Compounds as GPR183 inhibitors and their use

Abstract

The present invention relates to compounds as GPR183 inhibitors, as well as compositions and their use for the treatment or prevention of cancer, autoimmune diseases, pain, and osteoporosis, using GPR183 inhibitors to target immune cells.

Description

[Technical Field]

[0001] This specification provides novel compounds as GPR183 inhibitors, pharmaceutical compositions using GPR183 inhibitors to target immune cells for the treatment or prevention of cancer, autoimmune diseases, pain, and osteoporosis, and their uses. [Background technology]

[0002] The seven-transmembrane G protein-coupled receptor EBV-inducing gene 2 (EBI2), also known as GPR183, was identified when its expression was found to be highly upregulated in B cells during EBV infection. Following the initial identification of EBI2 expression in B cells, it was revealed that EBI2 is expressed in several hematopoietic cells, including T cells, natural killer cells, monocytes, macrophages, dendritic cells (DCs), neutrophils, eosinophils, platelets, and osteoclasts (in addition to B cells). Furthermore, EBI2 expression has been characterized in astrocytes and in the early stages of development of immune cells, including hematopoietic stem cells and progenitor cells, as well as thymocytes.

[0003] GPR183 ligands were identified as oxysterols resulting from the oxidation of cholesterol. 7α,25-dihydroxycholesterol (7α,25-diHC) exhibits the strongest affinity for GPR183, followed by 7α,27-diHC, while other oxysterols (monohydroxylated oxysterols, 25-HC and 7α-HC) show considerably lower activity. The synthesis of the GPR183 ligand 7α,25-diHC requires two steps: hydroxylation at the 25-position by the cholesterol 25-hydroxylase (CH25H) enzyme and hydroxylation at the 7α-position by cytochrome P450 family 7 subfamily member B1 (CYP7B1). Degradation of 7α,25-diHC is catalyzed by hydroxy-δ-5-steroid dehydrogenase, 3β- and steroid δ-isomerase enzymes.

[0004] When oxysterols bind to GPR183, intracellular calcium release, cAMP suppression, and internal translocation of GPR183 occur. The most important consequence of GPR183 activation is the migration of GPR183-expressing cells toward areas with higher concentrations of 7α,25-diHC. GPR183 contributes to the coordination of cell encounters at various levels by regulating the migration and positioning of DCs, T cells, and B cells. In addition to supporting the migration of lymphocytes and DCs, GPR183 coordinates the migration of innate lymphoid cells (ILCs). GPR183 also contributes to the organization of intestinal lymphoid tissue.

[0005] Genome-wide association studies (GWAS) have linked the GPR183-oxysterol system to inflammatory bowel disease (IBD). Experimental findings demonstrate a crucial role of GPR183 in the inflammation and pathogenesis of colitis, including in anti-CD40 mouse colitis models. Similarly, GPR183 evokes pro-inflammatory effects in IL-10 mouse chronic colitis models. Strong and consistent evidence exists for increased expression of the GPR183 ligand 7α,25-diHC synthase in human samples and different mouse colitis models, with enzyme levels correlating with inflammation severity. Several studies have directly investigated the role of EBI2 in the pathogenesis of autoimmune diseases. One such study demonstrated the role of EBI2 in the recruitment of pathogenic T cells to the CNS in an EAE model, suggesting that EBI2 is a key regulator of autoimmune diseases.

[0006] GPR183-oxysterol also promotes the migration of osteoclast precursors to the bone surface and regulates bone mass homeostasis. This study shows that GPR183 enhances the development of large osteoclasts by promoting osteoclast precursor motility and facilitating intercellular interactions and fusion, both in vitro and in vivo. GPR183 is necessary and sufficient for directing osteoclast precursors (OCPs) toward the bone surface. Deficiency in GPR183 signaling resulted in increased bone mass in male mice and protected female mice from age- and estrogen-deficiency-induced osteoporosis.

[0007] The GPR183-oxysterol system in the spinal cord is also a contributing factor to neuropathic pain. In in silico modeling, a library of 5 million compounds was screened to identify several novel small molecule GPR183 antagonists with nanomolar potency. These compounds were able to antagonistize 7α,25-diHC-induced calcium mobilization in vitro with IC50 values ​​of less than 50 nM. In vivo intrathecal injection of these antagonists during peak pain following chronic compressive nerve injury (CCI) surgery improved allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand 7α,25-diHC in naive mice induced dose-dependent allodynia. Importantly, this effect was blocked with the use of GPR183 antagonists, suggesting that GPR183 activation in the spinal cord is pro-nociceptive. This study aims to clarify the role of GPR183 in neuropathic pain and identify GPR183 as a promising target for therapeutic intervention.

[0008] The GPR183-oxysterol system is also involved in a role in non-alcoholic fatty liver disease. GPR183 is expressed in human hepatoma cell lines, and its expression is induced in vivo in mouse liver after a high-fat diet. Activation of GPR183 inhibits fat accumulation in primary mouse hepatocytes and HepG2 cells via Gi / o protein, p38MAPK, PI3K, and AMPK.

[0009] Francois Gessie et al. isolated a 4m compound, namely (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)-propa-2-en-1-one, and suggested that this compound plays a functional role in the oxysterol / EBI2 pathway in these immune cells (J.Med.Chem.2014,57,3358-3368). However, the 4m compound referenced by Francois Gessie et al. was found to have very poor solubility and poor pharmacokinetics (e.g., poor liver microsome stability, poor hepatocyte stability, poor human plasma stability, poor clearance, shortened half-life, decreased Vss and decreased AUC exposure), increased CYP inhibition, and increased hERG channel inhibition.

[0010] Given the role that GPR183 plays in the pathogenesis of various diseases, it is desirable to prepare compounds that inhibit GPR183 activity for use in the treatment of GPR183-mediated diseases such as cancer, autoimmune diseases, liver diseases, osteoporosis, and neuropathic pain. [Overview of the project] [Means for solving the problem]

[0011] A series of novel compounds as GPR183 inhibitors are provided. The inventors of the present invention have found that modifying the rightmost portion with a hydroxyl group, specifically an alpha-hydroxy group, a heterocyclyloxyalkyl (e.g., heterocyclyloxy-propan-2-yl), an aryloxyalkyl (e.g., aryloxy-propan-2-yl), a heteroaryloxyalkyl (e.g., heteroaryloxy-propan-2-yl), an alkoxyalkyl (e.g., alkoxy-propan-2-yl), a cyanosubstituted alkyl (e.g., cyano-propan-2-yl), or a sulfonate substituted alkyl (e.g., sulfonyl-propan-2-yl), results in improved or equivalent Ca 2+A series of novel compounds can be obtained that exhibit improved mobilization efficacy and pharmacokinetics (such as reduced or eliminated hERG channel inhibition) and / or improved solubility.

[0012] Formula (IA) [ka] A compound or its stereoisomer or a pharmaceutically acceptable salt thereof is provided. During the ceremony, [ka] The part is aromatic, X1 is =CH=, -NH-, or =N-, X2 is =CH=, -NH-, or =N-, X3 is either =CH- or =N-, X4 is either =CH- or =N-, X5 is either =CH or =N-, At least one of X1, X2, X3, X4, and X5 is = N-, m is either 0 or 1. R2, R3, and R4 are, independently of each other, hydrogen, hydroxy, alkyl, alkoxy, alkoxyalkyl (e.g., alkoxy-propan-2-yl), alkoxyalkoxy, heterocyclyloxyalkyl (e.g., heterocyclyloxy-propan-2-yl), aryloxyalkyl (e.g., aryloxy-propan-2-yl), heteroaryloxyalkyl (e.g., heteroaryloxy-propan-2-yl), alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, hydroxysubstituted cycloalkyl, cyanosubstituted alkyl, cyanosubstituted alkoxy, cyanosubstituted heterocyclyl, cyanosubstituted cycloalkyl, sulfosubstituted alkyl, sulfosubstituted alkoxy, sulfosubstituted heterocyclyl, sulfosubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. [ka] teeth, [ka] And a is 0, 1, or 2, b is 1, 2, or 3, and c is 1, 2, or 3. R stands for halogen, C stands for C 1-6 Alkyl, or halo C 1-6 It is an alkyl group, where t is 0, 1, or 2, and alternatively, two R groups attached to the same carbon atom form a spiro ring containing three, four, five, or six carbon atoms. however, If X2 = N-, then R2 does not exist. If X3 is = N-, then R3 does not exist, or If X4 = N-, then R4 does not exist. However, at least one of R2 and R4 is not hydrogen.

[0013] In some embodiments of formula (IA), [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0014] Equation (I) [ka] A compound or its stereoisomer or a pharmaceutically acceptable salt thereof is provided. During the ceremony, [ka] The part is aromatic, X1 is =CH=, -NH-, or =N-, X2 is =CH=, -NH-, or =N-, X3 is either =CH- or =N-, X4 is either =CH- or =N-, X5 is either =CH or =N-, At least one of X1, X2, X3, X4, and X5 is = N-, m is either 0 or 1. R2, R3, and R4 are each independently hydrogen, hydroxy, alkyl, alkoxy, alkoxyalkyl (e.g., alkoxy-propan-2-yl), alkoxyalkoxy, heterocyclyloxyalkyl (e.g., heterocyclyloxy-propan-2-yl), aryloxyalkyl (e.g., aryloxy-propan-2-yl), heteroaryloxyalkyl (e.g., heteroaryloxy-propan-2-yl), alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkynyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, hydroxysubstituted cycloalkyl, cyanosubstituted alkyl, cyanosubstituted alkoxy, cyanosubstituted heterocyclyl, cyanosubstituted cycloalkyl, sulfosubstituted alkyl, alkylsulfosubstituted alkyl, sulfosubstituted alkoxy, sulfosubstituted heterocyclyl, sulfosubstituted cycloalkyl, heterocyclyl, heterocyclyloxy, or di(alkyl)phosphoryl. R stands for halogen, C stands for C 1-6 Alkyl, or halo C 1-6 It is alkyl, t is 0, 1, or 2. however, If X2 = N-, then R2 does not exist. If X3 is = N-, then R3 does not exist, or If X4 = N-, then R4 does not exist. However, at least one of R2 and R4 is not hydrogen.

[0015] In some embodiments (unless otherwise specified, the embodiments discussed below pertain to both formula (IA) and formula (I)), [ka] R2 is 1H-pyrazole-3-yl or 1H-pyrazole-5-yl, where R2 is alkyl or hydroxyalkyl, if present.

