KR20090046596A - Chroman-2-carboxylic acid amide derivatives, method of the same and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to a novel chromman-2-carboxylic acid amide derivative, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient. Since the novel chroman-2-carboxylic acid amide derivatives have an ability to inhibit NF-κB activity, the pharmaceutical composition comprising the same as an active ingredient is a group consisting of diseases related to NF-κB, preferably multiple myeloma, rheumatoid arthritis and cancer. It can be used as a composition for the prevention or treatment of any one or more diseases selected from.

Chromman-2-carboxylic acid amide derivative, NF-κB

Description

CHROMAN-2-CARBOXYLIC ACID AMIDE DERIVATIVES, METHOD OF THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING SAME}

The present invention relates to a novel chromman-2-carboxylic acid amide derivative, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient.

Most human diseases are caused by a combination of abnormal elements and substances produced by gene expression during or when the disease occurs. Such diseases include autoimmune disease including autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease (IBD), and sepsis Septic shock, Lung Fibrosis, carcinogenesis, cancer, and Acquired Immune Deficiency Syndrome (AIDS). Generally, these genes are inactive or very insignificant in biological or physical processes. However, under certain conditions, such as exposure to environmental pollution, the expression of these genes increases exponentially with preexisting genetic elements. These genetic elements are nuclear, an essential transcription factor that regulates gene expression of cytokines, chemokines, growth factors, adhesion molecules, and acute phase proteins. regulated by factor-κB (NF-κB).

NF-κB was first identified as a transcriptional activator specific for B cells of the κ-light chain gene of immunoglobulins. Since then, NF-κB has been identified in various cells and is known to be activated by many factors. Such NF-κB has been widely studied in various fields such as immunology, molecular biology, biochemistry, genetics, cell biology and developmental biology.

NF-κB exists in the cytoplasm of most cells and is in the form of homo-dimers and hetero-dimers as a bond between groups of structurally similar proteins. (Baldwin, AS et al. Annu. Rev. Immunol , 14 : 649-683 (1996); Kopp, EB et al. , Adv. Immunol , 58 : 1-27 (1995)) of each of these groups of proteins. The element contains a protected amino terminus called the Rel-Homology Domain (RHD), which contains a DNA-binding domain, a dimerization domain and a nuclear localization signal in the RHD. signal, NLS). In mammals, in particular, NF-κB consists of five proteins, p65 (RelA), RelB, c-Rel, p50 / p105 (NF-κB1) and p52 / p100 (NF-κB2). p65 (RelA), RelB and c-Rel are produced as active proteins that cause transcription, and p50 / p105 (NF-κB1) and p52 / p100 (NF-κB2) are synthesized from precursors of 105 kDa and 100 kDa, respectively. The precursors of 105 kDa and 100 kDa turn into p50 and p52, the smaller active forms that cause transcription through several processes. Typical NF-κB has dimer forms of p65 (RelA) and p50 / p105 (NF-κB1). However, it has also been reported that various dimer forms exist that contain other Rel. (Michael, JM et al. , Immunol. Today , 19: 80-88 (1998)).

In the cytoplasm, NF-κB is present in an inactive form by binding to IkBa, IkBb, IkBe, IkBg, Bcl3 and the precursor proteins p100 and p105, known as inhibitory proteins (Simon, TW et al. , Semin. Cancer Biol. 8 : 75-82 (1997). All known IkBs include ankyrin repeat domains with various types of 30 to 33 amino acid sequences, and the special interaction between ankyrin repeat domains and RHD clearly characterizes the binding between NF-κB and IkB. In other words, the IkB group blocks NLS located near the carboxyl terminus of RHD of NF-κB, thereby regulating the DNA binding of NF-κB and the subcellular localization of Rel-NF-κB protein (Thomas, H. et. al . , Cell . 68 : 1121-1133 (1992).

