (MeOH + 0.05% NH ₃ ) 55/45): Rt = 2.26 min. 79 N-(6-(4-(4,4-difluoropiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, the intermediate C-T8 and 2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 1823464-54-5] are used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.02 (s, 1H), 8.51 - 8.46 (m, 1H), 8.25 (dd, 1H), 8.22 - 8.18 (m, 1H), 7.84 - 7.78 (m, 1H), 7.65 - 7.59 (m, 1H), 5.16 (s, 2H), 3.75 (d, 1H), 3.16 - 3.05 (m, 1H), 2.78 - 2.68 (m, 1H), 2.31 (m, 1H), 2.15 - 2.10 (m, 3H), 2.06 - 1.66 (m, 3H). UPLC-MS-2: Rt = 0.73 min; MS m/z [M+H] ⁺ 488.3. 80 N-(6-(4-(1-amino-3,3-difluorocyclobutyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, the intermediate C-T16 is used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.06 (s, 1H), 8.51 - 8.45 (m, 1H), 8.30 - 8.21 (m, 2H), 7.72 - 7.67 (m, 1H), 6.56 (s, 1H), 5.18 (s, 2H), 3.15 - 2.99 (m, 2H), 2.72 - 2.57 (m, 2H), 2.42 (s, 2H), 2.34 - 2.29 (m, 3H). UPLC-MS-8: Rt = 0.63 min; MS m/z [M+H] ⁺ 474.1. 81 (A mixture of non-mirror isomers) N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-piperano[2,3-b]pyridin-2-methylamine Similar to Example 5, intermediates C-M1 and A-M3 (a mixture of non-mirror isomers) are used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (s, 1H), 8.61 - 8.56 (m, 1H), 8.35 (dd, 1H), 8.23 - 8.17 (m, 1H), 7.85 (d, 1H), 7.59 (t, 1H), 7.48 (d, 1H), 5.18 - 5.11 (m, 1H), 3.05 - 2.94 (m, 3H), 2.94 - 2.82 (m, 1H), 2.44 - 2.36 (m, 1H), 2.35 - 2.27 (m, 1H), 2.22 - 2.13 (m, 1H), 2.13 - 2.04 (m, 2H), 1.95 - 1.85 (m, 1H), 1.71 (s, 3H). UPLC-MS-2: Rt = 1.19 min; MS m/z [M+H] ⁺ 508.1 82 - Racemic 82a - First eluted isomer 82b - Second eluted isomer N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 2, intermediate C-T15 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. After step 1 (Boc-protected racemic intermediate), C-SFC-20 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (75:25)) was used. This was followed by Boc deprotection, with the first eluted isomer and the second eluted isomer. The first eluted isomers showed the following ^¹H NMR spectra (600 MHz, DMSO- _d⁶ ): δ 11.02 (s, ¹H), 9.03 (s, ¹H), 8.52 (d, ¹H), 8.32 (dd, ¹H), 7.77 (t, ¹H), 7.72 (t, ¹H), 7.41 (t, ¹H), 4.00 (d, ¹H), 3.97 (s, 2H), 3.18 - 3.08 (m, ¹H), 3.04 - 2.92 (m, ¹H), 2.74 - 2.58 (m, ¹H), 2.21 - 2.12 (m, ¹H), 2.12 - 1.99 (m, 2H), 1.94 - 1.82 (m, 1H). UPLC-MS-8: Rt = 0.94 min; MS m/z [M+H] ⁺ 503.1. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values are: δ 11.02 (s, ¹H), 9.03 (s, ¹H), 8.52 (d, ¹H), 8.31 (dd, ¹H), 7.81 - 7.75 (m, ¹H), 7.72 (t, ¹H), 7.41 (t, ¹H), 4.02 - 3.98 (m, ¹H), 3.96 (s, 2H), 3.18 - 3.09 (m, ¹H), 3.04 - 2.93 (m, ¹H), 2.78 - 2.59 (m, ¹H), 2.22 - 2.12 (m, ¹H), 2.12 - 2.00 (m, 2H). 1.94 - 1.82 (m, 1H). UPLC-MS-8: Rt = 0.95 min; MS m/z [M+H] ⁺ 503.1. 83 N-(5-fluoro-6-(4-(1-hydroxycyclohexyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 5, the intermediate C-T17 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.93 (s, 1H), 8.50 - 8.45 (m, 1H), 8.28 (dd, 1H), 8.15 (t, 1H), 8.10 (t, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.53 - 7.48 (m, 1H), 4.60 (s, 1H), 4.07 (s, 2H), 1.92 - 1.80 (m, 2H), 1.74 - 1.60 (m, 4H), 1.59 - 1.50 (m, 1H), 1.48 - 1.39 (m, 2H), 1.30 - 1.19 (m, 1H). UPLC-MS-2: Rt = 0.94 min; MS m/z [M+H] ⁺ 464.4. 84 N-(5-fluoro-6-(4-(1-hydroxycyclopentyl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 5, the intermediate C-T19 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.05 (s, 1H), 8.47 (d, 1H), 8.25 (dd, 1H), 8.20 - 8.14 (m, 1H), 7.55 - 7.50 (m, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 4.77 (s, 1H), 2.32 (s, 3H), 2.05 - 1.93 (m, 2H), 1.86 - 1.64 (m, 6H). UPLC-MS-8: Rt = 0.92 min; MS m/z [M+H] ⁺ 453.1. 85 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-epoxypiperidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 18, the intermediate D-T2 and piperidin-2-one [CAS No. 675-20-7] are used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.94 (s, 1H), 8.48 (s, 1H), 8.30 (d, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.83 - 7.57 (m, 2H), 7.41 (s, 1H), 4.05 - 3.85 (m, 4H), 2.44 - 2.24 (m, 2H), 1.87 (s, 2H), 1.78 (s, 2H). UPLC-MS-2: Rt = 1.02 min; MS m/z [M+H] ⁺ 480.4. 86 N-(5-fluoro-6-(4-(3-hydroxy-1-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide (trans isomer) Similar to steps 1 and 2 in Example 26, use intermediate C-M9 ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 8.47 (d, 1H), 8.26 (dd, 1H), 8.23 - 8.18 (m, 1H), 7.57 (d, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 4.90 (d, 1H), 4.25 - 4.19 (m, 1H), 3.02 (d, 1H), 2.99 - 2.92 (m, 1H), 2.49 - 2.42 (m, 1H), 2.31 (s, 3H), 2.17 (s, 3H), 2.11 - 2.00 (m, 1H), 1.60 - 1.53 (m, 1H). UPLC-MS-8: Rt = 0.56 min; MS m/z [M+H] ⁺ 468.3. 87 - Racemic 87a - First eluted isomer 87b - Second eluted isomer N-(6-(3-(5,5-difluoropiperidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 2, intermediate C-T15 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. Following step 1 (the racemic mixture of the Boc-protected intermediate), C-SFC-20 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (80:20)) was used, followed by Boc deprotection, resulting in the first and second eluted isomers. The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) with the following δ values: 11.06 (s, ¹H), 9.04 (s, ¹H), 8.53 (d, ¹H), 8.32 (dd, ¹H), 8.10 (t, ¹H), 7.83 (d, ¹H), 7.77 (d, ¹H), 4.09 (s, 2H), 4.00 (d, 1H), 3.17 - 3.09 (m, ¹H), 3.04 - 2.92 (m, ¹H), 2.67 (s, ¹H), 2.22 - 2.13 (m, ¹H), 2.12 - 1.99 (m, 2H), and 1.92 - 1.84 (m, ¹H). UPLC-MS-8: Rt = 0.73 min; MS m/z [M+H] ⁺ 486.2. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values are: δ 11.06 (s, ¹H), 9.04 (s, ¹H), 8.53 (d, ¹H), 8.32 (dd, ¹H), 8.10 (t, ¹H), 7.83 (d, ¹H), 7.77 (d, ¹H), 4.09 (s, 2H), 4.03 - 3.97 (m, ¹H), 3.17 - 3.09 (m, ¹H), 3.04 - 2.92 (m, ¹H), 2.64 (s, ¹H), 2.21 - 2.12 (m, ¹H), 2.12 - 1.99 (m, 2H), 1.93 - 1.80 (m, 1H). UPLC-MS-8: Rt = 0.73 min; MS m/z [M+H] ⁺ 486.2. 88 - Racemic 88a - First eluted isomer 88b - Second eluted isomer 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-hydroxy-1,1-dioxotetrahydrothiophene-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 5, intermediate C-T20 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used, followed by C-SFC-22 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (70:30)). The first eluted isomer C-SFC-23 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (70:30)): Rt = 1.57 min. The second eluted isomer's ^¹H NMR (400 MHz, DMSO- _d⁶ ) values are: δ 10.96 (s, ¹H), 8.51 - 8.46 (m, ¹H), 8.29 (dd, ¹H), 8.27 - 8.24 (m, ¹H), 7.81 - 7.70 (m, 2H), 7.70 - 7.66 (m, ¹H), 7.41 (t, ¹H), 6.12 (s, ¹H), 3.95 (s, 2H), 3.51 (d, ¹H), 3.38 - 3.31 (m, 3H), 2.61 - 2.54 (m, ¹H), and 2.41 - 2.31 (m, ¹H). UPLC-MS-2: Rt = 0.85 min; MS m/z [M+H] ⁺ 517.1. C-SFC-23 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (70:30)): Rt = 2.16 min. 89 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea Similar to Example 27, the intermediate C-T2 (peak 1) is used. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.13 (br s, 1H), 8.41 (br s, 1H), 8.06-8.19 (m, 2H), 7.86 (br s, 1H), 7.77 (br s, 1H), 7.55 (br s, 1H), 7.49 (m, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 3.71 (m, 1H), 3.39-3.47 (m, 2H), 2.84 (br s 2H). UPLC-MS-8: Rt = 0.70 min; MS m/z [M+H] ⁺ 483.2. 90 1-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-(4-(olylin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-1-methylurea (single mirror isomer) Similar to Example 27, the intermediate C-T2 (peak 2) is used. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.12 (s, 1H), 8.41 (m, 1H), 8.14 (m, 1H), 8.12 (m, 1H), 7.86 (m, 1H), 7.77 (m, 1H), 7.54 (s, 1H), 7.49 (m, 1H), 3.89 (m, 1H), 3.79 (m, 1H), 3.70 (m, 1H), 3.41 (m, 1H), 2.83 (br s, 2H). UPLC-MS-8: Rt = 0.66 min; MS m/z [M+H] ⁺ 483.1. 91 N-(6-(4-(3,9-dioxane-7-azabicyclo[3.3.1]nonane-7-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 5, the intermediate C-T22 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 8.45 (s, 1H), 8.32 - 8.18 (m, 1H), 8.04 (s, 1H), 7.90 - 7.58 (m, 2H), 7.50 - 7.33 (m, 1H), 6.87 (s, 1H), 3.94 (s, 2H), 3.90 - 3.73 (m, 6H), 3.70 - 3.58 (m, 2H), 3.06 - 2.90 (m, 2H). UPLC-MS-2: Rt = 0.91 min; MS m/z [M+H] ⁺ 510.2. 92 - Racemic; 92a - First eluted isomer; 92b - Second eluted isomer N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 25, the intermediate C-T23 (racemic) and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used with C-SFC-25 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35 to 60:40 gradient)). The first eluted isomer C-SFC-5 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40)): Rt = 2.33 min. The second eluted isomer's ^¹H NMR (400 MHz, DMSO- _d⁶ ) values are: δ 10.94 (s, ¹H), 8.50–8.45 (m, ¹H), 8.27 (dd, ¹H), 8.18–8.13 (m, ¹H), 8.13–8.05 (m, ¹H), 7.86–7.80 (m, ¹H), 7.76 (d, ¹H), 7.48 (s, ¹H), 4.07 (s, 2H), 3.59–3.52 (m, ¹H), 3.04–2.96 (m, ¹H), 2.68–2.58 (m, ¹H), 2.39 (s, ¹H), 1.95–1.88 (m, 1H), 1.82 - 1.74 (m, 1H), 1.57 - 1.50 (m, 1H), 1.46 - 1.28 (m, 3H). UPLC-MS-2: Rt = 0.49 min; MS m/z [M+H] ⁺ 449.5. C-SFC-5 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40)): Rt = 3.35 min. 93 2-(4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 11, the intermediate C-T2 (peak 1) and 2-(4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 1006446-52-1] were used. ( Ent-1 ) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.06 (s, 1H), 8.50 - 8.45 (m, 1H), 8.37 - 8.32 (m, 1H), 8.24 (dd, 1H), 8.21 - 8.17 (m, 1H), 7.61 - 7.55 (m, 1H), 5.25 (s, 2H), 3.89 (dd, 1H), 3.80 (dd, 1H), 3.75 - 3.66 (m, 1H), 3.49 - 3.37 (m, 1H), 3.33 - 3.25 (m, 1H), 2.91 - 2.79 (m, 2H), 2.71 (s, 1H). UPLC-MS-8: Rt = 0.78 min; MS m/z [M+H] ⁺ 474.0. 94 2-(4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(oinolin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide (single mirror isomer) Similar to Example 11, intermediate C-T2 (peak 2) and 2-(4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 1006446-52-1] were used. ( Ent-2 ) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.06 (s, 1H), 8.50 - 8.45 (m, 1H), 8.37 - 8.32 (m, 1H), 8.24 (dd, 1H), 8.21 - 8.17 (m, 1H), 7.60 - 7.55 (m, 1H), 5.25 (s, 2H), 3.89 (dd, 1H), 3.80 (dd, 1H), 3.75 - 3.66 (m, 1H), 3.47 - 3.36 (m, 1H), 3.33 - 3.25 (m, 1H), 2.91 - 2.80 (m, 2H), 2.69 (s, 1H). UPLC-MS-8: Rt = 0.68 min; MS m/z [M+H] ⁺ 474.1. 95 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 3, the intermediate D-T2 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester [CAS No. 286961-14-6] were used. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.04 (s, 1H), 8.51 (d, 1H), 8.37 - 8.22 (m, 2H), 7.83 (s, 1H), 7.75 (dt, 2H), 7.41 (t, 1H), 6.51 - 6.32 (m, 1H), 3.96 (s, 2H), 3.88 - 3.64 (m, 2H), 3.31 (t, 2H), 2.61 (qd, 2H). UPLC-MS-2: Rt = 0.77 min; MS m/z [M+H] ⁺ 464.3. 96 N-(5-fluoro-6-(4-(piperidin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 11, the intermediate C-T26 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.94 (s, 1H), 8.49 - 8.44 (m, 1H), 8.27 (dd, 1H), 8.17 - 8.05 (m, 2H), 7.83 (d, 1H), 7.76 (d, 1H), 7.39 (s, 1H), 4.06 (s, 2H), 3.02 - 2.93 (m, 2H), 2.63 - 2.53 (m, 3H), 2.29 - 1.94 (m, 1H), 1.90 - 1.81 (m, 2H), 1.52 - 1.37 (m, 2H). UPLC-MS-2: Rt = 0.51 min; MS m/z [M+H] ⁺ 449.4. 97 N-(5-fluoro-6-(4-(4-hydroxytetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 5, the intermediate C-T27 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (s, 1H), 8.48 (d, 1H), 8.29 (dd, 1H), 8.21 - 8.16 (m, 1H), 8.10 (t, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.59 - 7.53 (m, 1H), 4.97 (s, 1H), 4.07 (s, 2H), 3.79 - 3.69 (m, 2H), 3.67 - 3.58 (m, 2H), 2.13 - 1.99 (m, 2H), 1.60 (d, 2H). UPLC-MS-2: Rt = 0.69 min; MS m/z [M+H] ⁺ 466.1. 98 N-(3-cyano-5-fluoro-4-(1-(acetazol-2-ylmethyl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 28, use the intermediate C-T28. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.35 (s, 1H), 8.12 (d, 1H), 7.90 (s, 1H), 7.89 - 7.83 (m, 2H), 7.78 - 7.68 (m, 2H), 7.40 (t, 1H), 7.24 (d, 1H), 5.66 (s, 2H), 3.92 (s, 2H). UPLC-MS-2: Rt = 1.00 min; MS m/z [M+H] ⁺ 488.2. 99 N-(6-(4-(3-aminooxocyclobutane-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 11, intermediate C-T29 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.48 (d, 1H), 8.33 - 8.23 (m, 2H), 7.81 - 7.66 (m, 3H), 7.41 (t, 1H), 4.82 (d, 2H), 4.51 (d, 2H), 3.95 (s, 2H), 2.88 (s, 2H). UPLC-MS-8: Rt = 0.73 min; MS m/z [M+H] ⁺ 454.3. 100 N-(5-cyano-6-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 28, the intermediate C-M10 and 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid [CAS No. 349-10-0] were used. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 9.11 (d, 1H), 8.59 (d, 1H), 8.50 (d, 1H), 8.15 (d, 1H), 7.88 (d, 1H), 7.83 (d, 1H), 7.73 - 7.66 (m, 1H), 7.63 (t, 1H), 6.95 (s, 1H), 5.53 (dd, 1H), 5.34 (s, 1H), 3.95 (dtd, 1H), 3.67 (ddd, 1H), 2.21 - 2.02 (m, 1H), 2.02 - 1.87 (m, 2H), 1.79 - 1.63 (m, 1H), 1.56 (tt, 2H). UPLC-MS-2: Rt = 1.06 min; MS m/z [MH] ^- 470.2. 101 N-(3-cyano-4-(1-(3,3-difluoropiperidin-4-yl)-1H-pyrazole-4-yl)-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 6, intermediates B-M3 and D-T4 are used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.84 (s, 1H), 8.19 (s, 1H), 8.09 (t, 1H), 7.94 - 7.90 (m, 1H), 7.90 - 7.85 (m, 2H), 7.83 (d, 1H), 7.76 (d, 1H), 5.06 - 4.90 (m, 1H), 4.05 (s, 2H), 3.24 - 3.13 (m, 1H), 3.09 - 3.01 (m, 1H), 2.98 - 2.83 (m, 1H), 2.75 - 2.66 (m, 1H), 2.64 - 2.54 (m, 1H), 2.35 - 2.21 (m, 1H), 2.11 - 2.02 (m, 1H). UPLC-MS-2: Rt = 0.68 min; MS m/z [M+H] ⁺ 509.2. 102 N-(3-cyano-4-(1-(3,3-difluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 15, using Example 101 and NaCNBH ₃ ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.84 (s, 1H), 8.22 (s, 1H), 8.09 (t, 1H), 7.94 - 7.91 (m, 1H), 7.90 - 7.85 (m, 2H), 7.83 (d, 1H), 7.76 (d, 1H), 4.97 - 4.81 (m, 1H), 4.05 (s, 2H), 3.22 - 3.11 (m, 1H), 2.97 - 2.90 (m, 1H), 2.52 - 2.36 (m, 2H), 2.32 - 2.22 (m, 4H), 2.13 - 2.04 (m, 1H). UPLC-MS-2: Rt = 0.79 min; MS m/z [M+H] ⁺ 523.3. 103 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 21, use Example 95 instead of HOAc. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.93 (s, 1H), 8.46 (d, 1H), 8.27 (dd, 1H), 8.15 (t, 1H), 7.74 (dt, 2H), 7.50 - 7.35 (m, 2H), 3.95 (s, 2H), 3.10 - 2.94 (m, 2H), 2.69 - 2.56 (m, 3H), 1.93 - 1.79 (m, 2H), 1.47 (dd, 2H). UPLC-MS-2: Rt = 0.75 min; MS m/z [MH] ^- 466.3. 104 - Racemic; 104a - First eluted isomer; 104b - Second eluted isomer 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxotetrahydrothiophen-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 1, 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 922516-24-3] was used, with C-SFC-22 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (70:30)). The first eluted isomer C-SFC-5 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (70:30)): Rt = 1.76 min. The second eluted isomer, ^¹H NMR (600 MHz, DMSO-d6), δ 11.20 (s, 1H), 8.49 (d, 1H), 8.30–8.25 (m, 2H), 7.83 (d, 1H), 7.14 (s, 1H), 5.30 (s, 2H), 3.28–3.21 (m, 1H), 3.17 (ddd, 1H), 2.76–2.67 (m, 1H), 2.23 (dddd, 1H), 2.17–2.08 (m, 2H), 1.65 (s, 3H). UPLC-MS-2: Rt = 0.91 min; MS m/z [M+H] ⁺ 521.2. C-SFC-5 (mobile phase: CO ₂ /MeOH + 0.05% NH ₃ (70 : 30)): Rt = 2.41 min. 105 - Racemic 105a - First eluted isomer 105b - Second eluted isomer N-(5-fluoro-6-(4-(2-methyl-1,1-dioxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 1, 2-(5-methyl-3-(trifluoro-methyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] was used, with C-SFC-29 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)). The first eluted isomer C-SFC-14 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)): Rt = 1.43 min. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 11.11 (s, ¹H), 8.49 (d, ¹H), 8.33–8.20 (m, 2H), 7.83 (s, ¹H), 6.57 (s, ¹H), 5.19 (s, 2H), 3.27–3.14 (m, 2H), 2.72 (dd, ¹H), 2.31 (s, 3H), 2.26–2.20 (m, ¹H), 2.14 (dd, 2H), and 1.65 (s, 3H). UPLC-MS-2: Rt = 0.82 min; MS m/z [M+H] ^⁺ = 501.2. C-SFC-14 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)): Rt = 1.98 min. 106 - Racemic; 106a - First eluted isomer; 106b - Second eluted isomer, confirmed by X-ray diffraction. 