[0016] In some embodiments, [ka] is pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl. In some embodiments, [ka] This is pyridine-3-yl, pyridine-4-yl, or pyridine-2-yl. In some embodiments, [ka] This is pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, or pyrimidine-6-yl. In some embodiments, [ka] This is pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, or pyridazine-6-yl. In some embodiments, [ka] These are pyrazine-2-yl, pyrazine-3-yl, pyrazine-5-yl, or pyrazine-6-yl.

[0017] In some embodiments, R2, R3, and R4 are, independently, hydrogen, hydroxy, alkyl, alkoxy, alkoxyalkyl (e.g., alkoxy-propan-2-yl), alkoxyalkoxy, heterocyclyloxyalkyl (e.g., heterocyclyloxy-propan-2-yl), aryloxyalkyl (e.g., aryloxy-propan-2-yl), heteroaryloxyalkyl (e.g., heteroaryloxy-propan-2-yl), alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, hydroxysubstituted cycloalkyl, cyanosubstituted alkyl, cyanosubstituted alkoxy, cyanosubstituted heterocyclyl, cyanosubstituted cycloalkyl, sulfosubstituted alkyl, sulfosubstituted alkoxy, sulfosubstituted heterocyclyl, sulfosubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. In some embodiments, R2 is an alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy, and both R3 and R4 are hydrogen. In some embodiments, R2 is an alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy, and R3 is hydrogen, and R4 is hydrogen, hydroxy, alkyl, or alkoxy. In some embodiments, R2 is an alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy, and R3 is hydrogen, hydroxy, alkyl, or alkoxy, and R4 is hydrogen.In some embodiments, R4 is an alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy, and both R2 and R3 are hydrogen. In some embodiments, R4 is an alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy, and R2 is hydrogen, and R3 is hydrogen, hydroxy, alkyl, alkoxy, or alkoxyalkoxy. In some embodiments, R4 is an alkylsulfonyl, hydroxysubstituted alkyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy, and R2 is hydrogen, hydroxy, alkyl, alkoxy, or alkoxyalkoxy, and R3 is hydrogen. In some embodiments, the heterocyclil is a monocyclic 3- to 6-membered saturated heterocyclil containing one or two heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heterocyclil is a monocyclic 3- to 6-membered saturated heterocyclil containing one oxygen heteroatom. In some embodiments, the heterocyclil is a monocyclic 3- to 6-membered saturated heterocyclil containing one nitrogen heteroatom.

[0018] In some embodiments, R2 is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, and both R3 and R4 are hydrogen. In some embodiments, R2 is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, and R3 is hydrogen, and R4 is hydrogen, hydroxy, alkyl, or alkoxy. In some embodiments, R2 is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, and R3 is hydrogen, hydroxy, alkyl, or alkoxy, and R4 is hydrogen. In some embodiments, R4 is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, and both R2 and R3 are hydrogen. In some embodiments, R4 is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, and R2 is hydrogen, and R3 is hydrogen, hydroxy, alkyl, or alkoxy. In some embodiments, R4 is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, R2 is hydrogen, hydroxy, alkyl, or alkoxy, and R3 is hydrogen. In some embodiments, the hydroxy substituent in the hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, or hydroxysubstituted cycloalkyl is located at the alpha position relative to the linking position.

[0019] In some embodiments, R2 is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropan-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropan-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy, R3 is hydrogen, and R4 is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy. In some embodiments, R2 is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropan-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropan-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy, R4 is hydrogen, and R3 is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy. In some embodiments, R4 is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropan-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropan-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy, R3 is hydrogen, and R2 is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy.In some embodiments, R4 is methylsulfonyl, oxetan-3-yloxy, 2-hydroxypropan-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetan-3-yl, 3-hydroxyazetidin-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropan-2-yl)oxy, 3-hydroxypyrrolidin-1-yl, or 2-hydroxy-2-methylpropoxy, R2 is hydrogen, and R3 is hydrogen, alkoxy, alkyl, alkoxyalkyl, or aryloxyalkoxy.

[0020] In some embodiments, the hydroxy-substituted alkyl is -C(OH)R 2a R 2b wherein R 2a and R 2b are each independently hydrogen or alkyl. In some embodiments, the hydroxy-substituted cycloalkyl is -C(OH)R 2a R 2b wherein R 2a and R 2b together with the carbon atom to which they are attached form a C3-C6 saturated carbocyclic ring. In some embodiments, the hydroxy-substituted heterocyclyl is -C(OH)R 2a R 2b wherein R 2a and R 2b together with the carbon atom to which they are attached form a C3-C6 saturated ring containing one or two heteroatoms selected from oxygen, nitrogen, or sulfur.

[0021] In some embodiments, the cyano-substituted alkyl is -C(CN)R 2a R 2b wherein R 2a and R 2b are each independently hydrogen or alkyl. In some embodiments, the cyano-substituted cycloalkyl is -C(CN)R 2a R 2b wherein R 2a and R2b These, together with the carbon atoms to which they are attached, form a 3- to 6-membered saturated carbon ring. In some embodiments, the cyano-substituted heterocyclyl is -C(CN)R 2a R 2b And in the formula, R 2a and R 2b These, together with the carbon atoms to which they are attached, form a 3- to 6-membered saturated ring containing one or two heteroatoms selected from oxygen, nitrogen, or sulfur.

[0022] In some embodiments, the sulfosubstituted alkyl is -C(SO3H)R 2a R 2b And in the formula, R 2a and R 2b Each is independently hydrogen or alkyl. In some embodiments, the sulfosubstituted cycloalkyl is -C(SO3H)R 2a R 2b And in the formula, R 2a and R 2b These, together with the carbon atoms to which they are attached, form a 3- to 6-membered saturated carbon ring. In some embodiments, the sulfosubstituted heterocyclyl is -C(SO3H)R 2a R 2b And in the formula, R 2a and R 2b These, together with the carbon atoms to which they are attached, form a 3- to 6-membered saturated ring containing one or two heteroatoms selected from oxygen, nitrogen, or sulfur.

[0023] In some embodiments, [ka] teeth, [ka] In the formula, X1, X2, X3, X4, X5, R2, R3, and R4 are defined as shown in formula (I).

[0024] In some embodiments, [ka] These are 5-(methylsulfonyl)pyridine-3-yl, 4-(2-(oxetane-3-yloxy)pyridine-4-yl, 6-(2-hydroxypropan-2-yl)pyridine-2-yl, 4-(2-hydroxypropan-2-yl)pyridine-2-yl, 5-(2-hydroxypropan-2-yl)pyridine-3-yl, 2-(2-hydroxypropan-2-yl)pyridine-4-yl, 2-(1-hydroxycyclobutyl)pyridine-4-yl, 6-( 2-Hydroxypropan-2-yl)pyridine-3-yl, 2-(1-Hydroxycyclopropyl)pyridine-4-yl, 5-(1-Hydroxycyclopropyl)pyridine-3-yl, 5-(1-Hydroxycyclobutyl)pyridine-3-yl, 4-(1-Hydroxycyclopropyl)pyridine-2-yl, 4-(1-Hydroxycyclobutyl)pyridine-2-yl, 2-(2-Hydroxypropoxy)pyridine-4-yl, 2-(2-Hydroxypropoxy Xy)pyridine-4-yl, 6-(2-hydroxypropan-2-yl)-5-methoxypyridine-2-yl, 5-(2-hydroxypropan-2-yl)-6-methoxypyridine-3-yl, 6-(2-hydroxypropan-2-yl)-4-methoxypyridine-2-yl, 2-(2-hydroxypropan-2-yl)-6-methoxypyridine-4-yl, 4-(2-hydroxypropan-2-yl)-6-methoxypyridine-2-yl, 2-(1-Sy) These are anocyclopropyl)pyridine-4-yl, 2-(oxetan-3-yl)pyridine-4-yl, 2-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-4-yl, 2-(1-hydroxyethyl)pyridine-4-yl, 5-(dimethylphosphoryl)pyridine-3-yl, 6-(hydroxymethyl)pyridine-2-yl, or 6-(2-(methylsulfonyl)propane-2-yl)pyridine-2-yl. In some embodiments, [ka] These are 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-yl, 2-morpholinopyrimidine-4-yl, 2-(2-methoxyethoxy)pyrimidine-4-yl, 2-(2-hydroxypropoxy)pyrimidine-4-yl, 2-(2-hydroxy-2-methylpropoxy)pyrimidine-4-yl, 6-(2-hydroxypropoxy)pyrimidine-4-yl, 6-((1-hydroxypropan-2-yl)oxy)pyrimidine-4-yl, 6-(2-hydroxy-2-methylpropoxy)pyrimidine-4-yl, 2-(2-hydroxypropan-2-yl)pyrimidine-4-yl, 6-(2-hydroxypropan-2-yl)pyrimidine-4-yl, 2-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-4-yl These are 2-(3-hydroxypyrrolidine-1-yl)pyrimidine-5-yl, 2-(2-methoxyethoxy)pyrimidine-5-yl, 6-(1-hydroxycyclopropyl)pyrimidine-4-yl, 6-(1-hydroxycyclobutyl)pyrimidine-4-yl, 4-(2-hydroxy-2-methylpropoxy)pyrimidine-2-yl, 4-(2-hydroxypropoxy)pyrimidine-2-yl, 4-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-2-yl, 4-((1-hydroxypropan-2-yl)oxy)pyrimidine-2-yl, 6-((3-hydroxybutan-2-yl)oxy)pyrimidine-4-yl, or 6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyrimidine-4-yl. In some embodiments, [ka] These are 6-(2-hydroxypropan-2-yl)pyridazin-4-yl, 6-(1-hydroxycyclopropyl)pyridazin-4-yl, 6-(1-hydroxycyclobutyl)pyridazin-4-yl, 5-(2-hydroxypropan-2-yl)-6-methoxypyridazin-3-yl, or 6-(2-hydroxypropan-2-yl)pyrazine-2-yl.