The factor regulating the binding of NF-κB and IkB is IkB kinase (IKK). By activation of IKK, the N -terminus of IkB is phosphorylated and the release of IkB is controlled. This IKK contains two kinase subunits of IKKa (IKK1) and IKKb (IKK2) and regulatory subunits that are NF-κB essential modifiers (NEMOs) or IKKg (Rothwarf, DM et al. , Sci, STKE). , 5 : re1. (1999)). In the normal NF-κB pathway, IKKb phosphorylates two N -terminal serine residues of IkB. In particular, IkBa phosphorylates at serine residues 32 and 36 and IkBb at serine residues 19 and 23. The role of IKKa is not clear in the general pathway of NF-κB, but recent research suggests that it regulates gene expression by altering histone phosphorylation in the nucleus. However, another NF-κB pathway is dependent on IKKa, which phosphorylates p100 and induces p52.

As such, each of the IkBs phosphorylated by the IKK complex is ubiquitated by a ubiqutin ligase such as SCF (or SCRF) to be degraded in the proteasome. When IkB is degraded, NF-κB becomes active and is moved by the NLS into the nucleus to express genes. In actual NF-κB activation there is a difference in the path by a large number of external signals. However, most pathways are identical in that they enhance the transcriptional capacity of NF-κB by activating IKK and releasing IkB. Among the studies of interest, the pathways that activate IKK by external signals include TNFR, TLR / IL-1R, TCR, and BCR (Matthew, SH et al. , Genes Dev. 18 : 2195-2224 (2004)). .

NF-κB is a cytokine, chemokine, adhesion molecule, acute phase proteins, anti-microbial peptide, cell surface receptor, inducible activates the transcriptional stages of genes expressing nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) (Barnes, PJ et al. , N. Engl. J. Med. 366 : 1066-1071 (1997); Xie, Q et al. , J. Biol. Chem . 269 : 4705-4708 (1994); Yamamoto, K. et al. , J. Biol. Chem. 270 : 31315-31320 (1995)).

In addition, stimulants that activate NF-κB are external substances such as toxic substances, bacteria, viruses, ultraviolet rays, and ionizing radiation, and internal substances are known to have cytokines, inflammatory mediators, growth factors, and oxygen deficiency (Delhase). , M. et al. , Nature , 406: 367-8 (2000); Mercurio, F. et al. , Curr.Opin.Cell Biol ., 11: 226-32 (1999)).

In addition, abnormal NF-κB activation is known to be associated with the cause or malignancy of refractory diseases and cancer diseases associated with various inflammatory diseases including myeloma, arthritis, arterial stenosis, and asthma (Aradhya, S et al. , Curr. Opin. Genet, Dev, 11: 300-7 (2001); Orlowski, RZ et al. , Trnds Mol. Med., 8: 385-9 (2002)). For example, bortezomib derived as an inhibitor of 26S proteasome involved in NF-κB activation is an anticancer agent for multiple myeloma and is approved by the US Food and Drug Administration for clinical use (Dispenzieri, AN Engl). J. Med ., 352: 2546-8 (2005)).

Therefore, in order to treat various inflammatory diseases such as arthritis, autoimmune diseases, multiple myeloma, cancer, and the like, development of a substance capable of effectively inhibiting the activation of NF-κB is required.

In order to meet the above demands, the present invention effectively inhibits the activation of NF-κB, thereby preventing any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer known to be invented due to the activation of NF-κB. It is an object of the present invention to provide a composition for the prevention or treatment of any one or more diseases selected from the group consisting of compounds which are useful for the prevention or treatment and have fewer side effects, methods for preparing the compounds, and effective multiple myeloma, rheumatoid arthritis and cancer containing the same. .

In order to achieve the above object, the present invention provides a novel Chroma-based derivative compound, a preparation method thereof and an NF-κB inhibitor containing the same as an active ingredient. The inhibitor may be used as a composition for preventing or treating a disease associated with NF-κB, and preferably relates to a composition for preventing or treating at least one disease selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer.

In view of the fact that the present inventors can inhibit and treat inflammation, multiple myeloma and cancer disease by inhibiting NF-κB activation, the NF-κB activation inhibitor can be used as a pharmaceutical composition useful for diseases such as inflammatory disease and cancer. Chromaman-2-carboxylic acid amide derivatives were derived and their preparation was established. In addition, the present invention was completed by confirming that they effectively inhibited NF-κB activation.

Hereinafter, the present invention will be described in more detail.