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyl-1,1-dioxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 1, 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] was used, with C-SFC-30 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)) for KKM222 (first eluted isomer) and GUE677 (second eluted isomer). (R-mirror isomer) First eluted isomer C-SFC-14 (mobile phase: CO ₂ /MeOH + 0.05% NH ₃ (65 : 35)): Rt = 1.46 min. (S-Mirror Image Isomer) Second eluted isomer ^¹H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.49 (d, 1H), 8.31 (dd, 1H), 8.26 (t, 1H), 7.82 (t, 1H), 7.77 (t, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 3.26 - 3.15 (m, 2H), 2.73 - 2.69 (m, 1H), 2.23 (tq, 1H), 2.16 - 2.09 (m, 2H), 1.65 (s, 3H). UPLC-MS-2: Rt = 0.97 min; MS m/z [M+H] ⁺ = 515.2. C-SFC-14 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)): Rt = 2.07 min. 107 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyl-1-oxotetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide It is obtained as an additional product in the synthesis of Example 106. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.49 (d, 1H), 8.30 (dd, 1H), 8.25 (t, 1H), 7.77 (t, 1H), 7.72 (t, 2H), 7.41 (t, 1H), 3.95 (s, 2H), 3.46 (ddd, 1H), 2.67 (dt, 2H), 2.33 (tt, 1H), 2.15 - 2.04 (m, 2H), 1.43 (s, 3H). UPLC-MS-2: Rt = 0.94 min; MS m/z [M+H] ⁺ = 499.2. 108 - Racemic; 108a - First eluted isomer; 108b - Second eluted isomer N-(5-fluoro-6-(4-(tetrahydrofuran-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 5, intermediate C-T30 and 2-(5-methyl-3-(trifluoro-methyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were used, followed by C-SFC-17 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)). The first eluted isomers showed the following ^¹H NMR values (600 MHz, DMSO- _d⁶ ): δ 11.11 (s, ¹H), 8.46 (d, ¹H), 8.26 (dd, ¹H), 8.19 (t, ¹H), 7.62–7.58 (m, ¹H), 6.57 (s, ¹H), 5.17 (s, 2H), 4.84 (t, ¹H), 3.88 (td, ¹H), 3.73 (td, ¹H), 2.31 (d, 3H), 2.19–2.10 (m, ¹H), 2.05–1.85 (m, 3H). UPLC-MS-2: Rt = 0.92 min; MS m/z [M+H] ^⁺ = 439. C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (65:35)): Rt = 1.43 min. Second eluted isomer C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (65:35)): Rt = 2.93 min. 109 N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 5, 2-(5-methyl-3-(trifluoro-methyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] and intermediate C-M1 were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 8.46 (d, 1H), 8.26 (dd, 1H), 8.20 (s, 1H), 7.58 (t, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 2.98 (td, 2H), 2.42 - 2.39 (m, 1H), 2.31 (s, 3H), 2.15 - 2.03 (m, 2H), 1.91 (ddd, 1H), 1.71 (s, 3H). UPLC-MS-2: Rt = 1.23 min; MS m/z [M+H] ⁺ = 483.2. 110 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-methyltetrahydrothiophene-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 5, 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] and intermediate C-M1 were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H), 8.46 (d, 1H), 8.28 (dd, 1H), 8.18 (t, 1H), 7.74 (dt, 2H), 7.57 (d, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 2.98 (td, 2H), 2.39 (td, 1H), 2.14 - 2.04 (m, 2H), 1.90 (ddd, 1H), 1.71 (s, 3H). UPLC-MS-2: Rt = 1.25 min; MS m/z [M+H] ⁺ = 483.2. 111 - Racemic 111a - First eluted isomer 111b - Second eluted isomer N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 25, intermediate C-T31 is used, and C-SFC-31 (mobile phase: _CO2 /EtOH + 0.05% _NH3 (83:17 to 80:20)) is used. The first eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 11.10 (s, ¹H), 8.46 (d, ¹H), 8.27 (dd, ¹H), 8.22 (t, ¹H), 7.63 (t, ¹H), 6.57 (s, ¹H), 5.17 (s, 2H), 3.26 (dq, ¹H), 3.19 (d, 2H), 2.78 (ddd, ¹H), 2.31 (d, 3H), 2.25 (ddd, ¹H), and 1.45 (s, 3H). UPLC-MS-8: Rt = 0.69 min; MS m/z [M+H] ^⁺ = 488. C-SFC-7 (mobile phase: _CO₂ /EtOH + 0.05% _NH₃ (80:20)): Rt = 1.94 min. Second eluted isomer C-SFC-7 (mobile phase: _CO₂ /EtOH + 0.05% _NH₃ (80:20)): Rt = 2.31 min. 112 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(6-(4-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)acetamide Similar to Example 25, 2-(5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 922516-24-3] and intermediate B-M17 were used, along with C-SFC-31 (mobile phase: _CO2 /EtOH + 0.05% _NH3 (80:20 to 77:23)). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 8.46 (d, 1H), 8.25 (dd, 1H), 8.22 (t, 1H), 7.64 (d, 1H), 7.14 (s, 1H), 5.29 (s, 2H), 3.19 (d, 3H), 2.78 (ddd, 1H), 2.25 (ddd, 1H), 1.45 (s, 3H). UPLC-MS-8: Rt = 0.78 min, MS m/z [M+H]+ = 508.0/510.0. C-SFC-7 (mobile phase: CO ₂ /EtOH + 0.05% NH ₃ (80 : 20)): Rt = 3.03 min. C-SFC-7 (mobile phase: CO ₂ /EtOH + 0.05% NH ₃ (80 : 20)): Rt = 2.43 min. 113 - Racemic 113a - First eluted isomer 113b - Second eluted isomer N-(6-(4-(4,4-difluoropyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 25, intermediate C-T18 was used, and C-SFC-26 (mobile phase: _CO2 /IPA + 0.05% _NH3 (50:50)) was used. The first eluted isomer ^¹H -NMR (600 MHz, DMSO- _d⁶ ) δ 11.10 (s, ¹H), 8.47 (d, ¹H), 8.27 (dd, ¹H), 8.23 (t, ¹H), 7.66 (q, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 4.33 (q, ¹H), 3.29 (d, ¹H), 3.11 (d, 2H), 2.59 - 2.51 (m, ¹H), 2.42 - 2.32 (m, ¹H), 2.31 (d, 3H). UPLC-MS-2: Rt = 0.61 min; MS m/z [M+H] ^⁺ = 474.3. C-SFC-5 (mobile phase: _CO2 /IPA + 0.05% _NH3 (70:30)): Rt = 1.77 min. Second eluted isomer C-SFC-5 (mobile phase: _CO2 /IPA + 0.05% _NH3 (70:30)): Rt = 2.65 min. 114 - Racemic 114a - First eluted isomer 114b - Second eluted isomer N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 25, intermediate C-T32 is used, and C-SFC-32 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (55:45)) is used. First eluted isomer C-SFC-15 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40)): Rt = 1.70 min. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 11.09 (s, ¹H), 8.49–8.42 (m, ¹H), 8.26 (d, ¹H), 8.17 (s, ¹H), 7.55 (s, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 4.03 (s, ¹H), 2.97 (s, ¹H), 2.79 (s, ¹H), 2.31 (s, 3H), 1.99 (s, ¹H), and 1.72 (s, 3H). UPLC-MS-2: Rt = 0.62 min; MS m/z [M+H] ^⁺ = 438.4. C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (60:40)): Rt = 2.98 min 115 - Racemic; 115a - First eluted isomer; 115b - Second eluted isomer 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(pyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 25, 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] and intermediate C-T32 were used, along with C-SFC-33 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40 to 45:55)). The first eluted isomer C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40)): Rt = 0.84 min. The second eluted isomers showed the following ^¹H NMR values (600 MHz, DMSO- _d⁶ ): δ 10.93 (s, ¹H), 8.46 (d, ¹H), 8.27 (dd, ¹H), 8.16 (s, ¹H), 7.77 (t, ¹H), 7.72 (t, ¹H), 7.54 (s, ¹H), 7.41 (t, ¹H), 4.03 (t, ¹H), 3.95 (s, 2H), 2.97 (dt, ¹H), 2.79 (dt, ¹H), 2.04–1.95 (m, ¹H), and 1.79–1.66 (m, 3H). UPLC-MS-2: Rt = 0.85 min; MS m/z [M+H] ⁺ = 452.4. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40)): Rt = 2.13 min. 116 N-(6-(4-(1-acetyl-2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 12, using Example 150 ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 8.46 (s, 1H), 8.26 (d, 1H), 8.13 (s, 1H), 7.43 (d, 1H), 6.76 - 6.48 (m, 1H), 5.43 - 5.10 (m, 2H), 3.61 (d, 2H), 2.36 - 2.28 (m, 3H), 2.18 (s, 1H), 2.00 - 1.58 (m, 9H). UPLC-MS-8: Rt = 0.92 min; MS m/z [M+H] ⁺ = 494.3. 117 - Racemic; 117a - First eluted isomer; 117b - Second eluted isomer 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(3-(2-methyl-1,1-dioxotetrahydrothiophen-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)acetamide Similar to Example 5, intermediate C-T33 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used, followed by C-SFC-34 (mobile phase: _CO2 /MeOH + 0.1% _NH4OH (50:50)). The first eluted isomer ^¹H NMR (600 MHz, DMSO- _d⁶ ) δ 11.06 (s, ¹H), 9.13 (s, ¹H), 8.53 (d, ¹H), 8.35 (dd, ¹H), 7.77 (t, ¹H), 7.73 (t, ¹H), 7.41 (t, ¹H), 3.97 (s, 2H), 3.30 (d, ¹H), 3.23 (ddd, ¹H), 2.94 (dt, ¹H), 2.35 - 2.28 (m, ¹H), 2.25 - 2.19 (m, ¹H), 2.16 (dt, ¹H), 1.73 (s, 3H). UPLC-MS-8: Rt = 0.98 min; MS m/z [M+H] ⁺ = 516.2. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (75:25)): Rt = 1.61 min. Second eluted isomer C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (75:25)): Rt = 2.02 min. 118 - Racemic; 118a - First eluted isomer; 118b - Second eluted isomer N-(5-fluoro-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 25, intermediate C-T34 was used, and C-SFC-35 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (60:40)) was used. The first eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 11.18 (s, ¹H), 9.05 (s, ¹H), 8.52 (d, ¹H), 8.30 (dd, ¹H), 6.57 (s, ¹H), 5.20 (s, 2H), 3.98 (dd, ¹H), 3.94 (dd, 1H), 3.71 (dt, ¹H), 3.57 (t, ¹H), 3.46 (td, ¹H), 2.91–2.80 (m, 2H), 2.73 (s, 1H), and 2.32 (s, 3H). UPLC-MS-8: Rt = 0.49 min; MS m/z [M+H] ^⁺ = 455.2. C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (65:35)): Rt = 2.12 min. Second eluted isomer C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (65:35)): Rt = 2.80 min. 119 N-(6-(3-(1-amino-3,3-difluorocyclobutyl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, the intermediate C-T35 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.17 (s, 1H), 9.07 (s, 1H), 8.52 (d, 1H), 8.31 (dd, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 3.18 (td, 2H), 2.78 (td, 2H), 2.55 (s, 2H), 2.32 (s, 3H). UPLC-MS-8: Rt = 0.68 min; MS m/z [M+H] ⁺ = 475.2. 120 - Racemic 120a - First eluted isomer 120b - Second eluted isomer N-(5-fluoro-6-(3-(3-methylphosphonolin-3-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 25, intermediate C-T36 was used, and C-SFC-33 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (75:25)) was used. The first eluted isomers showed the following ^¹H NMR values (600 MHz, DMSO- _d₆ ): δ 11.18 (s, ¹H), 9.03 (d, ¹H), 8.52 (d, ¹H), 8.31 (dd, ¹H), 6.57 (s, ¹H), 5.20 (s, 2H), 4.16 (d, ¹H), 3.57 (dt, ¹H), 3.51–3.45 (m, ¹H), 3.42 (d, ¹H), 2.92 (ddd, ¹H), 2.76 (s, ¹H), 2.67 (dt, ¹H), 2.35–2.29 (m, 3H), 1.23 (s, 3H). UPLC-MS-8: Rt = 0.53 min; MS m/z [M+H] ⁺ = 469.3. C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (75:25)): Rt = 1.39 min. Second eluted isomer C-SFC-7 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (75:25)): Rt = 2.71 min. 121 - Racemic 121a - First eluted isomer 121b - Second eluted isomer N-(6-(3-(3,3-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 25, intermediate C-T37 was used, and C-SFC-36 (mobile phase: _CO2 /IPA + 0.05% _NH3 (63:37)) was used. The first eluted isomers showed the following ^¹H -NMR values (600 MHz, DMSO- _d⁶ ): δ 11.19 (s, ¹H), 9.11 (s, ¹H), 8.53 (d, ¹H), 8.31 (dd, ¹H), 6.57 (s, ¹H), 5.20 (s, 2H), 4.40 (dd, 1H), 3.31–3.27 (m, ¹H), 3.10–2.99 (m, ¹H), 2.39–2.33 (m, 2H), 2.32 (s, 3H). UPLC-MS-8: Rt = 0.72 min; MS m/z [M+H] ^⁺ = 475. C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (63:37)): Rt = 1.37 min. Second eluted isomer C-SFC-15 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (63:37)): Rt = 2.30 min. 122 (S)-N-(6-(3-(4,4-difluoro-2-methylpyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, intermediate C-T38 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.17 (s, 1H), 9.05 (s, 1H), 8.52 (d, 1H), 8.31 (dd, 1H), 6.57 (s, 1H), 5.20 (s, 2H), 4.81 (s, 0H), 3.28 - 3.19 (m, 3H), 2.97 - 2.87 (m, 1H), 2.32 (s, 4H), 1.56 (s, 3H). UPLC-MS-8: Rt = 0.83 min; MS m/z [M+H] ⁺ = 489.1. 123 (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 11, the intermediate C-T40 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 9.06 (s, 1H), 8.53 (d, 1H), 8.313 (dd, 1H), 8.10 (t, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 4.51 (q, 1H), 4.09 (s, 2H), 3.30 (s, 1H), 3.17 (t, 1H), 2.66 (ddt, 1H), 2.55 (td, 1H). UPLC-MS-8: Rt = 0.68 min; MS m/z [M+H] ⁺ = 472.1. 124 (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 11, the intermediate C-T40 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] are used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.06 (s, 1H), 8.53 (d, 1H), 8.32 (dd, 1H), 7.77 (t, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 4.51 (q, 1H), 3.97 (s, 2H), 3.29 (s, 1H), 3.17 (td, 1H), 2.66 (ddt, 1H), 2.59 - 2.52 (m, 1H). UPLC-MS-8: Rt = 0.99 min; MS m/z [M+H] ⁺ = 472.1. 125 - Racemic; 125a - First eluted isomer; 125b - Second eluted isomer N-(6-(4-(1,1-dioxothio-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 32, using intermediate C-T42, and using C-SFC-11 (mobile phase: _CO2 /IPA + 0.05% _NH3 (50:50)). First eluted isomer C-SFC-5 (mobile phase: CO ₂ /IPA + 0.05% NH ₃ (50 : 50)): Rt = 1.50 min. The second eluted isomer, ^¹H NMR (600 MHz, DMSO- _d⁶ ), δ 11.10 (s, ¹H), 8.48 (d, ¹H), 8.27 (dd, ¹H), 8.24 (t, ¹H), 7.69 (q, ¹H), 6.57 (s, ¹H), 5.18 (s, 2H), 4.11 (ddd, ¹H), 3.39 (td, ¹H), 3.14 - 2.98 (m, 4H), 2.76 (s, 1H), 2.31 (d, 3H). UPLC-MS-2: Rt = 0.62 min, MS m/z [M+H] ^⁺ = 502. C-SFC-5 (mobile phase: _CO2 /IPA + 0.05% _NH3 (50:50)): Rt = 2.58 min. 126 N-(5-fluoro-6-(4-(tetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 5, the intermediate C-T43 and 2-(5-methyl-3-(trifluoro-methyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.46 (d, 1H), 8.26 (dd, 1H), 8.18 (t, 1H), 7.46 (q, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 3.90 (ddd, 2H), 3.43 (td, 2H), 2.78 (tt, 1H), 2.31 (s, 3H), 1.86 (ddq, 2H), 1.62 (dtd, 2H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ = 453.3. 127 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(tetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 5, the intermediate C-T43 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 8.46 (t, 1H), 8.27 (dt, 1H), 8.16 (d, 1H), 7.76 (t, 1H), 7.72 (t, 1H), 7.50 - 7.43 (m, 1H), 7.41 (t, 1H), 3.94 (s, 2H), 3.92 - 3.86 (m, 2H), 3.43 (tt, 2H), 2.78 (tt, 1H), 1.86 (ddt, 2H), 1.68 - 1.56 (m, 2H). UPLC-MS-2: Rt = 1.01 min; MS m/z [M+H] ⁺ = 467.3. 128 - Racemic; 128a - First eluted isomer; 128b - Second eluted isomer N-(6-(4-(1,1-dioxothio-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 32, using intermediate C-T42 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4], using C-SFC-37 (mobile phase: _CO2 /IPA + 0.05% _NH3 (65:35)). The first eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 10.96 (s, ¹H), 8.48 (d, ¹H), 8.29 (dd, ¹H), 8.23 (d, ¹H), 7.77 (t, ¹H), 7.72 (t, ¹H), 7.68 (s, ¹H), 7.41 (t, ¹H), 4.16–4.05 (m, ¹H), 3.95 (s, 2H), 3.43–3.36 (m, ¹H), 3.12–2.99 (m, 4H), and 2.76 (s, ¹H). UPLC-MS⁻²: Rt = 0.81 min; MS m/z [M+H] ^⁺ = 516. C-SFC-7 (mobile phase: _CO2 /IPA + 0.05% _NH3 (65:35)): Rt = 1.14 min. Second eluted isomer C-SFC-7 (mobile phase: _CO2 /IPA + 0.05% _NH3 (65:35)): Rt = 1.74 min. 129 - Racemic 129a - First eluted isomer 129b - Second eluted isomer N-(6-(4-(1,1-dioxothiolin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 32, intermediate C-T41 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used, along with C-SFC-38 (mobile phase: _CO2 /IPA + 0.05% _NH3 (48:52)). First eluted isomer C-SFC-14 (mobile phase: _CO2 /IPA + 0.05% _NH3 (50:50)): Rt = 1.40 min. The second eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values are: δ 10.97 (s, ¹H), 8.49 (d, ¹H), 8.31 (dd, ¹H), 8.28 (t, J = ¹H), 7.80 - 7.75 (m, 2H), 7.72 (t, 1H), 7.41 (t, 1H), 4.30 (dd, 1H), 3.95 (s, 2H), 3.40 - 3.36 (m, 1H), 3.28 (dd, 1H), 3.25 - 3.15 (m, 2H), 3.07 (d, 2H), and 1.27 - 1.22 (m, 1H). UPLC-MS-2: Rt = 0.76 min; MS m/z [M+H] ⁺ = 516. C-SFC-14 (mobile phase: _CO2 /IPA + 0.05% _NH3 (50:50)): Rt = 2.73 min. 130 N-(6-(4-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, the intermediate C-T44 is used. 1H NMR (600 MHz, DMSO) δ 11.08 (s, 1H), 8.46 (d, 1H), 8.25 (dd, 1H), 8.17 (s, 1H), 7.53 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 3.90 (t, 1H), 2.81 (s, 1H), 2.31 (s, 3H), 2.10 (dd, 1H), 1.83 (td, 1H), 1.39 (dq, 1H), 0.67 (d, 1H), 0.32 (d, 1H). UPLC-MS-8: Rt = 0.58 min; MS m/z [M+H] ⁺ = 450.2. 