[0025] In some embodiments, the compound is selected from the following: [Table 1-1]

[0026] [Table 1-2]

[0027] [Table 1-3]

[0028] [Table 1-4]

[0029] [Table 1-5]

[0030] [Table 1-6]

[0031] [Table 1-7]

[0032] [Table 1-8]

[0033] [Table 1-9]

[0034] In some embodiments, the compound is selected from the following: (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(9), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxy-2-methylpropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(11), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(12), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-((1-hydroxypropan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(13), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxy-2-methylpropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(14), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(15), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(16), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(17), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(18), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(2-hydroxypropan-2-yl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(19), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrazine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(20), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(21), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(22), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(23), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclobutyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(24), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(25), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxypyrrolidine-1-yl)pyrimidine-5-carbonyl)piperazine-1-yl)propa-2-en-1-one(26), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclopropyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(28), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclopropyl)pyridazin-4-carbonyl)piperazin-1-yl)propa-2-en-1-one(29), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclobutyl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(30), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclopropyl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(31), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclobutyl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(32), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(1-hydroxycyclopropyl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(33), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(1-hydroxycyclobutyl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(34), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(1-hydroxycyclopropyl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(35), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(1-hydroxycyclobutyl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(36), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxy-2-methylpropoxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(37), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(38), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(39), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(40), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(41), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(42), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(43), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropoxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(44), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropoxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(45), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)-5-methoxypicolinoyl)piperazine-1-yl)propa-2-en-1-one(46), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-6-methoxynicotinoyl)piperazine-1-yl)propa-2-en-1-one(47), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-6-methoxypyridazine-3-carbonyl)piperazine-1-yl)propa-2-en-1-one(48), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)-4-methoxypicolinoyl)piperazine-1-yl)propa-2-en-1-one(49), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)-6-methoxyisonicotinoyl)piperazine-1-yl)propa-2-en-1-one(50), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropan-2-yl)-6-methoxypicolinoyl)piperazine-1-yl)propa-2-en-1-one(51), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(52), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-((1-hydroxypropan-2-yl)oxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(55), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-((1-hydroxypropan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(56), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-((1-hydroxypropan-2-yl)oxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(57), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(((2R,3S)-3-hydroxybutan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(58), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(((2S)-3-hydroxybutan-2-yl)oxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(59), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(((2S,3R)-3-hydroxybutan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(60), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxy-3-methylbuta-1-in-1-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(61), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(62), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxyethyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(63), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(hydroxymethyl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(65), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-(methylsulfonyl)propan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(67), (E)-3-(4-bromophenyl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(68), (E)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)-3-(4-(trifluoromethoxy)phenyl)propa-2-en-1-one(69), (E)-3-(4-fluorophenyl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(70), or (E)-3-(2,4-dichlorophenyl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(71).

[0035] A pharmaceutical composition is provided comprising, optionally, a compound disclosed herein or its stereoisomer or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable pharmaceutical additive.

[0036] A method is provided for treating diseases mediated by GPR183, the method comprising administering the compounds disclosed herein or their stereoisomers or pharmaceutically acceptable salts thereof to a subject in need thereof. In some embodiments, the diseases mediated by GPR183 are cancer, autoimmune diseases, liver diseases, osteoporosis, and neuropathic pain. In one embodiment, the cancer is hematological cancer, brain cancer, breast cancer, colorectal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, or uterine cancer. In some embodiments, the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G protein-coupled receptor 2 (EBI2)-mediated signaling. [Modes for carrying out the invention]

[0037] The following terms have the meanings set forth throughout this specification. Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains.

[0038] The following terms have the meanings set forth throughout this specification. As used herein, including in the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless otherwise clearly indicated in the context.

[0039] The term "or" is used to mean "and / or" unless otherwise explicitly indicated in the context, and is used interchangeably with the term "and / or".

[0040] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (such as 1 to 12, or even 1 to 10, or even 1 to 8, or 1 to 6, or 1 to 4, etc.). 1-6 Examples of alkyl groups include, but are not limited to, methyl groups, ethyl groups, 1-propyl groups or n-propyl ("n-Pr") groups, 2-propyl groups or isopropyl ("i-Pr") groups, 1-butyl groups or n-butyl ("n-Bu") groups, 2-methyl-1-propyl groups or isobutyl ("i-Bu") groups, 1-methylpropyl groups or s-butyl ("s-Bu") groups, 1,1-dimethylethyl groups or t-butyl ("t-Bu") groups, and 1-pentyl groups. Examples include 2-pentyl group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 3-methyl-1-butyl group, 2-methyl-1-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 3-methyl-3-pentyl group, 2-methyl-3-pentyl group, 2,3-dimethyl-2-butyl group, and 3,3-dimethyl-2-butyl group.

[0041] The term "halogen" includes fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0042] The term "haloalkyl" includes alkyl groups in which one or more hydrogen atoms are substituted by one or more halogen atoms (such as fluoro, chloro, bromo, and iodine). An example of a haloalkyl is halo C 1-8 Alkyl, Halo C 1-6 Alkyl, or halo C 1-4 Alkyl compounds are examples, including, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, and similar compounds.

[0043] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, such as condensed cycloalkyl, cross-linked cycloalkyl, or spirocycloalkyl.

[0044] For example, a cycloalkyl group may contain 3 to 12 carbon atoms (e.g., 3 to 10, 3 to 8, 3 to 6, 3 to 5, or 3 to 4). Furthermore, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms (e.g., 3 to 10, 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Specifically, saturated monocyclic cycloalkyl groups (e.g., C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, the cycloalkyl group is a monocyclic ring (C) containing 3 to 6 carbon atoms. 3-6Bicyclic cycloalkyl groups (abbreviated as cycloalkyl) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as fused bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems.

[0045] "Heterocyclyl," "heterocycle," or "heterocyclic formula" are interchangeable and include non-aromatic heterocyclyl groups, which contain one or more (e.g., 1 to 3) heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic rings, fused rings, bridging rings, and spirocycles (i.e., monocyclic heterocyclyl groups, bridging heterocyclyl groups, spiroheterocyclyl groups, and fused heterocyclic groups).

[0046] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0047] Examples of monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino Morpholin-2-yl, Morpholin-3-yl, Oxyranil, Aziridin-1-yl, Aziridin-2-yl, Azocan-1-yl, Azocan-2-yl, Azocan-3-yl, Azocan-4-yl, Azocan-5-yl, Thiiranil, Azetidine-1-yl, Azetidine-2-yl, Azetidine-3-yl, Oxetanil, Thietanil, 1,2-Dithietanil, 1,3-Dithietanil, Dihydropyridinyl, Tetrahydropyridinyl, Thiomorpholinil, Thioxanil Piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepanil, 1,4-thiazepanil and 1,4-diazepanil, 1,4-dithianil, 1,4-azathanil, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiepanil This includes dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, or 1,1-dioxo-thiomorpholinyl.

[0048] The term "stereoisomer" refers to all isomers of an individual compound that differ only in the orientation of their atoms in space. The term stereoisomer includes enantiomers, racemates (mixtures of enantiomers), geometric isomers (cis / trans or syn / anti or E / Z), and diastereoisomers (isomers of compounds that have one or more chiral centers that are not mirror images of each other).

[0049] The compounds disclosed herein may contain chiral centers and therefore may exist as enantiomers. “Enantiomer” refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. If a compound disclosed herein has more than two chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, as substantially pure, divided enantiomers, their racemic mixtures, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specifically mentioned, a reference to one isomer applies to any of the possible isomers. Whenever an isomer composition is not specified, all possible isomers are included.

[0050] Where a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such a double bond is intended to include both E and Z geometric isomers.

[0051] Where a compound disclosed herein includes a disubstituted cyclic ring system, substituents on such a ring system can be in cis or trans configurations. A cis configuration means that both substituents are located on the upper side of the carbon atom, while a trans configuration means they are located on opposite sides. For example, a disubstituted cyclic ring system may be a cyclohexyl ring or a cyclobutyl ring.

[0052] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products from each step or series of steps are separated and / or purified (hereafter, separated) to the desired degree of homogeneity by methods common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example, reversed-phase and normal-phase, size exclusion, ion exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analysis, pseudo-moving bed ("SMB") and preparative thin-layer or preparative thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art can select and apply the method that is most likely to achieve the desired separation.

[0053] A "diastereomer" refers to a stereoisomer of a compound that has two or more chiral centers but is not a mirror image of one another. A mixture of diastereomers can be separated into its individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art (such as by chromatography and / or fractional crystallization). Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscheric acid chloride), separating the diastereomers, and converting the individual diastereoisomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0054] A single stereoisomer (e.g., a substantially pure enantiomer) may be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer using an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. “Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): pp.283-302). The racemic mixture of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of an ionic diastereomer salt with the chiral compound and separation by fractional crystallization or other methods; (2) the formation of a diastereomer compound with a chiral derivatizing reagent, separation of the diastereomer, and conversion to a pure stereoisomer; and (3) the direct separation of a substantially pure or enriched stereoisomer under chiral conditions. See Wainer, Irving W., Ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0055] A "pharmaceutically acceptable salt" means a salt that is suitable, within the bounds of sound medical judgment, for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, and the like, and that is commensurate with a reasonable benefit / risk ratio. A pharmaceutically acceptable salt may be prepared in insights during the final isolation and purification of the compounds disclosed herein, or it may be prepared separately by reacting a free basic functional group with a suitable organic acid or an acidic group with a suitable base.

[0056] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0057] As defined herein, “a pharmaceutically acceptable salt” includes salts of at least one compound of formula (I) and salts of stereoisomers of the compound of formula (I) (e.g., salts of enantiomers and / or salts of diastereomers).

[0058] In this specification, the terms “administer,” “administer,” “treat,” and “therapeutic” mean, when applied to animals, humans, subjects, cells, tissues, organs, or biological fluids, the contact of an exogenous pharmaceutically, therapeutic, or diagnostic agent or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Cell therapy includes contact of the reagent with the cell and contact of the reagent with the body fluid (if the body fluid is in contact with the cell). The terms “administer” and “therapeutic” also mean in vitro and ex vivo treatment, for example, in vitro and ex vivo treatment of cells, in vitro and ex vivo treatment with reagents, diagnostic agents, conjugates, or in vitro and ex vivo treatment with another cell. In this specification, the term “subject” includes any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0059] The terms “effective dose” or “therapeutically effective dose” refer to the amount of an active ingredient (such as a compound) sufficient to have an effect on such treatment of a disease, disorder, or symptom when administered to a subject to treat at least one of the clinical symptoms of the disease, disorder, or disorder. The term “therapeutically effective dose” may vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the symptoms of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. An appropriate dose in any given example may be obvious to those skilled in the art or may be determined by routine experimentation. In some embodiments, “therapeutically effective dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, that is effective in “treating” the disease or disorder in a subject as defined herein. In the case of combination therapy, the term “therapeutically effective dose” refers to the total amount of the combination subject for effective treatment of the disease, disorder, or condition.

[0060] The term “disease” refers to any illness, discomfort, disease, symptom, or sign, and is interchangeable with the terms “disorder” or “condition.”