In one aspect of the invention, the invention provides a novel Chroma-based derivative compound. The Chroma-based derivative compound may be a compound having a structure of Formula 1 below, and may be a pharmaceutically acceptable salt thereof.

In the above formula,

R ¹ and R ² may each be alkyl wherein R ¹ is C1 to C4 and R ² is H or R ¹ is H and R ² is C1 to C4,

R ³ to R ⁷ may be the same or different and each independently may be H, hydroxy, alkoxy of C1 to C4, alkyl of C1 to C4, nitro, trifluoromethyl or halogen.

The alkoxy may preferably be methoxy, the alkyl may preferably be methyl, and the halogen may preferably be chloro.

The compounds of the present invention are preferably 6-methyl-chroman-2-carboxylic acid phenylamide, 6-methyl-chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, 6-methyl-chroman-2 -Carboxylic acid (3-hydroxy-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4-hydroxy-phenyl) -amide, 6-methyl-chroman-carboxylic acid (2-methoxy- Phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3-methoxy-phenyl) -amide, 6-methyl-chroman-carboxylic acid (4-methoxy-phenyl) -amide, 6-methyl -Chroman-2-carboxylic acid (2-methyl-phenyl) amide, 6-methyl-chroman-2-carboxylic acid (3-methyl-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4-methyl -Phenyl) amide, 6-methyl-chroman-2-carboxylic acid (2-nitro-phenyl) -amide, 6-methyl-chroman-carboxylic acid (3-nitro-phenyl) -amide, 6-methyl-chrom Man-2-carboxylic acid (4-nitro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (2-trifluoromethyl-phenyl)- Amide, 6-methyl-chroman-2-carboxylic acid (3-trifluoromethyl-phenyl) -amide, 6-methyl-chroman-carboxylic acid (4-trifluoromethyl-phenyl) -amide, 6- Methyl-Chroman-2-carboxylic acid (2-chloro-phenyl) -amide, 6-Methyl-chroman-2-carboxylic acid (3-chloro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4 -Chloro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3,4-dichloro-phenyl) -amide, 6-methyl-chroman-carboxylic acid (3,5-dichloro-phenyl)- Amide, 6-methyl-chroman-2-carboxylic acid (2,5-dichloro-phenyl) -amide, 6-methyl-chroman-carboxylic acid (3,4-dimethyl-phenyl) -amide, 6-methyl- Chromman-2-carboxylic acid (3,5-dimethyl-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (2,5-dimethyl-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3,4-Dimethoxy-phenyl) -amide, '6-6-methyl-chroman-2-carboxylic acid (3,5-dimethoxy-phenyl) -amide, 6-methyl-chroman-2-car Carboxylic acid (2,5-dimethoxy-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3,5-ditrifluoromethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid Phenylamide, 7-methyl-chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, 7-methyl-chroman-carboxylic acid (3-hydroxy-phenyl) -amide, 7-methyl-chrom Man-2-carboxylic acid (4-hydroxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2-methoxy-phenyl) -amide, 7-methyl-chroman-carboxylic acid (3- Methoxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-methoxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2-methyl-phenyl) amide, 7- Methyl-Chroman-2-carboxylic acid (3-methyl-phenyl) -amide, 7-methyl-Chroman-2-carboxylic acid (4-methyl-phenyl) amide, 7-methyl-chroman-2-carboxylic acid (2- Nitro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3-nitro-phenyl) -amide, 7-methyl-chroman-carboxylic acid (4-nitro- Nil) -amide, 7-methyl-chroman-2-carboxylic acid (2-trifluoromethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3-trifluoromethyl-phenyl) -amide , 7-methyl-chroman-2-carboxylic acid (4-trifluoromethyl-phenyl) -amide, 7-methyl-chroman-carboxylic acid (2-chloro-phenyl) -amide, 7-methyl-chroman 2-carboxylic acid (3-chloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-chloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,4-dichloro -Phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,5-dichloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2,5-dichloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,4-dimethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,5-dimethyl-phenyl) -amide, 7-methyl-chroman 2-carboxylic acid (2,5-dimethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,4-dimethoxy-phenyl) -amide, '7-methyl- Roman-2-carboxylic acid (3,5-dimethoxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2,5-dimethoxy-phenyl) -amide and 7-methyl-chroman-2 It may be any one selected from the group consisting of -carboxylic acid (3,5-ditrifluoromethyl-phenyl) -amide, the substituent of the preferred compound may be as shown in Table 1 and Table 2.