131 - Racemic 131a - First eluted isomer 131b - Second eluted isomer N-(6-(4-(5-azaspiro[2.4]hept-6-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 25, using intermediate C-T45, and using C-SFC-39 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (45:55)). The first eluted isomers were analyzed by ^¹H NMR (600 MHz, DMSO- _d⁶ ) with the following δ values: 11.14 (s, 1H), 8.45 (s, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.59 (s, 1H), 6.56 (s, 1H), 5.17 (s, 2H), 4.24 (s, 1H), 2.95–2.82 (m, 1H), 2.75 (s, 1H), 2.31 (s, 3H), 1.91 (s, 2H), 1.24 (s, 1H), 0.57 (d, 1H), 0.53 (t, 2H), and 0.48 (s, 1H). UPLC-MS-2: Rt = 0.62 min; MS m/z [M+H] ⁺ = 464. C-SFC-7 (mobile phase: _CO2 /IPA + 0.05% _NH3 (65:35)): Rt = 1.29 min. Second eluted isomer C-SFC-7 (mobile phase: _CO2 /IPA + 0.05% _NH3 (65:35)): Rt = 2.66 min. 132 N-(6-(4-((1S,3R,4R)-2-azabicyclo[2.2.1]hept-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, the intermediate C-T46 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.46 (s, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.52 (d, 1H), 6.57 (t, 1H), 5.18 (q, 2H), 3.80 (s, 1H), 3.45 (s, 1H), 2.41 (s, 1H), 2.31 (t, 3H), 1.58 (d, 3H), 1.51 - 1.43 (m, 2H), 1.15 (s, 1H). UPLC-MS-2: Rt = 0.62 min; MS m/z [M+H] ⁺ = 464.3. 133 N-(6-(4-((1R,3S,4S)-2-azabicyclo[2.2.1]hept-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 11, the intermediate C-T47 is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.46 (d, 1H), 8.25 (dd, 1H), 8.18 (s, 1H), 7.51 (s, 1H), 6.57 (s, 1H), 5.18 (s, 2H), 3.81 (s, 1H), 3.46 (s, 1H), 2.41 (s, 1H), 2.31 (s, 3H), 1.60 (d, 3H), 1.46 (d, 2H), 1.15 (d, 1H). UPLC-MS-2: Rt = 0.63 min; MS m/z [M+H] ⁺ = 464.3. 134 N-(5-fluoro-6-(4-(4-hydroxytetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 5, the intermediate C-T27 and 2-(5-methyl-3-(trifluoro-methyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] were used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 8.48 (d, 1H), 8.26 (dd, 1H), 8.19 (d, 1H), 7.57 (d, 1H), 6.56 (s, 1H), 5.18 (s, 2H), 4.96 (s, 1H), 3.74 (td, 2H), 3.63 (dt, 2H), 2.32 (s, 3H), 2.07 (ddd, 2H), 1.61 (d, 2H). UPLC-MS-8: Rt = 0.79 min; MS m/z [M+H] ⁺ = 468.9. 135 N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(perfluoroethyl)phenyl)acetamide Similar to Example 5, intermediates C-M3 and A-M1 are used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 8.24 (d, 1H), 7.92 - 7.80 (m, 3H), 7.69 - 7.64 (m, 2H), 7.63 (s, 2H), 4.52 (tt, 1H), 3.97 (dt, 2H), 3.87 (s, 2H), 3.52 - 3.42 (m, 2H), 2.03 - 1.95 (m, 4H). UPLC-MS-2: Rt = 1.18 min; MS m/z [M+H] ⁺ = 523.2. 136 N-(3-cyano-5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro-λ, ⁶ -hydrothio)phenoxy)acetamide Similar to Example 11, intermediates A-M2 and C-T49 are used, and 4 N HCl/dioxane is used in step 2. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 8.21 (s, 1H), 7.95 (dd, 2H), 7.86 (d, 1H), 7.59 (t, 1H), 7.57 - 7.51 (m, 2H), 7.36 (dd, 1H), 4.90 (s, 2H), 4.31 (tt, 1H), 3.04 (dt, 2H), 2.59 (td, 2H), 2.16 (s, 1H), 1.97 (ddd, 2H), 1.81 (qd, 2H). UPLC-MS-2: Rt = 0.92 min; MS m/z [M+H] ⁺ = 546.3. 137 N-(5-fluoro-6-(3-(1-imino-1-oxotetrahydro-1H- ^1λ6 -thiophene-2-yl)-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 35/Steps 1-2, 2-(5-methyl-3-(trifluoro-methyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] is used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.22 (s, 1H), 9.25 - 9.04 (m, 1H), 8.54 (t, 1H), 8.32 (dt, 1H), 6.57 (s, 1H), 5.20 (s, 2H), 4.50 - 4.38 (m, 1H), 4.17 - 3.40 (m, 1H), 3.24 - 3.01 (m, 2H), 2.64 - 2.51 (m, 2H), 2.37 - 2.06 (m, 6H). UPLC-MS-9: Rt = 3.21 min; MS m/z [M+H] ⁺ = 487. 138 - Racemic; 138a - First eluted isomer; 138b - Second eluted isomer N-(6-(4-(1-acetylopyrrolidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 12, using the racemic mixture of Example 114, C-SFC-13 (mobile phase: _CO2 /MeOH + 0.05% _NH3 (65:35)) was used. The first eluted isomer's ^¹H NMR (600 MHz, DMSO- _d⁶ ) values were 11.11 (d, ¹H), 8.46 (s, ¹H), 8.25 (d, 2H), 7.65–7.37 (m, ¹H), 6.57 (d, ¹H), 5.36–5.12 (m, 2H), 5.13–4.94 (m, ¹H), 3.64 (s, 2H), 2.38–2.27 (m, 3H), 2.14–1.93 (m, 4H), and 1.92 (s, 3H). UPLC-MS-8: Rt = 0.86 min; MS m/z [M+H] ^⁺ = 480.4. C-SFC-5 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (65:35)): Rt = 1.66 min. Second eluted isomer C-SFC-5 (mobile phase: _CO₂ /MeOH + 0.05% _NH₃ (65:35)): Rt = 2.68 min. 139 N-(3-cyano-5-fluoro-4-(1-((1-methyl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 5, the intermediate C-T51 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 8.44 (d, 1H), 8.09 (t, 1H), 7.91 (q, 1H), 7.89 - 7.85 (m, 2H), 7.83 (dd, 1H), 7.76 (d, 1H), 5.93 (s, 2H), 4.09 (s, 3H), 4.04 (s, 2H). UPLC-MS-2: Rt = 0.77 min; MS m/z [M+H] ⁺ = 486.2. 140 N-(4-(1-(2-(4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to examples 36/37, ethyl methyliminolate is used in step 3. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 13.99 (s, 1H), 10.82 (s, 1H), 8.40 (s, 1H), 8.09 (t, 1H), 8.05 (s, 1H), 7.87 - 7.80 (m, 4H), 7.75 (d, 1H), 4.03 (s, 2H), 1.98 (s, 6H). UPLC-MS-2: Rt = 0.88 min; MS m/z [M+H] ⁺ = 499.3. 141 N-(4-(1-(2-(1,3,4-diazol-2-yl)propyl-2-yl)-1H-pyrazol-4-yl)-3-cyano-5-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Examples 36/37, in step 3, trimethyl ethyl orthoformate hydrochloride and 0.1 equivalent PPTS in toluene are used at 110°C. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 9.24 (s, 1H), 8.43 (s, 1H), 8.09 (t, 1H), 7.91 - 7.85 (m, 3H), 7.83 (d, 1H), 7.76 (d, 1H), 4.05 (s, 2H), 2.07 (s, 6H). UPLC-MS-2: Rt = 0.89 min; MS m/z [M+H] ⁺ = 500.2. 142 N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 28, the intermediate C-M3 and 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid [CAS No. 349-10-0] were used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.25 - 8.20 (m, 1H), 8.12 - 8.01 (m, 2H), 7.93 - 7.74 (m, 3H), 7.72 - 7.58 (m, 2H), 6.98 - 6.93 (m, 1H), 5.31 (d, 1H), 4.58 - 4.46 (m, 1H), 3.97 (dt, 2H), 3.47 (td, 2H), 1.99 (td, 4H). UPLC-MS-2: Rt = 1.02 min; MS m/z [M+H] ⁺ = 489.2. 143 N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-3-yl)-1H-pyrazol-4-yl)phenyl)-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 28, the intermediate C-T54 and 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid [CAS No. 349-10-0] were used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 8.26 (s, 1H), 8.10 (d, 1H), 8.06 (dt, 1H), 7.90 - 7.85 (m, 2H), 7.82 (d, 1H), 7.69 (d, 1H), 7.62 (t, 1H), 6.94 (s, 1H), 5.31 (s, 1H), 4.41 (tt, 1H), 3.99 (dd, 1H), 3.84 - 3.75 (m, 1H), 3.66 (ddd, 1H), 3.49 - 3.41 (m, 1H), 2.19 - 2.14 (m, 1H), 2.14 - 2.00 (m, 1H), 1.78 - 1.70 (m, 1H), 1.70 - 1.57 (m, 1H). UPLC-MS-2: Rt = 1.02 min; MS m/z [M+H] ⁺ = 489.2. 144 N-(3-cyano-5-fluoro-4-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro-λ, ⁶ -hydrothio)phenoxy)acetamide Similar to Example 11, intermediates A-M2 and C-T55 are used. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 8.26 (d, 1H), 7.99 - 7.93 (m, 2H), 7.86 (d, 1H), 7.59 (t, 1H), 7.56 - 7.52 (m, 2H), 7.36 (dd, 1H), 4.89 (s, 2H), 4.24 (tt, 1H), 3.17 (ddd, 1H), 2.86 (dt, 1H), 2.78 (dd, 1H), 2.48 - 2.45 (m, 1H), 2.11 (dd, 1H), 1.91 (qd, 1H), 1.71 (dt, 1H), 1.56 - 1.45 (m, 1H). UPLC-MS-2: Rt = 0.93 min; MS m/z [M+H] ⁺ = 546.2. 145 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 3, intermediate D-T2 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester [CAS No. 885693-20-9] are used, and BrettPhosPd-G3 is used in step 1 and 4N HCl/dioxane is used in step 2. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.47 (d, 1H), 8.35 (dd, 1H), 8.35 (m, 1H), 7.86 (s, 1H), 7.62-7.72 (m, 2H), 7.35 (t, 1H), 6.59 (m, 1H), 4.00-4.04 (m, 2H), 3.91-3.94 (m, 2H), 3.36 (m, 2H), 2.53-2.62 (m, 2H). HPLC-MS-5: Rt = 0.77 min; MS m/z [M+H] ⁺ = 464.2. 146 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 21, use Example 145 and EtOH instead of HOAc ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99 (s, 1H), 8.48 (d, 1H), 8.33 (s, 1H), 8.28 (dd, 1H), 8.17 (m, 1H), 7.69-7.80 (m, 2H), 7.50 (s, 1H), 7.41 (t, 1H), 3.95 (s, 2H), 3.05 (m, 1H), 2.76 (m, 1H), 2.59-2.65 (m, 2H), 2.01 (m, 2H), 1.72 (m, 1H), 1.56 (m, 2H). HPLC-MS-7: Rt = 1.32 min; MS m/z [M+H] ⁺ = 466.0. 147 - Racemic 147a - First eluted isomer 147b - Second eluted isomer N-(6-(4-(1-acetylopiperidin-3-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 12, using Example 146 and _Ac₂O /pyridine, C-HPLC-8 was used (mobile phase: hexane/(1:1 EtOH/MeOH + 0.1% HCOOH)). The first eluted isomer C-HPLC-9: (mobile phase: hexane/(80 : 20 EtOH/MeOH + 0.1% HCOOH) 70 : 30) Rt = 5.89 min. The second eluted isomer ^¹H NMR (400 MHz, _CD₃OD ) δ 8.44 (m, 1H), 8.33 (dt, 1H), 8.29 (m, 1H), 7.60–7.71 (m, 3H), 7.35 (t, 1H), 4.36–4.60 (m, 1H), 3.92 (s, 2H), 3.82–4.15 (m, 1H), 3.24 (m, 0.5H), 2.98 (m, 0.5H), 2.83 (m, 1H), 2.10–2.22 (m, 4H), 1.75–1.90 (m, 2H), 1.60 (m, 1H). HPLC-MS-5: Rt = 0.77 min; MS m/z [M+H] ⁺ = 508.1. C-HPLC-9: (Mobile phase: hexane/(80 : 20 EtOH/MeOH + 0.1% HCOOH) 70 : 30) Rt = 6.64 min. 148 - Racemic 148a - First eluted isomer 148b - Second eluted isomer 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(piperidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Examples 10 and 21, 6-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tributyl ester [CAS No. 865245-32-5] and BrettPhosPd-G3 were used, followed by N-Boc deprotection with 4N HCl/dioxane and C-HPLC. The first eluted isomer C-HPLC-9: (mobile phase: hexane/(50:50 IPA/MeOH + 0.1% Et ₂ NH) 85:15) Rt = 9.42 min. The second eluted isomer showed the following ^¹H NMR (400 MHz, _CD₃OD ) values: δ 8.47 (m, 1H), 8.38 (m, 1H), 8.36 (dd, 1H), 7.88 (s, 1H), 7.62–7.71 (m, 2H), 7.35 (t, 1H), 4.33 (dd, 1H), 3.93 (s, 2H), 3.43 (m, 1H), 3.18 (m, 1H), 2.24 (m, 1H), 1.93–2.10 (m, 3H), 1.70–1.84 (m, 2H). HPLC-MS-5: Rt = 0.72 min; MS m/z [M+H] ^⁺ = 466.1. C-HPLC-9: (Mobile phase: hexane/(50:50 IPA/MeOH + 0.1% Et ₂ NH) 85:15) Rt = 10.32 min. 149 N-(6-(4-(1-acetylopiperidin-2-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 12/Step 1, using Example 148 (racemic compound) and _Ac₂O /pyridine. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (m, 1H), 8.28-8.38 (m, 2H), 7.57-7.72 (m, 3H), 7.35 (t, 1H), 5.88 (m, 0.5H), 5.22 (m, 0.5H), 4.48 (m, 0.5H), 3.92 (d, 2H), 3.81 (m, 0.5H), 3.24 (m, 0.5H), 2.71 (m, 0.5H), 2.38 (m, 1H), 2.21/2.22 (s, 3H), 1.76-2.07 (m, 2H), 1.41-1.75 (m, 4H). HPLC-MS-5: Rt = 0.82 min; MS m/z [M+H] ⁺ = 508.1. 150 - Racemic 150a - First eluted isomer 150b - Second eluted isomer N-(5-fluoro-6-(4-(2-methylpyrrolidin-2-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide Similar to Example 25, intermediate C-T56 was used, and C-SFC-31 (mobile phase: _CO2 /EtOH + 0.05% _NH3 (60:40)) was used. The first eluted isomer C-SFC-7 (mobile phase: CO ₂ / EtOH + 0.05% NH ₃ (60 : 40)): Rt = 0.84 min. The second eluted isomer ^¹H NMR (600 MHz, DMSO- _d₆ ) δ 11.10 (s, 1H), 8.45 (s, 1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.53 (s, 1H), 6.57 (s, 1H), 5.17 (s, 2H), 2.84–2.95 (m, 2H), 2.31 (s, 3H), 2.08 (m, 1H), 1.75 (m, 1H), 1.57–1.70 (m, 2H), 1.37 (s, 3H), 1.23 (s, 1H). UPLC-MS-2: Rt = 0.67 min; MS m/z [M+H] ⁺ = 452.4. C-SFC-7 (mobile phase: _CO2 /EtOH + 0.05% _NH3 (60:40)): Rt = 2.99 min. 151 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(olinomethyl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 39, α-porphyrin is used in step 3. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.45 (d, 1H), 8.35 (dd, 1H), 8.31 (s, 1H), 7.74 (s, 1H), 7-61-7.72 (m, 2H), 7.35 (t, 1H), 3.93 (s, 2H), 3.66-3.75 (m, 4H), 3.58 (s, 2H), 2.50-2.62 (m, 4H). HPLC-MS-1: Rt = 1.02 min; MS m/z [M+H] ⁺ = 482.2. 152 N-(3-fluoro-4-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 10, using intermediate D-M3/step 1 and 1-(tetrahydro-2H-piperan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 1003846-21-6], using _PdCl2 (dppf) _{and K2CO3} ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 8.21 (d, 1H), 7.90 (d, 1H), 7.54-7.73 (m, 6H), 7.32 (dd, 1H), 5.44 (dd, 1H), 3.94 (m, 1H), 3.81 (s, 2H), 3.64 (m, 1H), 2.12 (m, 1H), 1.88-2.00 (m, 2H), 1.68 (m, 1H), 1.50-1.59 (m, 2H). HPLC-MS: Rt 2.53 min; MS m/z [M+H] ⁺ 448.0. 153 4-(4-(2-cyano-6-fluoro-4-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tributyl ester Similar to Example 5, the intermediate C-T49 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (s, 1H), 7.93 (m, 1H), 7.85 (dd, 1H), 7.80 (m, 1H), 7.61-7.70 (m, 2H), 7.34 (t, 1H), 4.47 (m, 1H), 4.17-4.28 (m, 2H), 3.89 (s, 2H), 2.86-3.09 (m, 2H), 2.08-2.15 (m, 2H), 1.91-2.04 (m, 2H), 1.48 (s, 9H). HPLC-MS-2: Rt 1.89 min; MS m/z [M-56+H] ⁺ 534.3. 154 N-(3-cyano-5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide (TFA salt) Example 153, using TFA/DCM/room temperature ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 7.97 (s, 1H), 7.87 (d, 1H), 7.82 (s, 1H), 7.60-7.71 (m 2H), 7.35 (t, 1H), 4.65 (m, 1H), 3.90 (s, 2H), 3.52-3.66 (m, 2H), 3.15-3.28 (m, 2H), 2.24-2.45 (m, 4H). HPLC-MS-1: Rt 1.37 min; MS m/z [M-56+H] ⁺ 489.8. 155 N-(3-cyano-5-fluoro-4-(1-(1-(1-(2-hydroxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 31, Example 154 and 2-bromoethane-1-ol are used. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.19 (s, 1H), 7.96 (m, 1H), 7.86 (d, 1H), 7,81 (m, 1H), 7.61-7.71 (m, 2H), 7.35 (t, 1H), 4.54 (m, 1H), 3.89 (s, 2H), 3.85 (t, 2H), 3.53-3.62 (m, 2H), 3.10 (t, 2H), 2.95-3.06 (m, 2H), 2.27-2.43 (m, 4H). HPLC-MS-1: Rt 1.36 min; MS m/z [M-56+H] ⁺ 533.8. 156 N-(3,5-difluoro-4-(1-(2-hydroxy-1-(1-methoxycyclobutyl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 2-azido-2-(1-methoxycyclobutyl)ethane-1-ol [CAS No. 1803570-54-8] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 8.25 (s, 1H), 7.67-7.77 (m, 2H), 7.37-7.48 (m, 3H), 4.84-4.94 (m, 2H), 3.91-4.08 (m, 2H), 3.90 (s, 2H), 3.19 (s, 3H), 2.34 (m, 1H), 2.16 (m, 1H), 2.06 (m, 1H), 1.59-1.73 (m, 2H), 1.49 (m, 1H). HPLC-MS-8: Rt 1.34 min; MS m/z [M+H] ⁺ 529.2. 157 N-(3,5-difluoro-4-(1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, (3R,4S)-3-azono-4-methoxytetrahydrofuran is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.79 (s, 1H), 8.43 (s, 1H), 7.67-7.77 (m, 2H), 7.34-7.46 (m, 3H), 4.34 (m, 1H), 4.11-4.20 (m, 2H), 4.08 (dd, 1H), 3.88 (s, 2H), 3.77 (dd, 1H), 3.42 (m, 1H), 3.35 (s, 3H). HPLC-MS-8: Rt 1.32 min; MS m/z [M+H] ⁺ 501.1. 158 N-(4-(1-((2,3-dihydrobenzo[b][1,4]dichloro-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 2-(azidomethyl)-2,3-dihydrobenzo[b][1,4]dimethyl ... ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.40 (s, 1H), 7.68-7.77 (m, 2H), 7.43 (d, 2H), 7.39 (t, 1H), 6.78-6.91 (m, 4H), 4.69-4.87 (m, 3H), 4.40 (d, 1H), 4.01 (m, 1H), 3.89 (s, 2H). HPLC-MS-8: Rt 1.45 min; MS m/z [M+H] ⁺ 549.2. 159 N-(3,5-difluoro-4-(1-(4-aminosulfonylphenyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 4-azidobenzenesulfonamide [CAS No. 36326-86-0] was used. HPLC-MS-8: Rt 1.35 min; MS m/z [M+H] ⁺ 555.9. 160 N-(4-(1-((1-benzylpyrrolidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 3-(azidomethyl)-1-benzylpyrrolidine [CAS No. 218293-49-3] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.39 (s, 1H), 7.67-7.77 (m, 2H), 7.37-7.47 (m, 3H), 7.24-7.40 (m, 4H), 7.19 (m, 1H), 4.30-4.43 (m, 2H), 3.88 (s, 2H), 3.52 (s, 2H), 2.69 (m, 1H), 2.37-2.55 (m, 2H), 2.30 (m, 1H), 1.84 (m, 1H), 1.52 (m, 1H). HPLC-MS-8: Rt 0.97 min; MS m/z [M+H] ⁺ 574.0. 161 N-(4-(1-(4,4-dimethyl-2-epoxytetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 3-azido-4,4-dimethyldihydrofuran-2(3H)-one [CAS No. 1824188-89-7] was used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 8.47 (s, 1H), 7.65-7.77 (m, 2H), 7.45 (d, 2H), 7.38 (t, 1H), 5.92 (s, 1H), 4.26 (s, 2H), 3.90 (s, 2H), 1.24 (s, 3H), 0.82 (s, 3H). HPLC-MS-8: Rt 1.36 min; MS m/z [M+H] ⁺ 513.3. 162 N-(3,5-difluoro-4-(1-((3-methyloxocyclobutane-3-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 3-(azidomethyl)-3-methyloxacyclobutane [CAS No. 90683-29-7] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.43 (s, 1H), 7.66-7.76 (m, 2H), 7.43 (d, 2H), 7.38 (t, 1H), 4.68 (s, 2H), 4.58 (d, 2H), 4.27 (d, 2H), 3.90 (s, 2H), 1.15 (s, 3H). HPLC-MS-8: Rt 1.30 min; MS m/z [M+H] ⁺ 485.1. 163 N-(3,5-difluoro-4-(1-((1-(methylsulfonyl)cyclohexyl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 1-(azidomethyl)-1-(methylsulfonylurea)cyclohexane [CAS No. 1934576-76-7] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.30 (s, 1H), 7.65-7.78 (m, 2H), 7.43 (d, 2H), 7.38 (t, 1H), 4.99 (s, 2H), 3.88 (s, 2H), 2.84 (s, 3H), 1.60-1.89 (m, 9H), 1.23 (m, 1H). HPLC-MS-8: Rt 1.36 min; MS m/z [M+H] ⁺ 575.0. 164 N-(3,5-difluoro-4-(1-(1-methyl-2-epoxypyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 3-azido-1-methylpyrrolidone-2-one [CAS No. 33693-59-3] was used. HPLC-MS-8: Rt 1.24 min; MS m/z [M+H] ⁺ 498.1. 165 N-(3,5-difluoro-4-(1-(pyrrolidin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 2-(azidomethyl)pyrrolidine [CAS No. 288083-80-7] is used. HPLC-MS-8: Rt 1.15 min; MS m/z [M+H] ⁺ 484.2. 