[0061] Throughout this specification and the subsequent claims, unless contextually required, the term “comprise,” and variations such as “comprises” and “comprising,” are intended to identify the presence of the features described therein, but not to exclude the presence or addition of one or more other features. As used herein, the term “comprising” may be replaced by the terms “containing,” “including,” or, in some cases, “having.”

[0062] Throughout this specification and subsequent claims, "C n-mThe term "range" indicates a range that includes the endpoint, where n and m are integers representing the number of carbon atoms. For example, C 1-8 , C 1-6 Examples include, and similar examples.

[0063] Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains. [Examples]

[0064] Abbreviation [Table 2]

[0065] intermediate Synthesis of common intermediate C4 [ka]

[0066] Step 1: (2E)-3-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)propane-2-enoic acid (C2) To a solution of propanedioic acid (308 mg, 2.96 mmol) in pyridine (15 mL), piperidine (0.3 mL) and 2,2-difluoro-2H-1,3-benzodioxol-5-carbaldehyde (500 mg, 2.69 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and concentrated HCl (10 mL) was added. The mixture was filtered. The cake was collected and dried under vacuum to obtain the subtitle compound (609 mg, 2.67 mmol, 99.4%) as a white solid. LC-MS (ESI): m / z 227.0 [MH] - .

[0067] Step 2: tert-butyl 4-[(2E)-3-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)prop-2-enoyl]piperazine-1-carboxylate (C3) To a solution of (2E)-3-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)propa-2-enoic acid (C2) (300 mg, 1.32 mmol) in DCM (10 mL), DIEA (0.7 mL, 4.47 mmol), HATU (750 mg, 1.97 mmol), and tert-butylpiperazine-1-carboxylate (304 mg, 1.63 mmol) were added. The reaction mixture was then stirred in RT for 3 hours. The mixture was diluted with H2O (50 mL), and the resulting mixture was extracted with DCM (50 mL x 2). The organic layer was combined, washed with brine (100 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 20 to 1 / 1) to obtain the subtitle compound (174 mg, 0.44 mmol, Y = 40.1%) as a yellow solid. LC-MS (ESI): m / z 341.1 [M-56+H] + .

[0068] Step 3: (2E)-3-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-1-(piperazine-1-yl)propa-2-en-1-one hydrochloride (C4) A solution of tert-butyl 4-[(2E)-3-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)prop-2-enoyl]piperazine-1-carboxylate (C3) (174 mg, 0.44 mmol) in 4 M HCl / dioxane (8 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain the crude secondary compound (158 mg, 0.47 mmol, 108.2%) as a white solid. The product was used in the next step without further purification. LC-MS (ESI): m / z 297.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) 9.64 (2H, br s), 7.96 (1H, d, 1.43), 7.57 (1H, m), 7.53 (1H, m), 7.45 (1H, d, J = 8.29 Hz), 7.31 (1H, d, J = 15.35 Hz), 3.98 (2H, s), 3.80 (2H, s), 3.11 (4H, br s).

[0069] Example 1 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(methylsulfonyl)nicotinoyl)piperazin-1-yl)propa-2-en-1-one(1) [ka]

[0070] Step 1. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(methylsulfonyl)nicotinoyl)piperazin-1-yl)propa-2-en-1-one(1) To a solution of 5-(methylsulfonyl)nicotinic acid (32.6 mg, 0.16 mmol) in DMF (1 mL), HATU (61.6 mg, 0.16 mmol), DIEA (52.4 mg, 0.41 mmol), and (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one hydrochloride (40.0 mg, 0.14 mmol) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed that the starting materials were completely consumed. The residue was purified by preparative HPLC (TFA conditions) to obtain the desired compound (60.0 mg, 0.13 mmol, 92.7%). LC-MS (ESI): m / z 480.1[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 2.2 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.54 (d, J = 15.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.41-7.20 (m, 1H), 3.95-3.58 (m, 8H), 3.40 (s, 3H).

[0071] The following compounds were synthesized by following the same procedure as described in Example 1. [Table 3]

[0072] Example 2 (E)-1-(4-(2-(1H-pyrazole-5-yl)pyrimidine-4-carbonyl)piperazine-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one(5) [ka]

[0073] Step 1. Methyl 2-(1H-pyrazole-5-yl)pyrimidine-4-carboxylate A mixture of methyl 2-chloropyrimidine-4-carboxylate (100 mg, 0.58 mmol), (1H-pyrazole-5-yl)boronic acid (77.8 mg, 0.70 mmol), K2CO3 (240 mg, 1.74 mmol), and tetrakis(triphenylphosphine)palladium (134 mg, 0.12 mmol) in DMF (4.0 mL) was degassed, purged three times with N2, and then stirred at 150°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was quenched by adding 10 mL of H2O at 25°C, diluted with 10 mL of EA, and extracted with 20 mL of EA (10 mL x 2). The integrated organic layer was washed with 20 mL of aqueous NaCl solution (10 mL x 2), dehydrated with MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (gradient with 0-50% ethyl acetate / petroleum ether eluent (30 mL / min)). Methyl 2-(1H-pyrazole-5-yl)pyrimidine-4-carboxylate (90.0 mg, 0.44 mmol, 76.1%) was obtained as a yellow oil.

[0074] Step 2.2-(1H-pyrazole-5-yl)pyrimidine-4-carboxylic acid To a solution of methyl 2-(1H-pyrazole-5-yl)pyrimidine-4-carboxylate (80.0 mg, 0.39 mmol) in THF (1.0 mL) and H2O (0.5 mL), LiOH (16.4 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched at 25°C by adding 10 mL of aqueous NH4Cl, then diluted with 10 mL of EA, and extracted with 20 mL of EA (10 mL x 2). The integrated organic layer was washed with 20 mL of aqueous NaCl (10 mL x 2), filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (gradient with 0-50% ethyl acetate / petroleum ether eluent (30 mL / min)). 2-(1H-pyrazole-5-yl)pyrimidine-4-carboxylic acid (40.0 mg, 0.21 mmol, 47.1%) was obtained as a colorless oil.

[0075] Step 3. (E)-1-(4-(2-(1H-pyrazole-5-yl)pyrimidine-4-carbonyl)piperazine-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one A mixture of (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one hydrochloride (30.0 mg, 0.09 mmol), 2-(1H-pyrazole-5-yl)pyrimidine-4-carboxylic acid (17.2 mg, 0.09 mmol), HATU (41.1 mg, 0.11 mmol), and DIEA (35.0 mg, 0.27 mmol) in DMF (0.5 mL) was degassed, purged three times with N2, and then stirred at room temperature under an N2 atmosphere for 1 hour. The residue was purified by preparative HPLC to obtain (E)-1-(4-(2-(1H-pyrazole-5-yl)pyrimidine-4-carbonyl)piperazin-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one (20.0 mg, 0.04 mmol, 47.4%). LC-MS (ESI): m / z 469.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.9 Hz, 1H), 7.95 (d, J = 22.8 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.64-7.42 (m, 4H), 7.32 (dd, J = 32.2, 15.2 Hz, 1H), 6.99 (d, J = 1.5 Hz, 1H), 3.90-3.47 (m, 8H).

[0076] Example 3 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(6) [ka]

[0077] Step 1. Methyl 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carboxylate To a solution of methyl 2-chloropyrimidine-4-carboxylate (200 mg, 1.16 mmol) in DMF (3.0 mL), K2CO3 (320 mg, 2.32 mmol) and azetidine-3-ol (110 mg, 1.51 mmol) were added. The mixture was stirred at 60°C for 12 hours. LC-MS showed that the starting materials were completely consumed. H2O (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (5 mL x 3), dehydrated with anhydrous Na2SO4, and concentrated under vacuum to obtain the residue methyl 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carboxylate (60.0 mg, 0.29 mmol, 24.7%). LC-MS (ESI): m / z 210.1 ([M+H] + ).

[0078] Step 2. 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carboxylic acid LiOH (36.1 mg, 0.86 mmol) was added to a solution of methyl 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carboxylate (60.0 mg, 0.29 mmol) in MeOH (2.0 mL) and H2O (0.5 mL). The mixture was stirred at 25°C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction solution was adjusted to pH=6 with 2N HCl. The reaction solution was concentrated. The residue was purified by preparative HPLC (TFA conditions) to obtain the desired compound, 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carboxylic acid (45.0 mg, 0.23 mmol, 80.4%). LC-MS (ESI): m / z 196.1 ([M+H] + ).

[0079] Step 3. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(6) To a solution of 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carboxylic acid (44.0 mg, 0.23 mmol) in DMF (2.0 mL), EDCI (64.7 mg, 0.34 mmol), HOBt (45.6 mg, 0.34 mmol), and (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (66.7 mg, 0.23 mmol) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed that the starting materials were completely consumed. The residue was purified by preparative HPLC (FA conditions) to obtain the desired compound (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carbonyl)piperazin-1-yl)propa-2-en-1-one (36.0 mg, 0.08 mmol, 33.8%). LC-MS (ESI): m / z 474.1 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.9 Hz, 1H), 7.94 (d, J = 20.9 Hz, 1H), 7.62-7.42 (m, 3H), 7.30 (dd, J = 31.8, 15.5 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 5.73 (d, J = 6.3 Hz, 1H), 4.65-4.52 (m, 1H), 4.26 (dd, J = 9.4, 6.6 Hz, 2H), 3.91-3.54 (m, 8H), 3.45 (d, J = 18.2 Hz, 2H).