The compound is more preferably 6-methyl-chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, 6-methyl-chroman-carboxylic acid (4-hydroxy-phenyl) -amide, 6 -Methyl-Chroman-2-carboxylic acid (4-nitro-phenyl) -amide, 6-methyl-Chroman-2-carboxylic acid (4-chloro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid ( 3,4-Dichloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-hydroxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3-methoxy-phenyl) -Amide, 7-methyl-chroman-2-carboxylic acid (4-methoxy-phenyl) -amide, 7-methyl-chroman-carboxylic acid (2-trifluoromethyl-phenyl) -amide, 7-methyl -Chroman-2-carboxylic acid (2-nitro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-nitro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2- Chloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-chloro-phenyl) -amide, 7-methyl-chroman-2-carboxy Acid (3,5-dichloro-phenyl) -amide and 7-methyl-chroman-2-carboxylic acid (3,5-di triple oro-phenyl) - may be any one selected from the group consisting of amide. The compound of the present invention may most preferably be 7-methyl-chroman-2-carboxylic acid (4-chloro-phenyl) -amide (WAL-1205).

R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ WAL-1208 CH ₃ H H H H H H WAL-1155 CH ₃ H OH H H H H WAL-1156 CH ₃ H H OH H H H WAL-1157 CH ₃ H H H OH H H WAL-1163 CH ₃ H CH ₃ H H H H WAL-1164 CH ₃ H H CH ₃ H H H WAL-1165 CH ₃ H H H CH ₃ H H WAL-1160 CH ₃ H OCH ₃ H H H H WAL-1161 CH ₃ H H OCH ₃ H H H WAL-1170 CH ₃ H H H OCH ₃ H H WAL-2013 CH ₃ H CF ₃ H H H H WAL-1166 CH ₃ H H CF ₃ H H H WAL-1167 CH ₃ H H H CF ₃ H H WAL-2004 CH ₃ H NO ₂ H H H H WAL-1176 CH ₃ H H NO ₂ H H H WAL-1183 CH ₃ H H H NO ₂ H H WAL-2006 CH ₃ H Cl H H H H WAL-1158 CH ₃ H H Cl H H H WAL-1159 CH ₃ H H H Cl H H TAL-1092 CH ₃ H H Cl Cl H H TAL-1093 CH ₃ H H Cl H Cl H TAL-1091 CH ₃ H Cl H H Cl H TAL-1087 CH ₃ H H CH ₃ CH ₃ H H TAL-1086 CH ₃ H H CH ₃ H CH ₃ H TAL-1085 CH ₃ H CH ₃ H H CH ₃ H TAL-1090 CH ₃ H H OCH ₃ OCH ₃ H H TAL-1108 CH ₃ H H OCH ₃ H OCH ₃ H TAL-1070 CH ₃ H OCH ₃ H H OCH ₃ H TAL-1088 CH ₃ H H CF ₃ H CF ₃ H