166 N-(4-(1-((3S,4R)-4-(1H-pyrazol-1-yl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 1-((3R,4S)-4-azonotetrahydrofuran-3-yl)-1H-pyrazole [CAS No. 2138050-98-1] was used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.30 (s, 1H), 7.65-7.78 (m, 2H), 7.43 (d, 2H), 7.38 (t, 1H), 4.99 (s, 2H), 3.88 (s, 2H), 2.84 (s, 3H), 1.60-1.89 (m, 9H), 1.23 (m, 1H). HPLC-MS-8: Rt 1.28 min; MS m/z [M+H] ⁺ 537.2. 167 N-(3,5-difluoro-4-(1-(2-hydroxylinoethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 4-(2-Azazoethyl)urarin [CAS No. 660395-39-1] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.38 (s, 1H), 7.64-7.77 (m, 2H), 7.44 (d, 2H), 7.39 (t, 1H), 4.52 (t, 2H), 3.88 (s, 2H), 3.47-3.53 (m, 4H), 2.78 (t, 2H), 2.37-2.42 (m, 4H). HPLC-MS-8: Rt 1.03 min; MS m/z [M+H] ⁺ 514.2. 168 N-(3,5-difluoro-4-(1-(2-((tetrahydrofuran-3-yl)oxy)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 3-(2-azidoethoxy)tetrahydrofuran [CAS No. 2126178-96-7] was used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.32 (s, 1H), 7.67-7.78 (m, 2H), 7.42 (d, 2H), 7.38 (t, 1H), 4.58 (t, 2H), 4.10 (s, 1H), 3.87 (s, 2H), 3.80 (s, 2H), 3.52-3.62 (m, 4H), 1.84 (m, 1H), 1.75 (m, 1H). HPLC-MS-8: Rt 1.29 min; MS m/z [M+H] ⁺ 515.1. 169 N-(3,5-difluoro-4-(1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 4-(2-Azadiethyl)-1-methyl-1H-1,2,3-triazole [CAS No. 1909326-98-2] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 8.34 (s, 1H), 7.80 (s, 1H), 7.65-7.74 (m, 2H), 7.43 (d, 2H), 7.39 (t, 1H), 4.72 (t, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.25 (t, 2H). HPLC-MS-8: Rt 1.23 min; MS m/z [M+H] ⁺ 510.1. 170 N-(3,5-difluoro-4-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 4-azido-1-methylpiperidine [CAS No. 1175146-68-5] is used. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 1H), 7.60-7.71 (m, 2H), 7.44 (d, 2H), 7.34 (t, 1H), 4.82 (m, 1H), 3.89 (s, 2H), 3.38-3.47 (m, 2H), 2.86-3.00 (m, 2H), 2.73 (s, 3H), 2.31-2.47 (m, 4H). HPLC-MS-2: Rt 0.37 min; MS m/z [M+H] ⁺ 498.2. 171 N-(3,5-difluoro-4-(1-((5-sideoxytetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 5-(azidomethyl)dihydrofuran-2(3H)-one [CAS No. 179532-81-1] was used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.30 (s, 1H), 7.65-7.78 (m, 2H), 7.43 (d, 2H), 7.38 (t, 1H), 4.96 (m, 1H), 4.67-4.81 (m, 2H), 3.89 (s, 2H), 2.26-2.40 (m, 2H), 1.98 (m, 1H). HPLC-MS-8: Rt 1.27 min; MS m/z [M+H] ⁺ 499.2. 172 (R)-N-(3,5-difluoro-4-(1-((6-epoxypiperidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, (R)-6-(azidomethyl)piperidin-2-one [CAS No. 1807939-24-7] was used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 8.35 (s, 1H), 7.67-7.78 (m, 2H), 7.60 (s, 1H), 7.42 (d, 2H), 7.38 (t, 1H), 4.55 (dd, 1H), 4.45 (m, 1H), 3.92 (s, 2H), 3.79 (m, 1H), 2.08 (m, 1H), 1.99 (m, 1H), 1.61-1.73 (m, 2H), 1.56 (m, 1H), 1.25 (m, 1H). HPLC-MS-8: Rt 1.22 min; MS m/z [M+H] ⁺ 512.1. 173 N-(3,5-difluoro-4-(1-(2-(2-epoxypyridin-1(2H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 1-(2-Azadiethyl)pyridin-2(1H)-one [CAS No. 1249203-09-5] was used. HPLC-MS-8: Rt 1.46 min; MS m/z [M+H] ⁺ 522.0. 174 (R)-N-(3,5-difluoro-4-(1-(1-(1-(1-methyl-1H-1,2,3-triazol-5-yl)ethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, (R)-5-(1-azidoethyl)-1-methyl-1H-1,2,3-triazole [CAS No. 1909286-88-9] is used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.54 (s, 1H), 7.93 (s, 1H), 7.66-7.78 (m, 2H), 7.42 (d, 2H), 7.38 (t, 1H), 6.33 (m, 1H), 3.89 (s, 3H), 3.87 (s, 2H), 1.95 (d, 3H). HPLC-MS-8: Rt 1.26 min; MS m/z [M+H] ⁺ 510.1. 175 N-(4-(1-(2-(1H-pyrazol-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,5-difluorophenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 1-(2-Azadiethyl)-1H-pyrazole [CAS No. 689157-81-1] is used. HPLC-MS-8: Rt 1.36 min; MS m/z [M+H] ⁺ 495.2. 176 N-(3,5-difluoro-4-(1-((4-sideoxy-3,5,7,8-tetrahydro-4H-piperano[4,3-d]pyrimidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 7, 2-(azidomethyl)-3,5,7,8-tetrahydro-4H-piperano[4,3-d]pyrimidin-4-one [CAS No. 1419953-82-4] was used. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.85 (br s, 1H), 10.73 (s, 1H), 8.48 (s, 1H), 7.64-7.77 (m, 2H), 7.42 (d, 2H), 7.38 (t, 1H), 5.55 (s, 2H), 4.33 (s, 2H), 3.91 (s, 2H), 3.79 (t, 2H). HPLC-MS-8: Rt 1.21 min; MS m/z [M+H] ⁺ 565.2. 177 Second washout peak N-(5-fluoro-6-(4-(olin-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid Similar to Example 25, using intermediate C-T2 and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propionic acid [CAS No. 1005566-34-6], a first C-HPLC-11 (mobile phase: TBME/EtOH/MeOH (85 : 10 : 5)) and then RP-HPLC-1 (mobile phase: H ₂ O/ACN 100 : 0 to 0 : 100) was used. UPLC-MS-8: Rt = 0.63 min; MS m/z [M+H] ⁺ 468.0. C-HPLC-12 (mobile phase: TBME/(EtOH + 0.1% Et ₂ NH)/(MeOH + 0.1% Et ₂ NH) (85 : 10 : 5)); Rt = 11.05 min. 178 N-(6-(4-((3-aminooxocyclobutane-3-yl)methyl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 35/Steps 1-2, intermediate C-T58 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] are used. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.19 (s, 1H), 8.52 (d, 1H), 8.31 (dd, 1H), 8.19 (s, 1H), 8.09 (t, 1H), 7.82 (d, 1H), 7.77 (d, 1H), 7.66 (s, 1H), 4.49 (d, 2H), 4.39 (d, 2H), 4.08 (s, 2H), 2.87 (s, 2H). 179 N-(3-fluoro-4-(1-(tetrahydro-2H-piperan-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 10, intermediate D-M3/step 1 and 1-(tetrahydro-2H-piperan-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-1H-pyrazole [CAS No. 1040377-03-4] are used with _PdCl2 (dppf) and _{K2CO3 .} ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.53-7.74 (m, 6H), 7.31 (d, 1H), 4.37-4.44 (m, 1H), 3.90-4.04 (m, 2H), 3.80 (s, 2H), 3.40-3.54 (m, 2H), 1.91-2.04 (m, 4H). HPLC-MS: Rt 2.48 min; MS m/z [M+H] ⁺ 448.1. 180 N-(6-(1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-5-cyanopyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide (TFA salt) Similar to Example 3, intermediates D-T7 and B-T39 were used with _PdCl₂ (dppf), DCM, and _{Cs₂CO₃ .} ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86 (d, 1H), 8.49 (d, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.61-7.72 (m, 2H), 7.35 (t, 1H), 4.89 (m, 1H), 4.22 (s, 2H), 4.18 (s, 2H), 3.92 (s, 2H), 2.80-2.97 (m, 4H). HPLC-MS-7: Rt 1.35 min; MS m/z [M+H] ⁺ 485.1. 181 N-(6-(1-(2-oxozyrospiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-5-cyanopyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 10, intermediates D-T7 and B-T40 are used with _PdCl2 (dppf), DCM, and _{Cs2CO3 .} ¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 9.03 (s, 1H), 8.99 (d, 1H), 8.64 (d, 1H), 7.61-7.73 (m, 2H), 7.36 (t, 1H), 5.32 (m, 1H), 4.85 (s, 2H), 3.95 (s, 2H), 3.72 (s, 2H), 2.73-2.82 (m, 2H), 2.11-2.20 (m, 2H). HPLC-MS-7: Rt 1.34 min; MS m/z [M+H] ⁺ 485.9. 182 N-(3-cyano-5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (TFA salt) Similar to Example 11, intermediate C-T49 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] were used. HPLC-MS-2: Rt 0.23 min; MS m/z [M+H] ⁺ 473.2. 183 N-(3-cyano-5-fluoro-4-(1-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazole-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 31, Example 182 and 1-chloro-2-methoxyethane [CAS No. 627-42-9] are used. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.46-10.39 (m, 1H), 7.93-8.04 (m, 3H), 7.68-7.80 (m, 3H), 7.53 (d, 1H), 4.61 (br s, 1H), 4.00 (s, 3H), 3.51-3.82 (m, 4H), 3.30-3.35 (m, 4H), 2.98 (m, 1H), 2.61-2.67 (m, 2H), 2.37-2.40 (m, 2H). HPLC-MS-2: Rt 0.46 min; MS m/z [M+H] ⁺ 531.3. 184 N-(3-cyano-5-fluoro-4-(1-(pyrrolidin-3-yl)-1H-pyrazole-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (TFA salt) Similar to Example 11, the intermediate C-T13 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid [CAS No. 1000565-32-1] are used. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (s, 1H), 8.00-8.06 (m, 2H), 7.88 (dd, 1H), 7.83 (s, 1H), 7.68-7.76 (m 2H), 5.35 (m, 1H), 4.04 (s, 2H), 3.81 (m, 1H), 3.66-3.76 (m, 2H), 3.52 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H). HPLC-MS-1: Rt 1.31 min; MS m/z [M+H] ⁺ 459.0. 185 N-(3-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (HCl salt) Similar to Example 6, intermediate D-M3/step 1 is used, along with _PdCl2 (dppf) and _K2CO3 from step 1 _, and 4NHCl/dioxane from step 2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 9.21 (m, 1H), 8.94 (m, 1H), 8.13 (d, 1H), 7.91 (s, 1H), 7.53-7.77 (m, 6H), 7.37 (dd, 1H), 4.52-4.61 (m, 1H), 3.84 (s, 2H), 3.39 (m, 2H), 3.06 (m, 2H), 2.10-2.30 (m, 4H). HPLC-MS-4: Rt 0.83 min; MS m/z [M+H] ⁺ 447.1. 186 N-(3-fluoro-4-(1-(2-epoxypiperidin-4-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 10, intermediates D-T8 and B-T41 were used with _PdCl2 (dppf) and _{K2CO3 .} ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.17 (d, 1H), 8.09 (t, 1H), 7.90 (s, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.61-7.71 (m, 3H), 7.33 (dd, 1H), 4.75 (m, 1H), 3.90-4.18 (m, 2H), 3.04-3.28 (m, 2H), 2.64- 2.73 (m, 2H), 2.05-2.22 (m, 2H). HPLC-MS-4: Rt 0.88 min; MS m/z [M+H] ⁺ 462.2 187 N-(4-(1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide (TFA salt) Similar to Example 6, intermediates D-T8 and B-T42 were used with _PdCl2 (dppf) and _{K2CO3 .} ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 8.81 (br s, 1H), 8.55 (br s, 1H), 8.14 (d, 1H), 8.09 (t, 1H), 7.93 (s, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.63-7.71 (m, 2H), 7.33 (dd, 1H), 4.84 (m, 1H), 4.01 (s, 2H), 3.18-3.31 (m, 2H), 1.98-2.25 (m, 4H), 1.39 (d, 6H). HPLC-MS-4: Rt 0.80 min; MS m/z [M+H] ⁺ 476.1. 188 N-(3-fluoro-4-(1-(6-epoxypiperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide Similar to Example 10, intermediates D-T8 and B-T43 were used with _PdCl2 (dppf) and _{K2CO3 .} ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 8.19 (d, 1H), 8.09 (t, 1H), 7.90 (s, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.63-7.71 (m, 2H), 7.58 (s, 1H), 7.33 (dd, 1H), 4.60-4.77 (m, 1H), 4.01 (s, 2H), 3.49-3.61 (m, 2H), 2.13-2.41 (m, 4H) HPLC-MS-4: Rt 0.88 min; MS m/z [M+H] ⁺ 462.2. 189 N-(3-fluoro-4-(1-(2-(4-methylpiperazol-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 6, intermediate D-M3/Step 1 and intermediate B-T45 are used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 (br s, 1H), 8.07-8.11 (m, 1H), 7.83 (s, 1H), 7.55-7.72 (m, 6H), 7.31 (dd, 1H), 4.23 (t, 2H), 3.80 (s, 2H), 2.70 (t, 2H), 2.20-2.48 (m, 8H), 2.12 (s, 3H). HPLC-MS: Rt 2.18 min; MS m/z [M+H] ⁺ 490.1. 190 N-(3-fluoro-4-(1-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (HCl salt) Similar to Example 6, intermediates D-M3/step 1 and B-T44 are used with (Ph _3P ) _4Pd in step 1 and 4NHCl/dioxane in step 2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 9.02 (br s, 1H), 8.65 (br s, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.52-7.78 (m, 6H), 7.39 (dd, 1H), 4.17 (s, 2H), 3.84 (s, 2H), 3.06-3.23 (m, 2H), 3.00 (q, 2H), 1.66-1.83 (m, 2H), 1.56 (d, 2H). HPLC-MS-4: Rt 0.83 min; MS m/z [M+H] ⁺ 477.2. 191 N-(4-(1-(2-(4H-1,2,4-triazol-3-yl)propyl-2-yl)-1H-pyrazol-4-yl)-3,5-difluorophenyl)-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 10, intermediates D-T1 and B-T27 are used with _PdCl2 (dtbpf) and _{Na2CO3 .} ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.98 (s, 1H), 10.63 (s, 1H), 8.39 (s, 1H), 7.91 (s, 1H), 7.77 (d, 1H), 7.70 (s, 1H), 7.56-7.67 (m, 3H), 7.34-7.45 (m, 2H), 3.82 (s, 2H), 1.97 (s, 6H). HPLC-MS: Rt 2.26 min; MS m/z [M+H] ⁺ 491.1. 192 N-(3,5-difluoro-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide Similar to Example 18, intermediates D-M5 and 2-bromopyridine are used with L-proline/DMF ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (br s, 1H), 8.89 (s, 1H), 8.52 (d, 1H), 8.17 (s, 1H), 7.95-8.08 (m, 2H), 7.71 (s, 1H), 7.55-7.68 (m, 3H), 7.49 (d, 2H), 7.41 (ddd, 1H), 3.85 (s, 2H). HPLC-MS: Rt 2.49 min; MS m/z [M+H] ⁺ 459.1. 193 N-(6-(4-(3,6-dihydro-2H-piperan-4-yl)-1H-imidazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide Similar to Example 10, the intermediate D-M4 is used with _PdCl2 (dppf) _. DCM and _K3PO4 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.48 (d, 1H), 8.27 (dd, 1H), 8.25 (s, 1H), 7.70 (s, 1H), 6.57 (s, 1H), 6.40 (s, 1H), 5.18 (s, 2H), 4.22 (m, 2H), 3.80 (t, 2H), 2.35-2.42 (m, 2H), 2.31 (s, 3H). UPLC-MS-2: Rt = 0.93 min; MS m/z [M+H] ⁺ = 451.0. 194 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-methoxypiperidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 24, intermediates D-T2 and 4-methoxypiperidine were used with NaOtBu/DMA ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.44 (d, 1H), 8.24 (dd, 1H), 8.01 (m, 1H), 7.67-7.80 (m, 2H), 7.40 (t, 1H), 6.92 (s, 1H), 3.94 (s, 2H), 3.39-3.48 (m, 2H), 3.29 (m, 1H), 3.26 (s, 3H), 2.71-2.80 (m, 2H), 1.87-1.96 (m, 2H), 1.44-1.56 (m, 2H). UPLC-MS-2: Rt = 1.07 min; MS m/z [M+H] ⁺ = 496.4. 195 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(2-sideoxypyrrolidin-1-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 18, using the intermediate D-T2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.48 (d, 1H), 8.30 (dd, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.68-7.81 (m, 2H), 7.41 (t, 1H), 3.95 (s, 2H), 3.91 (t, 2H), 2.44-2.49 (m, 2H), 2.05-2.16 (m, 2H). UPLC-MS-2: Rt = 1.00 min; MS m/z [M+H] ⁺ = 466.4. 196 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(3-sideoxy-lino)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 18, the intermediate D-T2 and α-lin-3-one were used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 8.49 (d, 1H), 8.31 (dd, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.69-7.81 (m, 2H), 7.41 (t, 1H), 4.25 (s, 2H), 3.96-4.02 (m, 4H), 3.95 (s, 2H). UPLC-MS-2: Rt = 0.94 min; MS m/z [M+H] ⁺ = 482.3. 197 2-(2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-fluoro-6-(4-(4-hydroxytetrahydro-2H-piperan-4-yl)-1H-imidazol-1-yl)pyridin-3-yl)acetamide Similar to Example 5, the intermediate C-T27 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 8.47 (d, 1H), 8.28 (dd, 1H), 8.18 (m, 1H), 7.69-7.80 (m, 2H), 7.56 (m, 1H), 7.41 (t, 1H), 4.96 (s, 1H), 3.95 (s, 2H), 3.68-3.79 (m, 2H), 3.58-3.68 (m, 2H), 2.01-2.13 (m, 2H), 1.56-1.65 (m, 2H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ = 483.5. 198 N-(6-(3-(1-amino-3,3-difluorocyclobutyl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamide Similar to Example 11, intermediate C-T35 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid [CAS No. 194943-83-4] were used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04 (br s, 1H), 9.05 (s, 1H), 8.53 (d, 1H), 8.33 (dd, 1H), 7.77 (t, 1H), 7.72 (t, 1H), 7.41 (t, 1H), 3.97 (s, 2H), 3.13-3.23 (m, 2H), 2.73-2.83 (m, 2H), 2.52 (br s, 2H). UPLC-MS-8: Rt = 0.85 min; MS m/z [M+H] ⁺ = 489.3. 199 N-(3-cyano-5-fluoro-4-(1-(tetrahydro-2H-piperan-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(pentafluoro- ^λ6 -hydrothio)phenoxy)acetamide Similar to Example 5, intermediates A-M2 and C-T54 are used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 8.29 (s, 1H), 7.94-7.98 (m, 2H), 7.89 (s, 1H), 7.59 (t, 1H), 7.52-7.56 (m, 2H), 7.36 1.75 (m, 1H), 1.66 (m, 1H). UPLC-MS-2: Rt = 1.19 min; MS m/z [M+H] ⁺ = 547.2. 200 N-(3,5-difluoro-4-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (HCOOH salt) Similar to Example 6, tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [CAS No. 1092563-74-0] was used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.79 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.55-7.67 (m, 3H), 7.40-7.49 (m, 2H), 4.37-4.50 (m, 1H), 3.84 (s, 2H), 3.38-3.39 (m, 1H), 2.97-3.10 (m, 2H), 2.68 (dt, 1H), 2.07-2.18 (m, 1H), 1.97 (ddd, 1H), 1.74-1.85 (m, 1H), 1.56-1.72 (m, 1H). HPLC-MS: Rt = 2.04 min; MS m/z [M+H] ⁺ = 465.0. 201 N-(5-fluoro-6-(4-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl)pyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide (TFA salt) Similar to Examples 10 and 21, intermediates D-M4 and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane _- cyclopentane [CAS No. 212127-80-5] are used with _PdCl₂ (dppf)/ _K₃PO₄ and _NH₄HCO₂ / _EtOH ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 8.73 (br s, 1H), 8.50 (d, 1H), 8.30 (dd, 1H), 7.78 (s, 1H), 6.57 (s, 1H), 5.19 (s, 2H), 3.99 (t, 1H), 3.87 (td, 1H), 3.79 (q, 1H), 3.69 (d, 1H), 3.68 (d, 1H), 2.31 (s, 3H), 2.25 (m, 1H), 2.06 (m, 1H). UPLC-MS-2: Rt = 0.86 min; MS m/z [M+H] ⁺ = 439.3.