[0080] The following compounds were synthesized by following the same procedure as described in Example 3. [Table 4]

[0081] Example 4 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-methoxyethoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(8) [ka]

[0082] Step 1. Methyl 2-[(2-methoxyethyl)oxy]pyrimidine-4-carboxylate To a stirred solution of 2-methoxyethane-1-ol (52.9 mg, 0.70 mmol) in THF (5.0 mL), NaH (34.8 mg, 0.87 mmol) was added. The mixture was then stirred at 25°C for 30 minutes, after which methyl 2-chloropyrimidine-4-carboxylate (100 mg, 0.58 mmol) was added. The mixture was stirred at 25°C for a further 2 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with RINKAN (100 mL). The combined organic layer was dehydrated with Na2SO4 and concentrated under vacuum. The crude product residue was combined with a batch of crude product obtained from a second reaction carried out on the same scale and purified by column chromatography using silica (100-200 mesh) and a solvent system of siRNA:hexane (1:1) to obtain methyl 2-[(2-methoxyethyl)oxy]pyrimidine-4-carboxylate (122.9 mg, yield 100.0%) as a yellow liquid. LC-MS (ESI): m / z 213.1 [M+H] +

[0083] Step 2.2 - [(2-methoxyethyl)oxy]pyrimidine-4-carboxylic acid To a solution of methyl 2-[(2-methoxyethyl)oxy]pyrimidine-4-carboxylate (122 mg, 0.58 mmol) in THF (2.0 mL) / H2O (2.0 mL), LiOH (72.4 mg, 1.73 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (FA conditions) to obtain the title compound 2-[(2-methoxyethyl)oxy]pyrimidine-4-carboxylic acid (113.00 mg, yield 100.0%) as a white solid. LC-MS (ESI): m / z 199.1 [M+H] +

[0084] Step 3. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-methoxyethoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one To a solution of 2-[(2-methoxyethyl)oxy]pyrimidine-4-carboxylic acid (30.0 mg, 0.10 mmol) in DMF (2.0 mL), (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (30.1 mg, 0.15 mmol), DIEA (65.4 mg, 0.51 mmol), and HATU (57.8 mg, 0.15 mmol) were added. The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (FA conditions) to obtain the title compound (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-methoxyethoxy)pyrimidine-4-carbonyl)piperazin-1-yl)propa-2-en-1-one (23.4 mg, yield 48.5%, purity 99.9%). LC-MS (ESI): m / z 477.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J = 4.9, 3.3 Hz, 1H), 7.94 (d, J = 21.2 Hz, 1H), 7.61-7.42 (m, 3H), 7.36-7.24 (m, 2H), 4.46-4.43 (m, 1H), 3.95-3.42 (m, 14H).

[0085] The following compounds were synthesized by following the same procedure as described in Example 4. [Table 5-1]

[0086] [Table 5-2]

[0087] [Table 5-3]

[0088] [Table 5-4]

[0089] [Table 5-5]

[0090] Example 5 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(15) [ka]

[0091] Step 1. Methyl 6-(1-ethoxyvinyl)-1,2-diazine-4-carboxylate Dioxane (20 mL) containing methyl 6-chloro-1,2-diazine-4-carboxylate (2000 mg, 11.6 mmol), bis(triphenylphosphine)palladium(II) chloride (813 mg, 1.16 mmol), and tri-n-butyl(1-ethoxyvinyl)tin (4604 mg, 12.7 mmol) was degassed and then heated at 90°C for 12 hours under N2. LC-MS showed that the starting materials were completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain methyl 6-(1-ethoxyvinyl)-1,2-diazine-4-carboxylate (2400 mg, 11.5 mmol, 99.5%). LC-MS (ESI): m / z 208.1 [M+H] + .

[0092] Step 2. Methyl 6-acetyl-1,2-diazine-4-carboxylate Methyl 6-(1-ethoxyvinyl)-1,2-diazine-4-carboxylate (1600 mg, 7.68 mmol) was added to a 20 mL solution of HCl / dioxane (4 M). The mixture was stirred at 25°C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain methyl 6-acetyl-1,2-diazine-4-carboxylate (1200 mg, 6.66 mmol, 86.7%). LC-MS (ESI): m / z 181.1 [M+H] + .

[0093] Step 3. 6-Acetyl-1,2-diazine-4-carboxylic acid LiOH (532 mg, 22.2 mmol) was added to a solution of methyl 6-acetyl-1,2-diazine-4-carboxylate (1000 mg, 5.55 mmol) in MeOH (7.5 mL) and H2O (2.5 mL). The mixture was stirred at 25°C for 12 hours. LC-MS showed that the starting material was completely consumed. The reaction solution was acidified with 2 M HCl to pH = 3-4, and the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions) to obtain the desired compound, 6-acetyl-1,2-diazine-4-carboxylic acid (330 mg, 1.99 mmol, 35.8%). LC-MS (ESI): m / z 167.1 [M+H] + .

[0094] Step 4. (E)-1-(4-(6-acetylpyridazine-4-carbonyl)piperazine-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one To a solution of 6-acetyl-1,2-diazine-4-carboxylic acid (330 mg, 1.986 mmol) in DMF (5 mL), EDCI (457 mg, 2.38 mmol), HOBt (322 mg, 2.38 mmol), and (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (588 mg, 1.99 mmol) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed that the starting materials were completely consumed. The residue was purified by preparative HPLC (FA conditions) to obtain the desired compound (E)-1-(4-(6-acetylpyridazine-4-carbonyl)piperazin-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one (600 mg, 1.35 mmol, 68.0%). LC-MS (ESI): m / z 445.1 [M+H] + .

[0095] Step 5. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(15) To a solution of (2E)-1-{4-[(6-acetyl-1,2-diazine-4-yl)carbonyl]piperazin-1-yl}-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one (570 mg, 1.28 mmol) in THF (5.0 mL), CH3MgBr (1.4 mL) was added at -40°C. The mixture was stirred at -40°C for 1 hour. LC-MS showed that the starting material was completely consumed. The reaction mixture was quenched by the addition of saturated ammonium chloride. The residue was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions) to obtain the desired compound (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(15) (118 mg, 0.26 mmol, 20.0%). LC-MS (ESI): m / z 461.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 25.6 Hz, 2H), 7.64-7.41 (m, 3H), 7.30 (dd, J = 36.6, 15.6 Hz, 1H), 5.60 (s, 1H), 4.12-3.45 (m, 8H), 1.57 (s, 6H).

[0096] The following compounds were synthesized by following the same procedure as described in Example 5. [Table 6]

[0097] Example 6 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(17) [ka]

[0098] Step 1. Methyl 6-(1-ethoxyvinyl)pyridine-2-carboxylate DMF (10 mL) containing methyl 6-chloropyridine-2-carboxylate (1000 mg, 5.83 mmol), bis(triphenylphosphine)palladium(II) chloride (409 mg, 0.58 mmol), and tri-n-butyl(1-ethoxyvinyl)tin (2315 mg, 6.41 mmol) was degassed and heated under N2 at 90°C for 12 hours. LC-MS showed that the starting materials were completely consumed. The reaction mixture was poured into H2O (10 mL). The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (10 mL x 3), dehydrated with anhydrous Na2SO4, and concentrated under vacuum to obtain the residue methyl 6-(1-ethoxyvinyl)pyridine-2-carboxylate (1000 mg, 4.83 mmol, 82.8%). LC-MS (ESI): m / z 208.1 [M+H] + .

[0099] Step 2. Methyl 6-acetylpyridine-2-carboxylate Methyl 6-(1-ethoxyvinyl)pyridine-2-carboxylate (600 mg, 2.90 mmol) was added to a 10 mL solution of HCl / dioxane. The mixture was stirred at 25°C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate = 1:1 to obtain methyl 6-acetylpyridine-2-carboxylate (400 mg, 2.23 mmol, 77.1%). LC-MS (ESI): m / z 180.1 [M+H] + .

[0100] Step 3. Methyl 6-(2-hydroxypropane-2-yl)pyridine-2-carboxylate To a solution of methyl 6-acetylpyridine-2-carboxylate (100 mg, 0.56 mmol) in THF (2.0 mL), CH3MgBr (1 M in THF) (0.6 mL) was added at -30°C. The mixture was stirred at 0°C for 30 minutes. LC-MS showed that the starting material was completely consumed. The reaction mixture was quenched by the addition of saturated ammonium chloride and extracted with EA (10 mL × 2). The integrated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue methyl 6-(2-hydroxypropa-2-yl)pyridine-2-carboxylate (100 mg, 0.51 mmol, 91.8%). LC-MS (ESI): m / z 196.1 [M+H] + .

[0101] Step 4. 6-(2-hydroxypropa-2-yl)pyridine-2-carboxylic acid To a solution of methyl 6-(2-hydroxypropa-2-yl)pyridine-2-carboxylate (100 mg, 0.51 mmol) in MeOH (2.0 mL) and H2O (0.5 mL), LiOH (64.5 mg, 1.54 mmol) was added. The mixture was stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed. The reaction solution was acidified with 2 M HCl to pH=3-4, and the reaction mixture was concentrated under reduced pressure to obtain the residue 6-(2-hydroxypropa-2-yl)pyridine-2-carboxylic acid (90.0 mg, 0.50 mmol, 97.0%). LC-MS (ESI): m / z 182.1 [M+H] + .

[0102] Step 5. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(17) To a solution of 6-(2-hydroxypropa-2-yl)pyridine-2-carboxylic acid (12.0 mg, 0.07 mmol) in DMF (1 mL), EDCI (15.2 mg, 0.08 mmol), HOBt (10.7 mg, 0.08 mmol), and (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (19.62 mg, 0.066 mmol) were added. The mixture was stirred at 25°C for 2 hours. LC-MS showed that the starting materials were completely consumed. The residue was purified by preparative HPLC (FA conditions) to obtain the desired compound (17) (14.0 mg, 0.03 mmol, 46.0%). LC-MS (ESI): m / z 460.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (q, J = 8.3, 7.8 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.67-7.41 (m, 4H), 7.31 (dd, J = 27.0, 15.2 Hz, 1H), 5.33 (s, 1H), 3.96-3.47 (m, 8H), 1.46 (s, 6H).

[0103] The following compounds were synthesized by following the same procedure as described in Example 6. [Table 7]

[0104] Example 7 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(21) [ka]

[0105] Step 1. Methyl 2-(2-hydroxypropane-2-yl)pyridine-4-carboxylate Under an N2 atmosphere, methyl 2-acetylpyridine-4-carboxylate (500 mg, 2.79 mmol) was incorporated into anhydrous THF (10 mL), cooled to 0°C, and then methylmagnesium bromide (3.1 mL, 3.07 mmol) was gradually added. The reaction mixture was stirred under an N2 atmosphere at 0°C for 4 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with siRNA (100 mL). The combined organic layer was dehydrated with Na2SO4 and concentrated under vacuum. The crude product residue was combined with a batch of crude product obtained from a second reaction carried out on the same scale and purified by column chromatography using silica (100-200 mesh) and a solvent system of siRNA:hexane (1:1) to obtain methyl 2-(2-hydroxypropa-2-yl)pyridine-4-carboxylate (218 mg, yield 40.0%) as a yellow liquid. LC-MS (ESI): m / z 196.1 [M+H] + .