R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ WAL-1220 H CH ₃ H H H H H WAL-1186 H CH ₃ OH H H H H WAL-1206 H CH ₃ H OH H H H WAL-1207 H CH ₃ H H OH H H WAL-1184 H CH ₃ CH ₃ H H H H WAL-1181 H CH ₃ H CH ₃ H H H WAL-1182 H CH ₃ H H CH ₃ H H WAL-1185 H CH ₃ OCH ₃ H H H H WAL-1177 H CH ₃ H OCH ₃ H H H WAL-1178 H CH ₃ H H OCH ₃ H H WAL-2026 H CH ₃ CF ₃ H H H H WAL-1209 H CH ₃ H CF ₃ H H H WAL-1179 H CH ₃ H H CF ₃ H H WAL-1190 H CH ₃ NO ₂ H H H H WAL-1189 H CH ₃ H NO ₂ H H H WAL-1180 H CH ₃ H H NO ₂ H H WAL-1195 H CH ₃ Cl H H H H WAL-1204 H CH ₃ H Cl H H H WAL-1205 H CH ₃ H H Cl H H TAL-1084 H CH ₃ H Cl Cl H H TAL-1083 H CH ₃ H Cl H Cl H TAL-1082 H CH ₃ Cl H H Cl H TAL-1052 H CH ₃ H CH ₃ CH ₃ H H TAL-1050 H CH ₃ H CH ₃ H CH ₃ H TAL-1049 H CH ₃ CH ₃ H H CH ₃ H TAL-1047 H CH ₃ H OCH ₃ OCH ₃ H H TAL-1106 H CH ₃ H OCH ₃ H OCH ₃ H TAL-1048 H CH ₃ OCH ₃ H H OCH ₃ H TAL-1081 H CH ₃ H CF ₃ H CF ₃ H

In another aspect of the present invention, the present invention provides a method for preparing a compound having the structure of Formula 1.

The compounds of the present invention may be prepared by the method shown in the following schemes, but are not limited to these examples. The following schemes represent the preparation steps of representative compounds of the present invention, and other compounds may be prepared by appropriate changes in reagents and starting materials known to those skilled in the art.

The method for preparing a compound having the structure of Formula 1 may be as described in Scheme 1 below.

More specifically, the preparation method of Scheme 1,

(a) reacting a 2-hydroxy-acetophenone derivative with an oxalic acid diester to prepare a compound having the structure of Formula 2;

(b) reducing the compound having the structure of Formula 2 to prepare a compound having the structure of Formula 3;

(c) hydrolyzing the compound having the structure of Formula 3 to produce a compound having the structure of Formula 4; And

(d) treating the compound having the structure of Formula 4 and the amine compound to prepare a chromaman-2-carboxylic acid amide derivative having the structure of Formula 1

It may be a method for preparing a chromman-2-carboxylic acid amide derivative comprising a.

In Formula 2 to Formula 4,

R ¹ and R ² may each be alkyl wherein R ¹ is C1 to C4, R ² may be H or R ¹ may be H and R ² may be C1 to C4. Alkyl of C1 to C4 may be methyl.

The step (a) may be carried out by treating a 2-hydroxy-acetophenone derivative and an oxalic acid diester under a base, followed by an acid treatment to prepare a compound having the structure of Chemical Formula 2, for example sodium ethoxide After adding 2-hydroxy-acetophenone derivative and oxalic acid diester to the solution, it can be carried out by the reaction under reflux under a nitrogen stream, the compound having the structure of Formula 2 is prepared after the reaction product is weakly acidic It can be carried out by a method obtained through column chromatography.

The 2-hydroxy-acetophenone derivative may be, for example, 2-hydroxy-5-methylacetophenone or 2-hydroxy-4-methylacetophenone, and the compound having the structure of Chemical Formula 2 may be, for example, 6-Methyl-4-oxo- 4H -chroman-2carboxylic acid ethyl ester (WAL-1111) or 7-methyl-4-oxo- 4H -chroman-2-carboxylic acid ethyl ester (TAL-1037) yl Can be.

Step (b) may be carried out by a method of catalytic reduction of the compound having the structure of Formula 2 under ethanol-acetic acid solvent and Pd / C catalyst to obtain a compound having the structure of Formula 3, for example The compound having the structure of 2 may be dissolved in ethanol, reacted with acetic acid and the Pd / C catalyst under a hydrogen stream, and then filtered and chromatographed to obtain the compound having the structure of Chemical Formula 3 above. The Pd / C catalyst may be preferably 7% to 12% Pd / C catalyst, most preferably 10% Pd / C catalyst.

The compound having the structure of Formula 3 may be, for example, 6-methyl-chroman-2carboxylic acid ethyl ester (WAL-1145) or 7-methyl-chroman-2carboxylic acid ethyl ester (TAL-1045).

Step (c) may be performed by a method of obtaining a compound having the structure of Formula 4 by hydrolyzing the compound having the structure of Formula 3 with potassium hydroxide, for example, the structure of Formula 3 It can be carried out by dissolving a compound having a water and adding potassium hydroxide and reacting.