Example 202 : (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl-2-d)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide

Step 1: A solution of NBS (175 mg, 0.9835 mmol) in ACN (1.5 ml) was added to a solution of (S)-2-(1-(5-amino-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (intermediate C-T40, 360 mg, 0.9366 mmol) in ACN (8 ml) at 0°C under Ar conditions. After 1 h, the temperature was increased to 7°C. The reaction mixture was quenched with _H₂O and extracted with EtOAc. The organic layer was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under vacuum. The residue was purified on silicone (cyclohexane/EtOAc 100:0 to 50:50) to give (S)-2-(1-(5-amino-6-bromo-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester. UPLC-MS-8: Rt = 0.97 min; [M+H] ⁺ = 463.2/465.2.

Step 2: DIPEA (415 µl, 2.38 mmol) and then T3P (50% in EtOAc) (708 µl, 1.19 mmol) were added to a solution of (S)-2-(1-(5-amino-6-bromo-3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (Step 1, 375 mg, 0.793 mmol) and 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid [CAS No. 345637-71-0] (191 mg, 0.873 mmol) in THF (8 ml) at 0°C. The cooling bath was removed and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc, quenched with _H₂O , and washed with 10% citric acid (2×), _H₂O , saturated _NaHCO₃ aqueous solution, and brine. The organic layer ( _Na₂SO₄ ) was dried and concentrated in a _vacuum . The residue was first purified on silicone [cyclohexane/(3:1 TBME/EtOH) 100:0 to 50:50] and then by RP-HPLC-4 (mobile phase: ( _H₂O + 0.1% TFA)/ACN 80/20 to 10/90) to give (S)-2-(1-(6-bromo-3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamino)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester. UPLC-MS-8: Rt = 1.26 min; [M+H] ^⁺ = 653.1/655.1.