[0106] Step 2. 2-(2-hydroxypropa-2-yl)pyridine-4-carboxylic acid A solution of methyl 2-(2-hydroxypropa-2-yl)pyridine-4-carboxylate (100 mg, 0.51 mmol) in THF (2.0 mL) / H2O (2.0 mL) was mixed with LiOH (43.0 mg, 1.02 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (FA conditions) to obtain the title compound 2-(2-hydroxypropa-2-yl)pyridine-4-carboxylic acid (93.00 mg, yield 100.0%) as a white solid. LC-MS (ESI): m / z 182.1 [M+H] +

[0107] Step 3. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(21) To a solution of 2-(2-hydroxypropa-2-yl)pyridine-4-carboxylic acid (30.0 mg, 0.10 mmol) in DMF (2.0 mL), (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (18.4 mg, 0.10 mmol), DIEA (25.9 mg, 0.20 mmol), TCFH (36.4 mg, 0.13 mmol), and NMI (18.9 mg, 0.23 mmol) were added. The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCOOH conditions) to obtain the title compound (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(21) (41.8 mg, yield 90.0%, purity 99.6%). LC-MS (ESI): m / z 460.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 5.1 Hz, 1H), 7.93 (d, J = 26.2 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J = 15.4 Hz, 2H), 7.43 (dd, J = 13.1, 6.7 Hz, 2H), 7.29 (dd, J = 40.1, 15.4 Hz, 1H), 3.88-3.33 (m, 8H), 1.49 (s, 6H).

[0108] Example 8 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(22) [ka]

[0109] Step 1.2-(6-chloropyrimidine-4-yl)propan-2-ol Under an N2 atmosphere, methylmagnesium bromide (290 mL, 290 mmol) was incorporated into anhydrous THF (100 mL), cooled to -70°C, and then THF (200 mL) containing methyl 6-chloropyrimidine-4-carboxylate (25.0 g, 145 mmol) was gradually added. The reaction mixture was stirred under an N2 atmosphere at 0°C for 1 hour. After the reaction was complete, the reaction mixture was quenched with ice-cold water (500 mL) and extracted with  (500 mL). The combined organic layer was washed with brine (2 × 200 mL) and dehydrated with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(6-chloropyrimidine-4-yl)propan-2-ol as a yellow solid (25.0 g, 100%), which was used without further purification. LC-MS (ESI): m / z 173.0 [M+H] +

[0110] Step 2.6-(2-hydroxypropane-2-yl)pyrimidine-4-carbonitride A mixture of 2-(6-chloropyrimidine-4-yl)propan-2-ol (25.0 g, 145 mmol), Zn(CN)2 (20.4 g, 174 mmol), Pd2(dba)3 (6.63 g, 7.24 mmol), and xanthophos (8.4 mg, 14.5 mmol) in DMF (500 mL) was degassed, purged three times with N2, and then stirred at 100°C for 10 hours under an N2 atmosphere. After the reaction was complete, the reaction mixture was quenched with water (1500 mL) and extracted with SiO2 (1500 mL). The combined organic layer was washed with brine (2 × 300 mL) and dehydrated with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EA / PE = 1 / 5 to 1 / 2) to obtain 6-(2-hydroxypropa-2-yl)pyrimidine-4-carbonitrile (23.0 g, yield 97.3%) as a yellow solid. LC-MS (ESI): m / z 164.1 [M+H] +

[0111] Step 3. 6-(2-hydroxypropane-2-yl)pyrimidine-4-carboxylic acid To a solution of 6-(2-hydroxypropa-2-yl)pyrimidine-4-carbonitrile (20.0 g, 123 mmol) in EtOH (300 mL) / H2O (300 mL), KOH (24.3 mg, 368 mmol) was added. The reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The pH was adjusted to 3-4 by adding 15% aqueous hydrochloric acid in small amounts, and the residue was concentrated under reduced pressure to obtain 6-(2-hydroxypropa-2-yl)pyrimidine-4-carboxylic acid as a yellow solid (22.0 g, 98.5%), which was used without further purification. LC-MS (ESI): m / z 183.1 [M+H] +

[0112] Step 4. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(22) To a solution of 6-(2-hydroxypropa-2-yl)pyrimidine-4-carboxylic acid (20.0 g, 110 mmol) in DMF (300 mL), (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (32.5 g, 110 mmol), DIEA (28.4 g, 220 mmol), TCFH (37.0 g, 132 mmol), and NMI (18.9 g, 231 mmol) were added. The mixture was stirred at 25°C for 4 hours. After the reaction was complete, the reaction mixture was quenched with water (1000 mL) and extracted with ELISA (1000 mL). The combined organic layer was washed with brine (3 × 500.0 mL) and dehydrated with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1 to 1 / 0) to obtain the title compound (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazin-1-yl)propa-2-en-1-one(22) (27.0 g, yield 53.4%, purity 99.0%). LC-MS (ESI): m / z 461.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.19-9.17 (m, 1H), 8.03-7.82 (m, 2H), 7.59-7.41 (m, 3H), 7.37-7.23 (m, 1H), 5.58 (s, 1H), 3.88-3.44 (m, 8H), 1.47 (s, 6H).

[0113] The following compounds were synthesized by following the same procedure as described in Example 22. [Table 8-1]

[0114] [Table 8-2]

[0115] [Table 8-3]

[0116] Example 9 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclobutyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(24) [ka]

[0117] Step 1.2-(hydroxycyclobutyl)pyridine-4-carboxylic acid To a solution of 2-bromopyridine-4-carboxylic acid (200 mg, 0.99 mmol) in THF (5.0 mL), n-BuLi (0.7 mL, 1.54 mmol) was added at -78°C, and the mixture was stirred for 20 minutes. Cyclobutanone (100 mg, 1.43 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. LC-MS showed that SM was completely consumed. NH4Cl was added to the reaction mixture, and the reaction mixture was evaporated to obtain crude oil. The crude oil was purified by preparative HPLC to obtain 2-(hydroxycyclobutyl)pyridine-4-carboxylic acid (20.0 mg, 0.10 mmol, yield: 10.5%) as a white solid. LC-MS (ESI): m / z 194.1 [M+H] +

[0118] Step 2. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclobutyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(24) A solution of (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)prop-2-en-1-one hydrochloride (35.0 mg, 0.11 mmol) and 2-(hydroxycyclobutyl)pyridine-4-carboxylic acid (18.0 mg, 0.09 mmol) in DMF (2.0 mL) was treated with HATU (45.0 mg, 0.12 mmol) and DIEA (70.0 mg, 0.54 mmol), and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete consumption of the SM. The reaction mixture was purified by preparative HPLC to afford (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclobutyl)isonicotinoyl)piperazin-1-yl)prop-2-en-1-one (24) (30.0 mg, 0.06 mmol, yield: 68.3%). LC-MS (ESI): m / z 472.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 4.9 Hz, 1H), 7.93 (d, J = 27.0 Hz, 1H), 7.49 (dd, J = 31.0, 12.0 Hz, 4H), 7.32 (dd, J = 20.8, 6.1 Hz, 2H), 5.86 (s, 1H), 3.71 (t, J = 52.5 Hz, 6H), 3.35 (s, 2H), 2.57 (ddd, J = 11.9, 9.0, 4.9 Hz, 2H), 2.28 - 2.19 (m, 2H), 1.99 - 1.79 (m, 2H).

[0119] The following compounds were synthesized by following the same procedure as described for Example 24.

Table 9-1

[0120]

Table 9-2

[0121] Example 10 (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(23) [ka]

[0122] Step 1. Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate To a solution of methyl 2-(2-hydroxypropa-2-yl)pyridine-4-carboxylate (500 mg, 2.42 mmol) in MeOH (5.0 mL), MeONa (131 mg, 2.42 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product residue was combined with a batch of crude product obtained from a second reaction carried out on the same scale, and purified by column chromatography using silica (100-200 mesh) and a solvent system of Â1:hexane (1:2) to obtain methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (310 mg, yield 63.4%) as a white solid. LC-MS (ESI): m / z 203.0 [M+H] +

[0123] Step 2. Methyl 2-acetyl-6-methoxypyrimidine-4-carboxylate A mixture of methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (1000 mg, 4.94 mmol), methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (1783 mg, 4.94 mmol), and methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (173.2 mg, 0.25 mmol) in dioxane (10 mL) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. Subsequently, 2 M HCl (10 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, EA:PE=1:2) to obtain methyl 2-acetyl-6-methoxypyrimidine-4-carboxylate (1000 mg, yield 96.4%) as a yellow solid. LC-MS (ESI): m / z 211.1 [M+H] +

[0124] Step 3. 2-acetyl-6-methoxypyrimidine-4-carboxylic acid A solution of methyl 2-acetyl-6-methoxypyrimidine-4-carboxylate (500 mg, 2.38 mmol) in THF (5.0 mL) / H2O (5.0 mL) was mixed with LiOH (200 mg, 4.76 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (FA conditions) to obtain the title compound 2-acetyl-6-methoxypyrimidine-4-carboxylic acid (50.0 mg, yield 10.7%) as a white solid. LC-MS (ESI): m / z 197.1 [M+H] +

[0125] Step 4. (E)-1-(4-(2-acetyl-6-methoxypyrimidine-4-carbonyl)piperazin-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one To a solution of 2-acetyl-6-methoxypyrimidine-4-carboxylic acid (50.0 mg, 0.26 mmol) in DMF (2.0 mL), (2E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(piperazin-1-yl)propa-2-en-1-one (75.5 mg, 0.26 mmol), DIEA (98.8 mg, 0.77 mmol), and HATU (116.3 mg, 0.31 mmol) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (FA conditions) to obtain the title compound (E)-1-(4-(2-acetyl-6-methoxypyrimidine-4-carbonyl)piperazin-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one (20.0 mg, yield 16.5%) as a white solid. LC-MS (ESI): m / z 475.1 [M+H] +

[0126] Step 5. (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(23) Under an N2 atmosphere, (E)-1-(4-(2-acetyl-6-methoxypyrimidine-4-carbonyl)piperazin-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one (20.0 mg, 0.04 mmol) was incorporated into anhydrous THF (3 mL), cooled to 0°C, and then methylmagnesium bromide (0.13 mL, 0.13 mmol) was gradually added. The reaction mixture was stirred under an N2 atmosphere at 0°C for 2 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ELISA (50 mL). The combined organic layer was dehydrated with Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC (FA conditions) to obtain the title compound (23) (3.7 mg, yield 17.8%). LC-MS (ESI): m / z 491.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 14.5 Hz, 1H), 7.53 (d, J = 15.4 Hz, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.30 (dd, J = 26.5, 15.6 Hz, 1H), 6.97 (d, J = 4.8 Hz, 1H), 4.01 (s, 3H), 3.85 - 3.62 (m, 6H), 3.46 (s, 2H), 1.50 (s, 6H).