Step 3: At room temperature, TFA (1 ml, 12.98 mmol) was added to a solution of (S)-2-(1-(6-bromo-3-fluoro-5-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4,4-difluoropyrrolidone-1-carboxylic acid tributyl ester (Step 2, 320 mg, 0.485 mmol) in DCM (5 ml). After 2 h, the reaction mixture was concentrated under vacuum. The residue was partitioned between EtOAc and a saturated aqueous solution of _NaHCO3 . The organic layer was washed with saturated _NaHCO3 aqueous solution and brine, _dried ( _Na2SO4 ), and concentrated under vacuum. The residue was diluted with 1:1 EtOAc/heptane and concentrated under vacuum to give (S)-N-(2-bromo-6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. UPLC-MS-8: Rt = 0.81 min; [M+H] ⁺ = 553.0/555.0.

Step 4: Add Et ₃ N (30 µl, 0.215 mmol) and 10% Pd/C (20 mg) to a solution of (S)-N-(2-bromo-6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide (Step 3, 22 mg, 0.0394 mmol) in DMF (2 ml). Degas the mixture using a freeze-thaw cycle (2×) and then refrozen and purged with deuterium from the _D2 line. Stir the mixture at room temperature under a _D2 atmosphere for 90 min. The mixture was diluted with EtOAc and filtered through a membrane filter. The filtrate was washed with _H₂O (3×) and brine, dried ( _Na₂SO₄ ), and concentrated under _vacuum . The residue was dissolved in MeOH and concentrated under vacuum. The residue was purified by RP-HPLC-3 (mobile phase: ( _H₂O + 0.1% TFA)/ACN 90/10 to 60/40). The fraction containing the product was quenched with a saturated aqueous solution _{of NaHCO₃} and extracted with EtOAc (3×). The combined organic layer was washed with brine, _dried ( _Na₂SO₄ ), and concentrated under vacuum. The residue was diluted with heptane, ultrasonically treated, and then concentrated in a vacuum to obtain (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl-2-d)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.17 (s, 1H), 9.07 (s, 1H), 8.30 (dd, 1H), 6.57 (d, 1H), 5.20 (s, 2H), 4.52 (q, 1H), 3.38 (s, 1H), 3.10-3.24 (m, 2H), 2.53-2.73 (m, 2H), 2.32 (s, 3H). UPLC-MS-8: Rt = 0.70 min; [M+H] ⁺ = 476.2.

Example 203 : Preparation and characterization of the crystalline form of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate. The preparation method of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyrrolidin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide monohydrate was obtained by the following method: (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide ( 33a (3.5 g)) was weighed into a 250 ml reactor, followed by the addition of 140 ml MeOH/ _H₂O (33:67 ratio). The mixture was slurried at room temperature for 24 h. The solid was then obtained by filtration (Buchner funnel) and washed with MeOH/ _H₂O (33:67 ratio) (3×). The solid was then dried at room temperature under vacuum (< 100 mbar) to obtain the monohydrate form of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide.

Characterization of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate : XRPD analysis . Figure 1 shows a representative XRPD diffraction pattern of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate, and Table 1 below provides a list of corresponding reflectances (peak lists) and relative peak intensities from 12 to 30° 2θ. [ Table 1 ] peak Angle (°2θ) d value relative strength 1 12.36 7.15 9.4% 2 16.90 5.24 100.0% 3 17.49 5.07 28.5% 4 19.21 4.62 6.4% 5 20.15 4.40 5.9% 6 21.77 4.08 9.2% 7 23.01 3.86 12.6% 8 23.47 3.79 4.1% 9 25.91 3.44 19.2% 10 29.88 2.99 15.6%

Table 1: The reflectance (peak) positions of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate are in the range of 12 to 30° 2θ; the typical accuracy of the 2θ values is within ± 0.2° 2θ, and preferably within ± 0.1° 2θ. The most characteristic XRPD peaks are in bold and italics.

B : Differential Scanning Calorimetry ( DSC ) analysis was performed on (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate using a Mettler Toledo DSC1/DSC3+ STARe system. Approximately 1–10 mg of sample was heated from 20°C to 350°C at a rate of 10°C/min in an aluminum dish with a perforated cap. Nitrogen gas (40 ml/min) was used as the purge gas. Figure 2 shows the DSC curve of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate, in which an endothermic bee was obtained with an initial temperature of about 175.4°C and a peak temperature of about 176.8°C.

C : Thermogravimetric analysis ( TGA ) was performed using a Mettler Toledo TGA/DSC3+ STARe system to study (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide monohydrate. Approximately 1–10 mg of sample was heated in an aluminum pan. The cap was automatically punctured at the start of the measurement. The sample was heated from 20°C to 350°C at a rate of 10°C/min. Nitrogen gas (20 ml/min) was used as the purge gas. The TGA curve is shown in Figure 3, where a mass loss of 3.56% was observed before the sample melted.

Biological data lipolysis assays revealed that potato glycoprotein-like phospholipase inclusion domain 3 (PNPLA3) is a triglyceride (TAG) hydrolase located on lipid droplet (LD) membranes. Point mutations in PNPLA3I148M (G/G genotype) are associated with the genetic predisposition to progressive fatty liver disease. PNPLA3I148M exhibits reduced lipolytic activity and accumulates on hepatic LDs. On hepatic LDs, PNPLA3I148M can interfere with normal LD function, leading to steatosis and steatohepatitis in patients and animal models of non-alcoholic steatohepatitis (NASH). PNPLA3I148M negatively regulates lipolysis by competitively binding to CGI58 and thereby inhibiting PNPLA2 function. Compounds that bind to PNPLA3I148M and release CGI58 restore PNPLA2-mediated cellular lipolysis. Cytometry using human hepatocytes expressing PNPLA3I148M was used to identify compounds that restore (i.e., normalize) PNPLA2-mediated cellular lipolysis. Measurement reads were based on the reduction of residual deuterated oleic acid-containing TAGs measured by LC-MS.

Abbreviation list abbreviation describe AC Activity control AC ₅₀ Active concentration 50% Amax The maximum value of the fitted curve at any concentration (Helios terminology) ATCC American Center for Type Cultures BSA Bovine serum albumin CRC Concentration response curve c/w Cells/pores Data (Cmax) The average value of data points at the highest concentration in the concentration response curve (Helios terminology). d9-OA Deuterated oleic acid DMSO Dimethyl monoxide f.c. Final Concentration FCS Fetal bovine serum FFA Free fatty acids Huh7 Human liver cell line Huh7 LC-MS Liquid chromatography-mass spectrometry ISTD Internal Standard LD lipid droplets LDV Low dead volume LMW Low molecular weight NC Neutral contrast PBS Phosphate buffered brine PP Polypropylene rhu Reconstructed Person RT Room temperature S/B Signal-to-background ratio SD standard deviation TAG Triglycerides (17:0) wp Orifice plate

method [ surface 2 ] :Material Material company Cat Number DMEM DMEM (Phenol Red Free) GIBCO GIBCO 31966-021 21063-029 FBS (Heat Inactivation) GIBCO A3161001 Hepes GIBCO 15630-080 Magnapordin Penicillin/Streptomycin GIBCO 15140-122 OptiMEM GIBCO 31985-062 PBS GIBCO 10010-023 NaOH Trypsin-EDTA 0.25% GIBCO 25200-056 Transfection reagent FuGene EZ31A 70 μM Cellular Filter BD Falcon 352350 PCR plate Eppendorf 0030128.508 BSA (No fatty acids) Biowest P6156-100 g d9-Oleic Acid Avanti polar lipids 8618090-10 mg Butanol Sigma-Aldrich 537993 Isopropanol BioSolve 0016264101BS _H₂O (LCMS grade) Honeywell Corporation 14263 Methanol Honeywell Company 14262 Triglycerides (17:0_17:0_17:0) Sigma-Aldrich T2151-100MG Black transparent bottom, 384wp, plastic Greiner 781091 [ surface 3 ] Instruments Instruments company Vanquish, TSQ-Quantum (LC-MS) Thermo Fisher Scientific 384/1536wp Multidrop Distributor Thermo Fisher Scientific CyBi 384-hole distributor Cybio Corporation Echo sound wave distributor LabCyte Cell counter Invitrogen Incubator Liconic Company [ surface 4 ] buffer and culture medium Name Composition Growth medium DMEM + 10% FBS heat inactivation + 1% P/S + 1% Hepes Assay medium DMEM (phenol red-free) + 2% BSA Extraction solution Butanol + 100 ng/ml triglycerides f.c

HUH7-hPNPLA3(I148M)-RFP overexpressing cells were cultured in DMEM, 10% heat-inactivated FBS, Pen/Strep, and 10 mM Hepes containing 10 µg/ml blastomycin. Cells were passaged twice weekly. If cells were cultured for 4 days, they were seeded at a density of 3 × ^10⁶ /150 ^cm² flasks, and if cultured for 3 days, they were seeded at a density of 5 × ^10⁶ /150 ^cm² flasks.

On day one of the assay, 9 million HUH7-PNPLA3(I148M)-RFP cells were seeded in 9.75 ml of growth medium in a T75 cm² flask and incubated for approximately 6 h in a 5% _CO₂ /37°C incubator. After 6 h of incubation, 250 µl of 8 mM d9-OA (prepared as described below) was added to each 75 ^cm² flask.

The following procedure was followed to prepare 8 mM d9-OA: A d9-OA glass tube was centrifuged in a 50 mL Falcon tube and then broken within the tube. A 200 mM d9-OA solution was prepared by adding 515 µl of 0.2 M NaOH to 30 mg of d9-OA. The solution was then incubated at 72°C with shaking at 1000 rpm for 30 min. The 200 mM d9-OA solution was then diluted by adding 5.92 mL of DMEM + 20% BSA to 515 µl of d9-OA in NaOH to prepare a 16 mM d9-OA solution in DMEM + 20% BSA. Finally, 8 mM d9-OA in 10% BSA was obtained by adding 6.43 mL of phenol red-free DMEM.

Compound preparation involved diluting a 10 mM test compound solution in 50 µl of assay medium (phenol red-free DMEM + 2% BSA) to achieve a final compound concentration in the assay plate ranging from 10 µM to 31.4 nM, containing 0.05% DMSO, for 10-point CRC. A neutral control compound was similarly obtained.

Cell suspension preparation: Cells in each T75 cm² flask were washed with PBS (GIBCO, 10010-023) and separated for 5 min in a 5% _CO₂ /37°C incubator with 1 mL of 0.25% Typsin/EDTA (GIBCO, 25200-056). Then, 9 mL of assay medium (DMEM + 2% BSA) was added, and the cell suspension was passed through a 70 µm cell filter. Cells were centrifuged in an Eppendorf 5810 R centrifuge at 1000 rpm for 5 min, and the supernatant was discarded. The cells were resuspended in 7.5 mL of assay medium and the cell density was adjusted to approximately 2.5 × ^10⁵ /ml by dilution.

Add 50 µl of cell suspension to each well of the prepared compound plate to achieve approximately 12,500 cells/well. Then incubate the cells with the test compound titrant at 37°C for 24 h.

After TAG extraction and treatment with the test compound for 24 h, the culture medium was removed from the wells, and 50 µl of butanol containing 100 ng/ml TAG 17:0_17:0_17:0 (ISTD) was added to each well. The plate was sealed and then shaken at 600 rpm for 30 min. The plate was then centrifuged at 2000 rpm for 10 min at room temperature. 40 µl of the supernatant from each well was transferred to a new 240 µl low-binding Eppendorf deep-well plate.

TAG measurement , and then the amount of d9-OA containing TAG and ISTD is measured using LCMS under the following conditions: UPLC Waters UPLC Acquity column Agilent Zorbax 300SB-C8; 3.5 µm; 50 mm × 1.0 mm Column temperature 40°C mobile phase A: 80% _H₂O + 20% MeOH, 5 mM NH₄Ac, 0.1% HCOOH B: 100% isopropanol, 5 mM NH₄Ac, 0.1% HCOOH flow 150 µl/min Gradient (%B) 0 min 65% B 0.1 min: 65% B, 1 min 85% B 2.3 min 95% B 3 min 95% B 3.1 min 65% B Equilibrium Time 1.5 min injection 2.5 µL MS TSQ Quantum Access Max; Thermo Fisher Scientific Ionization mode +ESI SRM m/z 866.70 --> m/z 579.30; 0.1 s/Da Neutral loss 308.30 Da m/z 810-940, within 0.5 s; Q1 peak width [FWHM]: 0.7 Da; 26 V collision energy.

Data analysis was performed to determine the activity of the test compound by measuring the reduction of the remaining TAG-containing d9-OA using LC-MS. +: Positive control (DMSO) -: Negative control (cell-free)

Table 5 shows the in vitro activities of the example compounds, where AC ₅₀ represents the compound concentration required to reduce TAG levels by 50% relative to the control. [Table 5]: Plotting the in vitro activity of PNPLA3I148M Example number Lipolysis AC ₅₀ ( nM ) Example number Lipolysis AC ₅₀ ( nM ) 1 nd 89 **** 1a ** 90 *** 1b **** 91 *** 1c * 92 ***** 1d ***** 92a ***** 2 nd 92b *** 2a ** 93 ***** 2b ** 94 **** 3 ***** 95 ***** 4 **** 96 ***** 4a **** 97 ***** 4b ***** 98 ***** 5 **** 99 ***** 6 **** 100 ****** 7 **** 101 ****** 8 nd 102 ****** 8a ***** 103 ******* 8b * 104 nd 9 *** 104a *** 10 *** 104b ** 11 *** 105 ** 12 nd 105a *** 12a **** 105b ** 12b *** 106 ** 13 **** 106a *** 13a **** 106b *** 13b **** 107 *** 14 ****** 108 *** 15 ***** 108a ** 16 ***** 108b *** 17 ** 109 *** 18 *** 110 *** 19 **** 111 ** 20 *** 111a ** twenty one *** 111b ** twenty two *** 112 *** twenty three ***** 113 *** twenty four *** 113a ** 25 nd 113b ** 25a ****** 114 nd 25b ****** 114a **** 26 ** 114b **** 26a ** 115 nd 26b *** 115a ***** 27 *** 115b **** 28 **** 116 ***** 29 **** 117 nd 30 ***** 117a ** 31 ***** 117b *** 32 *** 118 nd 32a *** 118a *** 32b *** 118b *** 33 nd 119 ** 33a ** 120 nd 33b **** 120a *** 34 *** 120b *** 35 ***** 121 nd 35a ***** 121a *** 35b *** 121b *** 35c **** 122 *** 35d *** 123 *** 36 ***** 124 *** 37 ***** 125 nd 38 ******* 125a *** 39 ******* 125b ** 40 ***** 126 *** 41 nd 127 **** 41a *** 128 nd 41b *** 128a *** 42 *** 128b *** 43 **** 129 nd 44 nd 129a *** 44a *** 129b *** 44b **** 130 *** 45 ***** 131 nd 46 nd 131a *** 46a *** 131b *** 46b ***** 132 *** 47 **** 133 **** 47a **** 134 *** 47b *** 135 **** 48 ***** 136 ** 49 ***** 137 **** 50 ***** 138 nd 51a *** 138a *** 51b *** 138b **** 52 nd 139 ***** 52a *** 140 ****** 52b *** 141 ****** 53a *** 142 ****** 53b *** 143 ******* 54 nd 144 ******* 54a *** 145 ***** 54b *** 146 ***** 55 *** 147 ** 55a ******* 147a *** 55b ***** 147b ** 55c * 148 nd 55d ***** 148a ***** 56 *** 148b **** 56a ** 149 *** 56b ** 150 *** 57 ** 150a ***** 57a *** 150b **** 57b ** 151 **** 58 *** 152 **** 59 *** 153 **** 60 *** 154 ***** 61 *** 155 ****** 62 **** 156 ***** 63 **** 157 ***** 63a *** 158 ***** 63b *** 159 ***** 64 **** 160 ***** 65 **** 161 ***** 66 ***** 162 ***** 66a ***** 163 ***** 66b ****** 164 ****** 67 ***** 165 ****** 68 ******* 166 ****** 69 ******* 167 ****** 70 ** 168 ******* 71 **** 169 ******* 72 *** 170 ******* 72a ** 171 ******* 72b ** 172 ******* 73 ** 173 ******* 73a *** 174 ******* 73b *** 175 ******* 74 ***** 176 ******* 75 ** 177 ***** 75a *** 178 ***** 75b ** 179 ***** 76 nd 180 ******* 76a ** 181 ******* 76b *** 182 ******* 77 ** 183 ******* 78 nd 184 ******* 78a *** 185 ****** 78b ** 186 ***** 79 ** 187 **** 80 ** 188 **** 81 ** 189 ******* 82 nd 190 ******* 82a *** 191 ***** 82b ** 192 *** 83 ** 193 *** 84 *** 194 *** 85 *** 195 *** 86 *** 196 *** 87 nd 197 *** 87a **** 198 *** 87b *** 199 *** 88 *** 200 *** 88a **** 201 *** 88b *** 202 nd Note: * EC ₅₀ < 0.5 nM ; ** EC ₅₀ 0.5 nM to 5 nM ; *** EC ₅₀ > 5 nM to 50 nM ; **** EC ₅₀ > 50 nM to 100 nM ; ***** EC ₅₀ > 100 nM to 500 nM ; ****** EC ₅₀ > 500 nM to 1000 nM ; ******* EC ₅₀ > 1000 nM ; nd undetermined .

without

[ Figure 1] : The representative powder X-ray diffraction (XRPD) curve of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate is shown.

[ Figure 2] : This shows a representative differential scanning calorimetry (DSC) curve for (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate.

[ Figure 3] : This shows the representative thermogravimetric analysis (TGA) curves of (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate.

without

Claims (33)