[0127] Example A: Calcium mobilization assay of GPR183 antagonist 2+ Mobilization assay The calcium mobilization assay is a cell-based secondary messenger assay for measuring calcium flux associated with the activation or inhibition of G protein-coupled receptors. Changes in fluorescence intensity are directly correlated with the amount of intracellular calcium released into the cytoplasm in response to ligand activation of the receptor of interest.

[0128] GPR183-Gqi5-CHO-K1 cells (constructed by Genomeditech) were rapidly recovered from liquid nitrogen and maintained in complete medium (F12K medium, 10% FBS, 1% penicillin-streptomycin, 4 μg / mL puromycin) at 37 °C in 5% CO2. The cells were passaged twice before use. Approximately 1.5 × 104 GPR183-Gqi5-CHO-K1 cells were seeded into each well of a 384-well black plate (clear bottom) containing 25 μL of medium and cultured overnight. Loading buffer was prepared with minor modifications according to the instructions of the manufacturer of the FLIPR® Calcium6 assay kit. Specifically, FLIPR buffer (1× Hank's balanced salt solution (HBSS) containing 20 mM HEPES, pH 7.4) supplemented with 2.5 mM probenecid and 0.5× dye was prepared immediately before use. The culture medium was discarded completely and replaced with 50 μL of loading buffer, and the cell plate was incubated at 37 °C with 5% CO2 for 2 hours. Compounds diluted to the desired concentration (5×) in 12.5 μL of assay buffer were added to each well and incubated with the cells at room temperature for 30 minutes. 7α,25-OHC was added to each well at a final concentration of 100 nM. The mobilization of Ca 2+ was detected using a FLIPR Tetra instrument equipped with an ICCD camera according to the manufacturer's instructions. For each experiment, two replicate experiments were performed simultaneously. Curves of relative fluorescence signal and the logarithm of the test compound concentration were plotted using GraphPad Prism software, and non-linear regression analysis was performed to obtain the half-maximal inhibitory concentration (IC 50 ).

[0129] Example B: hERG Inhibition Assay A HEK293 cell line (catalog number K1236) stably expressing the hERG channel was purchased from Invitrogen. The cells were cultured in medium containing 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, 5 μg / mL blasticidin, and 400 μg / mL geneticin. The cells were cultured with 5% CO2 in a 25 cm2 The cells were grown in cell culture bottles at 37°C. TrypLE® Express was used approximately three times a week to separate the cells and maintain a confluence of approximately 40% to 80%. Before the assay, the cells were induced with 1 μg / mL doxycycline for 48 hours. On the day of the experiment, the induced cells were resuspended and 5 × 10⁶ cells were removed before use. 5 Individual cells were seeded on coverslips in 3.5 cm cell culture dishes and cultured in a medium free of blastosidine and geneticin. The test compound was initially prepared as a stock solution in DMSO to a final concentration of 10 mM. Before the experiment, the diluted standard solution was finally prepared by diluting the intermediate solution described above 1000-fold using extracellular solution. The final DMSO concentration was kept within the range of 0.1%.

[0130] First, a baseline was established by applying a media control to cells. The compound was applied once it was confirmed that the hERG current was stable for 5 minutes. The hERG current in the presence of the test compound was recorded for approximately 5 minutes until a steady state was reached, and then five sweeps were recorded. For the dose-response study, five doses of the compound were applied to cells cumulatively from low to high concentrations. After measuring the hERG current with the highest concentration of the test compound, a positive control, dofetilide at a concentration of 150 nM, was also applied to each cell as an internal control for normalizing the inhibition rate. To ensure that the cultured cells and procedures functioned well, the same cell batch used for the compound was tested using dofetilide, the positive control, at five different dosing concentrations. Using Graphpad Prism 8.0, the dose-response curve of the test compound was plotted as inhibition % against the concentration of the test compound, and the data were fitted to a sigmoid dose-response curve with a variable slope.

[0131] Example C: Solubility in PBS Stock solutions of the test compound and the control compound, progesterone, were prepared at a concentration of 10 mM in DMSO. To prepare the solubility sample plates, 30 μL of each stock solution (10 mM) was placed in appropriate wells of a 96-well rack. Next, 970 μL of PBS (pH 7.4) was added to each vial of the capless solubility sample plate. The assay was performed in a double-row system. One stirring bar was added to each vial, and the plates were sealed using molded PTFE / silicone plugs. The solubility sample plates were transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C and 1100 RPM for 2 hours. After 2 hours of incubation, the plugs were removed, and the stirring bars were removed using a magnet. The samples were transferred from the solubility sample plates to a filter plate and filtered using a vacuum manifold. A 5 μL sample was taken from the filtrate, and then 5 μL of DMSO and a mixture of H2O and acetonitrile (v / v 1:1) were added. The dilution ratio was adjusted according to the solubility value and LC-MS signal response.

[0132] For the DMSO STD plates, 15 μL was transferred from the 10 mM DMSO STD plate to the remaining empty plate, and then 485 μL of DMSO was added to adjust the STD concentration to 300 μM. Next, 5 μL of DMSO STD was transferred from the 300 μM DMSO STD plate to the remaining empty plate, and then 5 μL of PBS (pH 7.4) and 490 μL of a mixture of H2O and acetonitrile (v / v 1:1) were added to adjust the final STD concentration to 3 μM. The concentrations of the standard samples were adjusted according to the LC-MS signal response. The plates were placed in a well-plate autosampler, and the samples were evaluated by LC-MS / MS analysis.

[0133] The table below shows the Ca of the compounds disclosed herein. 2+ Mobilization IC 50 hERG close 50 This is a summary of inhibition percentages or solubility at (μM) or 30 μM. [Table 10-1]

[0134] [Table 10-2]

[0135] Where any prior art publication is referenced in this specification, it will be understood that such reference does not constitute an endorsement that such publication forms part of the common general knowledge in the art in any country.

[0136] All publications, patents, patent applications, and published patent application disclosures referenced herein by specific citation are incorporated herein by reference in their entirety.

[0137] Although the aforementioned invention has been described in some detail with illustrations and examples for the purpose of clarifying understanding, it will be apparent to those skilled in the art that certain minor changes and modifications will be made. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. Equation (I) 【Chemistry 1】 A compound of the same or its stereoisomer or a pharmaceutically acceptable salt thereof, During the ceremony, 【Chemistry 2】 The part is aromatic, X 1 However, =CH=, -NH-, or =N-, X 2 However, =CH=, -NH-, or =N-, X 3 However, =CH- or =N-, X 4 However, =CH- or =N-, X 5 However, =CH or =N-, X 1 , X 2 , X 3 , X 4 , and X 5 at least one of which is = N−, m is 0 or 1, R 2 , R 3 , and R 4 Each of these is independently a hydroxysubstituted alkyl, a hydroxysubstituted alkynyl, hydrogen, hydroxy, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, hydroxysubstituted cycloalkyl, cyanosubstituted alkyl, cyanosubstituted alkoxy, cyanosubstituted heterocyclyl, cyanosubstituted cycloalkyl, sulfosubstituted alkyl, alkylsulfosubstituted alkyl, sulfosubstituted alkoxy, sulfosubstituted heterocyclyl, sulfosubstituted cycloalkyl, heterocyclyl, heterocyclyloxy, or di(alkyl)phosphoryl. R is halogen, C 1-6 Alkyl, or halo C 1-6 It is alkyl, t is 0, 1, or 2, however, X 2 If R = N-, 2 It does not exist, X 3 If R = N-, 3 If it does not exist, or X 4 If R = N-, 4 It does not exist, However, R 2 and R 4 A compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein at least one of the elements is not hydrogen. 【Request Item 2】 【Chemistry 3】 The compound according to claim 1, wherein the compound is pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; pyridine-3-yl, pyridine-4-yl or pyridine-2-yl; pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl or pyrimidine-6-yl; pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl or pyridazin-6-yl; or pyrazine-2-yl, pyrazine-3-yl, pyrazine-5-yl or pyrazine-6-yl.

3. a) R 2 However, R is a hydroxysubstituted alkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. 3 and R 4 Both are hydrogen, or b) R 2 However, R is a hydroxysubstituted alkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. 3 However, it is hydrogen, R 4 However, it is hydrogen, hydroxyl, alkyl, or alkoxy, or c) R 2 However, R is a hydroxysubstituted alkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. 3 However, R is hydrogen, hydroxyl, alkyl, or alkoxy. 4 However, it is hydrogen, or d) R 4 However, R is a hydroxysubstituted alkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. 2 and R 3 Both are hydrogen, or e) R 4 However, R is a hydroxysubstituted alkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. 2 However, it is hydrogen, R 3 However, it is hydrogen, hydroxyl, alkyl, alkoxy, or alkoxyalkoxy, f) R 4 However, R is a hydroxysubstituted alkyl, alkylsulfonyl, hydroxysubstituted alkoxy, hydroxysubstituted heterocyclyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxysubstituted cycloalkyl, heterocyclyl, or heterocyclyloxy. 2 However, R is hydrogen, hydroxyl, alkyl, alkoxy, or alkoxyalkoxy, 3 The compound according to claim 1, wherein the compound is hydrogen. 【Request Item 4】 【Chemistry 4】 but, 【Transformation 5】 And in the formula, X 1 , X 2 , X 3 , X 4 , X 5 , R 2 , R 3 , and R 4 The compound according to claim 3, defined as shown in formula (I).

5. a) R 2 However, R is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, 3 and R 4 Both are hydrogen, or b) R 2 However, R is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, 3 However, it is hydrogen, R 4 However, it is hydrogen, hydroxyl, alkyl, or alkoxy, or c) R 2 However, R is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, 3 However, R is hydrogen, hydroxyl, alkyl, or alkoxy. 4 However, it is hydrogen, or d) R 4 However, R is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, 2 and R 3 Both are hydrogen, or e) R 4 However, R is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, 2 However, it is hydrogen, R 3 However, it is hydrogen, hydroxyl, alkyl, or alkoxy, or f) R 4 However, R is a hydroxysubstituted alkoxy, a hydroxysubstituted heterocyclyl, or a hydroxysubstituted cycloalkyl, 2 However, R is hydrogen, hydroxyl, alkyl, or alkoxy. 3 The compound according to claim 3, wherein the compound is hydrogen.

6. The compound according to any one of claims 1 to 4, wherein the hydroxy substituent in the hydroxy-substituted alkoxy, hydroxy-substituted heterocyclyl, or hydroxy-substituted cycloalkyl is located at the alpha position relative to the linking position.