A compound having formula (I) or a pharmaceutically acceptable salt thereof, (I) Wherein: -X=Y- refers to ^-CRx = ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx refers to H, D, halogen, or _C1 - _C4 alkyl; ^Ry refers to H, D, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^R5 refers to H, halogen, -CN, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, or _C1 - _C4 alkoxy; ^RA refers to: (i) unsubstituted or substituted with 1, 2, 3, or 4 ^R1 groups; (ii) partially saturated 9-, 10-, 11-, or 12-membered bicyclic carbocyclic groups that are unsubstituted or substituted with 1 to 4 ^R1 groups; (iii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups; or (iv) a partially saturated 8, 9, 10, 11, or 12-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 ring members independently selected from N, ^NR4 , O, and S, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4 ^R1 groups; each ^R1 is independently selected from the group consisting of: halogens, _C1 - _C4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _{C1 -C4} alkoxy, _C1 - _C4 alkoxycarbonyl, _C3 -C6 cycloalkyl, C1- _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, pentafluorohydrothio, _C1 - _C4 hydroxyalkyl, _C1 - _C4 thioalkyl, azido, _diC1 - _C4 alkylamino, _diC1 - _C4 alkylaminocarbonyl, D, _CD3 , cyano, methyl, phenyl, and 5- to 6 _- membered heterocycloalkyl groups comprising one or two ring members independently selected from N, ^NR4 , O, and S; _L1 -linked, -( ^CR2R3 ) _p- , - ₍ ^{CR2R3 )} _p - ^NR4- , -( ^CR2R3 ) _p -O-, ^{-NR4 ( CR2R3 ) q} -、-(CR ² R ³ ) _q NR ⁴ -、-O-(CR ² R ³ ) _p- 、or -S-(CR ² R ³ ) _p- ; R ² is H, D, halogen, or C ₁ -C ₄ alkyl; R ³ is H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, OH, amino, or t -Boc-amino; or R ² and R ³ are connected together with the C atom to which they are attached to form an unsubstituted or substituted C 3-C ₄ cycloalkyl group, either by a single substituent selected from C _{1 -} C ₄ alkyl and an alkyl group; each R ⁴ is independently selected from the group consisting of: H and C ₁ -C ₄ alkyl; p is 1, 2, or 3; q is 0, 1, or 2; Z ₁ is N or C; Z ₂ is N or CR ^z ; Z _Z3 is N or CR ^z ; _Z4 is N or C; _Z5 is N or CR ^z ; wherein each R ^z is independently selected from the group consisting of: H, halogen, _C1 - _C4 alkyl, and _C1 - _C4 fluoroalkyl; and provided that at least two and no more than four of _Z1 , _Z2 , _Z3 , _Z4 and _Z5 are N; _L2 is a bond, -( ^CR6R7 ) _n- , or -( ^CR6R7 ) _nO- *, where the * indicates the attachment point with ^R8 ; each ^R6 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; ^{each R7} is ^{independently} selected from the group consisting of: H, _C1 -C4 alkyl, C1- _C4 fluoroalkyl, and C1 _-C4 hydroxyalkyl. -C ₄ fluoroalkyl and C ₁ -C ₄ hydroxyalkyl; or R ⁶ and R ⁷ are connected together with the C atom to which they are attached to form C ₃ -C ₆ cycloalkyl, oxocyclobutyl, tetrahydrofuranyl, or tetrahydropiperanyl; n is 1, 2, or 3; R ⁸ is: (i) a 4-, 5-, or 6-membered heterocycloalkyl having 1, 2, or 3 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 substituents each independently selected from: -OH, -CN, -N(R ¹⁰ ) ₂ , halogen, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkyl, C ₁ -C (i) ₄ -alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 ring members independently selected from N, ^NR , O, and S, wherein the monocyclic heteroaryl is unsubstituted; (ii) 4-, 5-, or 6-membered heterocyclic alkyl, wherein one ring member is S(=O) _₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl is unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from -OH, _C₁ - _C₄ alkyl, and lateral alkyl; (iii) 4-, 5-, or 6-membered heterocyclic alkyl, wherein one ring member is S(=O) _₂ or S(=O), and 1, 2, or 3 other ring members independently selected from N, NR, O, and S. (iv) A partially saturated _5- or 6-membered heterocyclic group having one or two ring members independently selected from N, ^NR9 , ^O , and S, wherein the partially saturated heterocyclic group is unsubstituted or substituted by one, two, three, or four ring members independently selected from -OH, _C1 - _C4 alkyl, and lateral oxygen; (v) A partially saturated 5- or 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and one, _two , or three other ring members are independently selected from N, ^NR9 (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 - _C4 alkoxy, and C1-C4 alkyl; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, _C1 -C4 alkoxy, and C1- _C4 alkyl; ( ^vii ) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 ring members independently selected from -OH, C1-C4 alkoxy, and _C1 - _C4 alkyl ^. (viii) A 6- or 7-membered fused bicyclic heterocyclic group having 1, 2, 3, or 4 substituents, each independently selected from -OH, -N( ^{R10 )} , _C1 - _C4 alkyl- _NH2 , halogen, _{C1 - C4} alkyl, and lateral oxygen groups ^; _2. Substituents of _{C1- C4} alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (ix) A 6-, 7-, 8-, 9-, or 10-membered spirobicyclic heterocyclic alkyl group having 1, 2, or 3 ring members independently selected from N, ^NR9 , O, and S, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted or substituted with 1, 2, 3, or 4 ring members independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen, _C1 - _C4 alkyl, and lateral oxygen groups; (x) A 6-membered heterocyclic alkyl group having 1 to 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group has C ₁ - _C3 alkyl-bridged or _{-CH2OCH2 -} bridged; (xi) phenyl, which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from -S(=O) _2N ( ^R10 ) ₂ , -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkyl; or (xii) _C4 - _C8 cycloalkyl, which is unsubstituted or substituted with 1, ₂ , 3 or 4 substituents each independently selected from -OH, -N( ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen, C1- _C4 alkoxy, _C1 - _C4 alkyl and phenoxy; ^R9 is H, _C1 -C _4- alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl. A compound having formula (I) as described in claim 1, having a structure of formula (Ia) or formula (Ib); or a pharmaceutically acceptable salt thereof, (Ia) (Ib). A compound having formula (I) as described in claim 1, having a structure of formula (Ic) or formula (Id); or a pharmaceutically acceptable salt thereof, (Ic) (Id). The compound or its pharmaceutically acceptable salt as described in any of claims 1 to 3, wherein: ^-X =Y- is -CRx= ^CRy- , ^-CRx =N-, or -N= ^CRy- ; ^Rx is H, D, or a halogen; ^Ry is H, D, a halogen, or -CN; ^R5 is a halogen or -CN; each ^R1 is independently selected from the group consisting of: halogen, D, _CD3 , _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, _C1 - _C4 fluoroalkoxy, _C3 - _C6 cycloalkyl, and pentafluorohydrothio; _L1 is -( ^CR2R3 ) _p- , ^{-NR4 ( CR2R3 )} _q- , or -O-( ^CR2R3 ) _p- ; ^R2 is H, D ^, or a halogen; R ³ -H, D, halogen, OH, or _C1 - _C4 alkyl; or ^R2 and ^R3 are connected together with the C atoms to which they are attached to form _C3 - _C4 cycloalkyl, which are unsubstituted ^R4 -H or _C1 - _C4 alkyl; p-1; q-0; _Z1 - ^N , _Z2 -CRz, _Z3 -N, _Z4 -C, and _Z5 -N; or _Z1 - ^N , _Z2 -CRz, _Z3 -N, _Z4 -C, and _Z5 - ^CRz ; or _Z1 -C, _Z2 - ^CRz , _Z3 -N, _Z4 -N, and _Z5 - ^CRz ; or _Z1 -C, _Z2 -N, _Z3 -N, _Z4 -N, and _Z5 - ^CRz ; each ^Rz is H; L ₂ -group bond ^, -( ^CR6R7 ) _n- , or -( ^CR6R7 ) _nO- *, where the * indicates the attachment site with ^R8 ; each ^R6 is independently selected from the group consisting of: H, _C1 - ^C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; each ^R7 is independently selected from the group consisting of: H, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and _C1 - _C4 hydroxyalkyl; or _R6 and ^R7 are linked together with the C atom to which they ^are attached to to form a tetrahydropiperanyl group; n is 1 or 2; ^R8 group: (i) having 1 or 2 independently selected from N, ^NR9 (i) A 4-, 5-, or 6-membered heterocyclic alkyl group having a ring member of O and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral alkyl, and a 5- or 6-membered monocyclic heteroaryl group having 1 or 2 ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted; (ii) A 5-membered heterocyclic alkyl group having a ring member of S(=O) ₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted by -OH and _C10. (iii) A ₆ -membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S(=O), and the other ring member is selected from N, ^NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (iv) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR₉ , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (v) A partially saturated 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , and the other ring member is selected from N, NR₉, and S. (vi) A 5- or 6-membered monocyclic heteroaryl group having 1, ² , 3 or 4 ring members independently selected from N, NR ⁹ and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy and _C1 -C4 alkyl; (vii) A 6-membered fused bicyclic heteroaryl group having 1 ring member selected from N and NR ⁹ , wherein the fused bicyclic heteroaryl group is unsubstituted or substituted with a substituent; (viii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, ₃ or 4 ring members independently selected from N, NR 9 and O. A partially saturated 10-membered fused bicyclic heterocyclic group having a ring member of N, NR ⁹ , or O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with an oxy group; (ix) a 7-membered spirobicyclic heterocyclic alkyl group having one ring member selected from N, NR ⁹ , or O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) a 6-membered heterocyclic alkyl group having one or two independently selected ring members selected from N, NR ⁹ , or O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or _{a -CH2OCH2} -bridge; (xi) a phenyl group substituted with -S(=O) _2N ( ^R10 ) ₂ ; or (xii) a C4 _-C10 ... _8- cycloalkyl group, which is substituted by 1, 2 or 3 substituents independently selected from -OH, -N ₍ ^R10 ) ₂ , -S(=O) ^2R10 , _C1 - _C4 alkyl- _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl. The compound or its pharmaceutically acceptable salt as described in any of claims 1 to 4, wherein: ^-X =Y- is -CRx= ^CRy- , or ^-CRx =N-; ^Rx is H; ^Ry is H, halogen, or -CN; ^R5 is halogen or -CN; each ^R1 is independently selected from the group consisting of: halogen, _C1 - _C4 alkyl, _C1 - _C4 fluoroalkyl, and pentafluorohydrothioyl; _L1 ^is -( ^CR2R3 ) _p- , ^-NR4 ( ^CR2R3 ) _q- , or -O-( ^CR2R3 ) _p- ; ^R2 is H; ^R3 is H, ^OH , or _C1 - _C4 alkyl; ^R4 is H, or _C1 - _C4 alkyl; p is 1; ^q is 0; _Z1 is N, _Z2 is ^CRz , Z ₃ -series N, _Z4 -series C, and _Z5 -series N; or _Z1- series N, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series C, and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series CR ^z , _Z3 -series N, _Z4 -series N, and _Z5 -series CR ^z ; or _Z1 -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N, and _Z5 -series CR ^z ; each R ^z is H; _L2 -series bond, -(CR ⁶ R ⁷ ) _n -, or -(CR ⁶ R ⁷ ) _n O-*, where the * indicates the attachment point with R ⁸ ; each R ⁶ is independently selected from the group consisting of: H, _C1 - _C4 alkyl, and _C1 - _C4 hydroxyalkyl; each R ^7. Independently selected from the group consisting of: H, _C1 - _C4 alkyl, and _C1 - _C4 hydroxyalkyl; n-system: 1 or 2; ^R8- system: (i) 4-, 5-, or 6-membered heterocyclic alkyl groups having 1 or 2 ring members independently selected from N, ^NR9 , O, and S, wherein the heterocyclic alkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from: -OH, -CN, -N( ^R10 ) ₂ , halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, lateral oxy, and 5- or 6-membered monocyclic heteroaryl groups having 1 or 2 ring members independently selected from N and ^NR9 , wherein the monocyclic heteroaryl group is unsubstituted; (ii) (iii) A 5-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ , S(=O), or S(=O)(=NH), and wherein the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from -OH and _C₁ - _C₄ alkyl groups; (iv) A 6-membered heterocyclic alkyl group, wherein one ring member is S(=O) _₂ or S(=O), and one other ring member is selected from N, ^NR₉ , and O, and wherein the heterocyclic alkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (v) A partially saturated 6-membered heterocyclic alkyl group having one or two ring members independently selected from N, ^NR₉ , O, and S, wherein the partially saturated heterocyclic alkyl group is unsubstituted or substituted with a lateral oxygen group; (vi) A partially saturated 6-membered heterocyclic group, wherein one ring member is S(=O) ₂ and the other ring member is selected from N, ^NR4 and O, wherein the partially saturated heterocyclic group is unsubstituted or substituted with a side-oxy group; (vii) A 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 ring members independently selected from N, ^NR9 and O, wherein the monocyclic heteroaryl group is unsubstituted or substituted with a substituent selected from -OH, _C1 - _C4 alkoxy and _C1 - _C4 alkyl; (vii) A 6-membered fused bicyclic heterocyclic group having 1 ring member selected from N and ^NR9 , wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with a side-oxy group; (viii) A partially saturated 10-membered fused bicyclic heterocyclic group having 1, 2, or 3 ring members independently selected from N, NR ⁹ , and O, wherein the fused bicyclic heterocyclic group is unsubstituted or substituted with a side-oxy group; (ix) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from N, NR ⁹ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (x) A 6-membered heterocyclic alkyl group having 1 to 2 ring members independently selected from N, NR ⁹ , and O, wherein the heterocyclic alkyl group has a _C1 - _C3 alkyl bridge or a -CH ₂ OCH ₂ -bridge; (xi) A phenyl group bonded by -S(=O) _2N (R ¹⁰ ). _2- substituted; or (xii) _C4 - _C8 cycloalkyl, which is substituted by 1 ^{, 2 or 3 substituents independently selected from -OH, -N(R10)2, -S(=O)2R10 ,} _{C1 - C4 alkyl} - _NH2 , halogen and _C1 - _C4 alkoxy; ^R9 is H, _C1 - _C4 alkyl, benzyl, _C1 - _C4 alkyl- ^OR10 , -C(=O) ^OR10 or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl. The compound or its pharmaceutically acceptable salt as described in any of claims 1 to 5, wherein: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is a halogen; each R ¹ is independently selected from the group consisting of: halogens, _C1 - _C4 alkyl, and _C1 - _C4 fluoroalkyl; L _1- (CR ² R ³ ) _p- ; R ² is H; R ³ is H, or _C1 - _C4 alkyl; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; or Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is CR ^z ; or Z ₁ is C, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is N, and Z ₅ is CR ^z ; or Z ₁ -series C, _Z2 -series N, _Z3 -series N, _Z4 -series N, and _Z5 -series CR ^z ; each R ^z is H; _L2 -series bond or -(CR ⁶ R ⁷ ) _n- ; each R ⁶ is independently selected from the group consisting of H and _C1 - _C4 alkyl; each R ⁷ is independently selected from the group consisting of H and _C1 - _C4 alkyl; n is 1 or 2; R8 ^-series : (i) a 4-, 5-, or 6-membered cyclohexaalkyl ring having 1 or 2 ring members independently selected from N, NR ⁹ , O, and S, wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, halogen, _C1 - _C4 fluoroalkyl, _C1 - _C4 alkyl, and lateral oxygen; (ii) (iii) A 5-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (iv) A 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O), and one other ring member is selected from N, ^NR₉ , and O, and wherein the heterocycloalkyl group is unsubstituted or substituted with a substituent selected from _C₁ - _C₄ alkyl groups; (v) A partially saturated 6-membered heterocycloalkyl group having one or two ring members independently selected from O and S, wherein the partially saturated heterocycloalkyl group is unsubstituted; (vi) A partially saturated 6-membered heterocyclic group, wherein one ring member is S(=O) _₂ and the other ring member is O, wherein the partially saturated heterocyclic group is unsubstituted; (vii) A 5-membered monocyclic heteroaryl group having 3 ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered fused bicyclic heterocyclic group having 1 ring member selected from ^NR₉ , wherein the fused bicyclic heterocyclic group is unsubstituted; (viii) A 7-membered spirobicyclic heterocyclic alkyl group having 1 ring member selected from N, ^NR₉ , and O, wherein the spirobicyclic heterocyclic alkyl group is unsubstituted; (ix) A six-membered heterocycloalkyl group having one ring member selected from NR ⁹ , wherein the heterocycloalkyl group has _C1 - _C3 alkyl bridging; or (x) _C4 - _C8 cycloalkyl group substituted by one, two or three substituents independently selected from -OH, -N( ^R10 ) ₂ , _C1 - _C4 alkyl- _NH2 and halogen; ^R9 is H, _C1 - _C4 alkyl, or -C(=O) ^R10 , and ^R10 is H or _C1 - _C4 alkyl. The compound or its pharmaceutically acceptable salt as described in any of claims 1 to 6, wherein: -X=Y- is -CRx=N-; ^Rx is H; ^R5 is F; each ^R1 is independently selected from the group consisting of: F, Cl, methyl, and _-CF3 ; _L1 is -( ^{CR2R3 )} _p- , ^R2 is H; ^R3 is H or methyl; p is 1; _Z1 is N, _Z2 is ^CRz , _Z3 is N, _Z4 is C, and _Z5 is N; or _Z1 is N, _Z2 is ^CRz , _Z3 is N, _Z4 is C, and _Z5 is ^CRz ; each ^Rz is H; _L2 is bonded or -( ^CR6R7 ) _n- ; each ^R6 is independently selected from the group consisting of: H and ^methyl ; each R ^7. Independently selected from the group consisting of: H and methyl; n is 1 or 2; R ⁸ is: (i) a 4-, 5-, or 6-membered cyclohexaalkyl group having 1 or 2 ring members independently selected from N, ^NR , O, and S, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from -OH, F, _CF , methyl, and lateral oxygen; (ii) a 5-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O)(=NH), and wherein the heterocycloalkyl group is unsubstituted or substituted by methyl; (iii) a 6-membered heterocycloalkyl group, wherein one ring member is S(=O) _₂ or S(=O), and one other ring member is selected from N, NR (iv) A partially saturated 6-membered heterocyclic group having one or two ring members independently selected from O and S, wherein the partially saturated heterocyclic group is unsubstituted; ( ^v ) A partially saturated 6-membered heterocyclic group having one ring member S(=O) ₂ and one other ring member O, wherein the partially saturated heterocyclic group is unsubstituted; (vi) A 5-membered monocyclic heteroaryl group having three ring members independently selected from N and O, wherein the monocyclic heteroaryl group is unsubstituted; (vii) A 6-membered heteroaryl group having one ring member selected from NR (viii) A ⁶ -membered fused and bicyclic heterocyclic group having one ring member selected from NR ⁹ and O, wherein the fused and bicyclic heterocyclic group is unsubstituted; (ix) A 6-membered heterocyclic alkyl group having one ring member selected from NR ⁹ , wherein the heterocyclic alkyl group is _C1 - _C3 alkyl-bridged; or (x) A cyclobutyl, cyclopentyl, or cyclohexyl group substituted by one, two, or three substituents independently selected from -OH, _-NH₂ , _-CH₂NH₂ , and F; and ^R₉ is H, methyl, or -C ₍ =O) _CH₃ . The compound or its pharmaceutically acceptable salt as claimed in any of claims 1 to 7, wherein: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is halogen; each R ¹ is independently selected from the group consisting of: halogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ fluoroalkyl; L ₁ is -(CR ² R ³ ) _p- ; R ² is H; R ³ is H; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; each R ^z is H; L ₂ is bond; R ⁸ is pyrrolidyl group, which is substituted by one or two substituents each independently selected from halogen and C ₁ -C ₄ fluoroalkyl. The compound or its pharmaceutically acceptable salt as claimed in any of claims 1 to 8, wherein: -X=Y- is -CR ^x =N-; R ^x is H; R ⁵ is F; each R ¹ is independently selected from the group consisting of: F, Cl, methyl, and CF ₃ ; L ₁ is -(CR ² R ³ ) _p- ; R ² is H; R ³ is H; p is 1; Z ₁ is N, Z ₂ is CR ^z , Z ₃ is N, Z ₄ is C, and Z ₅ is N; each R ^z is H; L ₂ is bond; R ⁸ is pyrrolidyl group, which is substituted by one or two substituents each independently selected from F and CF ₃ . The compound described in claim 1 or its pharmaceutically acceptable salt, selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and . The compound described in claim 1 or its pharmaceutically acceptable salt, selected from: , and . A pharmaceutical composition comprising a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable acid addition salt thereof, and one or more pharmaceutically acceptable carriers. A method for treating PNPLA3I148M-related diseases, the method comprising administering to a subject in need a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. A method for treating PNPLA3I148M-related disease by normalizing lipolysis, wherein the method comprises administering to a subject in need a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. Use of any compound described in claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the treatment of diseases related to PNPLA3I148M. Use of any compound described in claims 1 to 11 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases related to PNPLA3I148M. The method as described in claims 14 to 15 or the use as described in claims 16 to 17, wherein the PNPLA3I148M-related disease is a liver disease. The method as described in claims 14 to 15 or the use as described in claims 16 to 17, wherein the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASLD). The method as described in claims 14 to 15 or the use as described in claims 16 to 17, wherein the PNPLA3I148M-related disease is non-alcoholic fatty liver disease (NAFLD). The method as described in claims 14 to 15 or the use as described in claims 16 to 17, wherein the PNPLA3I148M-related disease is metabolic disorder-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), cirrhosis with liver fibrosis, or hepatocellular carcinoma (HCC). The method as described in claims 14 to 15 or the use as described in claims 16 to 17, wherein the PNPLA3I148M-related disease is metabolic disorder-associated fatty liver disease (MASH). A method for normalizing fat breakdown, which is carried out by administering to a subject in need a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. A method for normalizing lipolysis by disrupting the PNPLA3I148M-ABHD5 complex, wherein the method comprises administering to a subject in need a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. The compound having formula (I) as described in claim 1, wherein the compound is (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide and has the following structure . The compound described in claim 23 is crystalline (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide. The compound as claimed in claim 24 is characterized in that, when measured with Cu-Kα radiation having a wavelength of 0.15406 nm at a temperature in the range of 20°C to 40°C, the powder X-ray diffraction pattern of the compound includes at least four reflections at a 2θ angle selected from the following groups: (12.36 ± 0.2)°, (16.90 ± 0.2)°, (17.49 ± 0.2)°, (19.21 ± 0.2)°, (20.15 ± 0.2)°, (21.77 ± 0.2)°, (23.01 ± 0.2)°, (23.47 ± 0.2)°, (25.91 ± 0.2)°, and ( 29.88 ± 0.2)°. The compound as claimed in claim 25 is characterized in that, when measured with Cu-Kα radiation having a wavelength of 0.15406 nm at a temperature in the range of 20°C to 40°C, the powder X-ray diffraction pattern of the compound includes reflections at 2θ angles of (16.90 ± 0.2)°, (17.49 ± 0.2)°, (23.01 ± 0.2)°, (25.91 ± 0.2)°, and ( 29.88 ± 0.2)°. The compound described in any of claims 24 to 26 is characterized in that, when measured at a heating rate of 10 °C/min, the differential scan calorimetry curve of the compound includes an endothermic peak with a peak temperature of (176.8 °C ± 0.5) °C. The compound described in any of claims 24 to 27 is characterized in that, when heated from 20°C to 350°C at a rate of 10 °C/min, the thermogravimetric analysis curve of the compound shows a mass loss of no more than 3.56% by weight of the (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide monohydrate. The compound described in any of claims 24 to 28 is (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide monohydrate. The compound described in any of claims 24 to 28 is (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide monohydrate and has the following structure . The compound as described in claim 23, wherein the compound is amorphous (S)-N-(6-(3-(4,4-difluoropyrrolidin-2-yl)-1H-1,2,4-triazol-1-yl)-5-fluoropyridine-3-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)acetamide.