7. a) R 2 However, R is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropane-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropane-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy. 3 However, it is hydrogen, R 4 However, it is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy, b) R 2 However, R is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropane-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropane-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy. 4 However, it is hydrogen, R 3 However, it is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy, c) R 4 However, R is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropane-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropane-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy. 3 However, it is hydrogen, R 2 However, it is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy, d) R 4 However, R is methylsulfonyl, oxetane-3-yloxy, 2-hydroxypropane-2-yl, 1-hydroxycyclobutyl, 1-hydroxycyclopropyl, 2-hydroxypropoxy, 1-cyanocyclopropyl, oxetane-3-yl, 3-hydroxyazetidine-1-yl, morpholino, 2-methoxyethoxy, (1-hydroxypropane-2-yl)oxy, 3-hydroxypyrrolidine-1-yl, or 2-hydroxy-2-methylpropoxy. 2 However, it is hydrogen, R 3 The compound according to claim 1, wherein the compound is hydrogen, alkoxy, alkyl, alkoxyalkyl, or alloxyalkoxy.

8. a) Hydroxysubstituted alkyl is -C(OH)R 2a R 2b And in the formula, R 2a and R 2b Each of these is independently hydrogen or alkyl, b) Hydroxysubstituted cycloalkyl is -C(OH)R 2a R 2b And in the formula, R 2a and R 2b However, together with the carbon atoms to which they are attached, they form a saturated carbon ring of 3 to 6 members. c) the hydroxy-substituted heterocyclyl is -C(OH)R 2a R 2b wherein R 2a and R 2b together with the carbon atom to which they are attached form a 3- to 6-membered saturated ring containing one or two heteroatoms selected from oxygen, nitrogen, or sulfur, a compound according to any one of claims 1 to 4. 【Request Item 9】 【Transformation 6】 but, a) 5-(methylsulfonyl)pyridine-3-yl, 4-(2-(oxetan-3-yloxy)pyridine-4-yl, 6-(2-hydroxypropan-2-yl)pyridine-2-yl, 4-(2-hydroxypropan-2-yl)pyridine-2-yl, 5-(2-hydroxypropan-2-yl)pyridine-3-yl, 2-(2-hydroxypropan-2-yl)pyridine-4-yl, 2-(1-hydroxycyclobutyl)pyridine-4-yl, 6-(2-hydroxypropan-2-yl)pyridine-3-yl, 2-(1-hydroxycyclopropyl)pyridine-4-yl, 5-(1-hydroxycyclopropyl)pyridine-3-yl, 5-(1-hydroxycyclobutyl)pyridine-3-yl, 4-(1-hydroxycyclopropyl)pyridine-2-yl, 4-(1-hydroxycyclobutyl)pyridine-2-yl, 2-(2-hydroxypropoxy)pyridine-4-yl, 2-(2-Hydroxy Xypropoxy)pyridine-4-yl, 6-(2-hydroxypropan-2-yl)-5-methoxypyridine-2-yl, 5-(2-hydroxypropan-2-yl)-6-methoxypyridine-3-yl, 6-(2-hydroxypropan-2-yl)-4-methoxypyridine-2-yl, 2-(2-hydroxypropan-2-yl)-6-methoxypyridine-4-yl, 4-(2-hydroxypropan-2-yl)-6-methoxypyridine-2-yl , 2-(1-cyanocyclopropyl)pyridine-4-yl, 2-(oxetan-3-yl)pyridine-4-yl, 2-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-4-yl, 2-(1-hydroxyethyl)pyridine-4-yl, 5-(dimethylphosphoryl)pyridine-3-yl, 6-(hydroxymethyl)pyridine-2-yl, or 6-(2-(methylsulfonyl)propane-2-yl)pyridine-2-yl, b) 2-(3-hydroxyazetidine-1-yl)pyrimidine-4-yl, 2-morpholinopyrimidine-4-yl, 2-(2-methoxyethoxy)pyrimidine-4-yl, 2-(2-hydroxypropoxy)pyrimidine-4-yl, 2-(2-hydroxy-2-methylpropoxy)pyrimidine-4-yl, 6-(2-hydroxypropoxy)pyrimidine-4-yl, 6-((1-hydroxypropan-2-yl)oxy)pyrimidine-4-yl, 6-(2-hydroxy-2-methylpropoxy)pyrimidine-4-yl, 2-(2-hydroxypropan-2-yl)pyrimidine-4-yl, 6-(2-hydroxypropan It is either 2-(2-yl)pyrimidine-4-yl, 2-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-4-yl, 2-(3-hydroxypyrrolidine-1-yl)pyrimidine-5-yl, 2-(2-methoxyethoxy)pyrimidine-5-yl, 6-(1-hydroxycyclopropyl)pyrimidine-4-yl, 6-(1-hydroxycyclobutyl)pyrimidine-4-yl, 4-(2-hydroxy-2-methylpropoxy)pyrimidine-2-yl, 4-(2-hydroxypropoxy)pyrimidine-2-yl, or 4-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-2-yl, or c) The compound according to claim 1, wherein the compound is 6-(2-hydroxypropan-2-yl)pyridazin-4-yl, 6-(1-hydroxycyclopropyl)pyridazin-4-yl, 6-(1-hydroxycyclobutyl)pyridazin-4-yl, 5-(2-hydroxypropan-2-yl)-6-methoxypyridazin-3-yl, 6-(2-hydroxypropan-2-yl)pyrazine-2-yl, 4-((1-hydroxypropan-2-yl)oxy)pyrimidine-2-yl, 6-((3-hydroxybutan-2-yl)oxy)pyrimidine-4-yl, or 6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyrimidine-4-yl.

10. The aforementioned compound, (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(methylsulfonyl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(1), (E)-1-(4-(1H-pyrazole-3-carbonyl)piperazine-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one(2), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(1-methyl-1H-pyrazole-3-carbonyl)piperazine-1-yl)propa-2-en-1-one(3), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(1-(2-hydroxyethyl)-1H-pyrazole-3-carbonyl)piperazine-1-yl)propa-2-en-1-one(4), (E)-1-(4-(2-(1H-pyrazole-5-yl)pyrimidine-4-carbonyl)piperazine-1-yl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-2-en-1-one(5), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxyazetidine-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(6), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-morpholinopyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(7), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-methoxyethoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(8), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(9), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(oxetan-3-yloxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(10), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxy-2-methylpropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(11), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(12), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-((1-hydroxypropan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(13), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxy-2-methylpropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(14), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(15), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(16), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(17), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(18), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(2-hydroxypropan-2-yl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(19), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrazine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(20), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(21), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(22), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(23), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclobutyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(24), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(25), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxypyrrolidine-1-yl)pyrimidine-5-carbonyl)piperazine-1-yl)propa-2-en-1-one(26), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-methoxyethoxy)pyrimidine-5-carbonyl)piperazine-1-yl)propa-2-en-1-one(27), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxycyclopropyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(28), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclopropyl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(29), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclobutyl)pyridazine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(30), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclopropyl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(31), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(1-hydroxycyclobutyl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(32), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(1-hydroxycyclopropyl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(33), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(1-hydroxycyclobutyl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(34), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(1-hydroxycyclopropyl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(35), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(1-hydroxycyclobutyl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(36), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxy-2-methylpropoxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(37), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(38), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(39), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(40), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropoxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(41), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(42), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropoxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(43), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropoxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(44), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropoxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(45), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)-5-methoxypicolinoyl)piperazine-1-yl)propa-2-en-1-one(46), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-6-methoxynicotinoyl)piperazine-1-yl)propa-2-en-1-one(47), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-6-methoxypyridazine-3-carbonyl)piperazine-1-yl)propa-2-en-1-one(48), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)-4-methoxypicolinoyl)piperazine-1-yl)propa-2-en-1-one (49), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(2-hydroxypropan-2-yl)-6-methoxyisonicotinoyl)piperazine-1-yl)propa-2-en-1-one(50), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropan-2-yl)-6-methoxypicolinoyl)piperazine-1-yl)propa-2-en-1-one(51), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-(2-hydroxypropan-2-yl)-6-methoxypyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(52), (E)-1-(4-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)piperazine-1-carbonyl)pyridine-2-yl)cyclopropane-1-carbonitrile (53), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(oxetan-3-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(54), (S,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(4-((1-hydroxypropane-2-yl)oxy)pyrimidine-2-carbonyl)piperazine-1-yl)propa-2-en-1-one(55), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-((1-hydroxypropan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(56), (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-((1-hydroxypropane-2-yl)oxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(57), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(((2R,3S)-3-hydroxybutan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(58), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(((2S)-3-hydroxybutan-2-yl)oxy)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(59), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(((2S,3R)-3-hydroxybutan-2-yl)oxy)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(60), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(3-hydroxy-3-methylbuta-1-in-1-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(61), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(62), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(2-(1-hydroxyethyl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one(63), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(5-(dimethylphosphoryl)nicotinoyl)piperazine-1-yl)propa-2-en-1-one(64), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(hydroxymethyl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(65), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-(methylsulfonyl)propan-2-yl)picolinoyl)piperazine-1-yl)propa-2-en-1-one(66), (E)-3-(4-chlorophenyl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(67), (E)-3-(4-bromophenyl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one(68), (E)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)-3-(4-(trifluoromethoxy)phenyl)propa-2-en-1-one(69), (E)-3-(4-fluorophenyl)-1-(4-(2-(2-hydroxypropan-2-yl)isonicotinoyl)piperazine-1-yl)propa-2-en-1-one (70), (E)-3-(2,4-dichlorophenyl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)piperazine-1-yl)propa-2-en-1-one (71), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)-1,4-diazepan-1-yl)propa-2-en-1-one(72), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)-3-methylpiperazine-1-yl)propa-2-en-1-one(73), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(7-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)-4,7-diazaspiro[2.5]octan-4-yl)propa-2-en-1-one(74), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)propa-2-en-1-one(75), (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(6-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)propa-2-en-1-one(76), or The compound according to claim 1, selected from (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(6-(6-(2-hydroxypropan-2-yl)pyrimidine-4-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)propa-2-en-1-one (77).

11. A pharmaceutical composition comprising, optionally, a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable pharmaceutical additive.

12. A method for treating a disease mediated by GPR183, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. The method according to claim 11, wherein the disease mediated by GPR183 is cancer, autoimmune disease, liver disease, osteoporosis, and neuropathic pain.

14. The method according to claim 12, wherein the cancer is a blood cancer, brain cancer, breast cancer, colorectal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, or uterine cancer.

15. The method according to claim 13, wherein the cancer produces molecules involved in Epstein-Barr virus (EBV)-induced G protein-coupled receptor 2 (EBI2)-mediated signaling.

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