The compound having the structure of Chemical Formula 4 may be, for example, alkyl-chroman-2-carboxylic acid, preferably 6-methyl-chromen-2-carboxylic acid (WAL-1116) or 7-methyl-chromen 2-carboxylic acid (TAL-1046).

The step (d) may be performed by treating the compound having the structure of Chemical Formula 4 with an amine compound to prepare a chroman-2-carboxylic acid amide derivative having the structure of Chemical Formula 1, for example, alkyl-cro The man-2-carboxylic acid may be dissolved in anhydrous tetrahydrofuran, and reacted by adding N, N -carbonyldiimidazole, followed by adding an amine compound and reacting under a nitrogen stream.

The amine compound is phenylamine, aminophenol, methoxyphenylamine, tolylamine, trifluoromethylphenylamine, nitrophenylamine, chlorophenylamine, dichlorophenylamine, dimethylamine, dimethoxyphenylamine corresponding to a derivative which is a final compound. , Ditrifluoromethylphenylamine, and the like. For example, 6-methyl-chroman-2-carboxylic acid phenylamide (WAL-1208), 6-methyl-chroman-carboxylic acid (2-hydroxy-phenyl) -amide (WAL-1155), 6-methyl -Chroman-2-carboxylic acid (2-methyl-phenyl) amide (WAL-1163), 6-methyl-chroman-2-carboxylic acid (2-methoxy-phenyl) -amide (WAL-1160), 6-methyl -Chroman-2-carboxylic acid (2-trifluoromethyl-phenyl) -amide (WAL-2013), 6-methyl-chroman-2-carboxylic acid (2-nitro-phenyl) -amide (WAL-2004) , 6-methyl-chroman-2-carboxylic acid (2-chloro-phenyl) -amide (WAL-2006), 6-methyl-chroman-carboxylic acid (3,4-dichloro-phenyl) -amide (TAL- 1092), 6-methyl-chroman-2-carboxylic acid (3,4-dimethyl-phenyl) -amide (TAL-1087), 6-methyl-chroman-carboxylic acid (3,4-dimethoxy-phenyl) Phenylamine, aminophenol, methoxyphenyl corresponding to amide (TAL-1090) and 6-methyl-chroman-2-carboxylic acid (3,5-ditrifluoromethyl-phenyl) -amide (TAL-1088) Amines, tolylamines, Trifluoromethylphenylamine, nitrophenylamine, chlorophenylamine, dichlorophenylamine, dimethylamine, dimethoxyphenylamine, ditrifluoromethylphenylamine and the like.

In another aspect of the present invention, the present invention also provides a composition for inhibiting NF-κB activation comprising a compound having the structure of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present inventors measured the amount of secretory alkaline phophatase (SEAP) produced together with NF-κB activation in relative fluorescence units (relative fluoresecnce uint (RFU)). It was confirmed that it can inhibit the -κB activation.

Since NF-κB transduces into the nucleus and induces a transcription process in the nucleus, the pharmaceutical composition of the present invention which inhibits NF-κB activation is cytokine, chemokine, adhesion molecule, acute stage protein. by inhibiting the transcriptional phase activation of acute phase proteins, anti-microbal peptides, cell surface receptors, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) genes. It has been found that it is possible to prevent or treat any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer that may be affected by the genes.

Therefore, the composition for inhibiting NF-κB activation comprising the compound having the structure of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient is preferably selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer. It can be applied as a composition for the prevention or treatment of one or more diseases.

The chromaman-2-carboxylic acid amide derivative having the structure of Formula 1 may be used alone in the composition for inhibiting NF-κB activation or in the composition for preventing or treating diseases, and other pharmacologically acceptable carriers, excipients, or Diluents may be further included. In this case, the content of the chroman-2-carboxylic acid amide derivative in the composition may be 0.001% by weight to 99.9% by weight, 0.1% by weight to 99% by weight or 1% by weight to 50% by weight, but is not limited thereto. Depending on the mode of use and the method of use of the composition, the content of the compound may be appropriately adjusted to the desired content.

When a composition comprising a compound having the structure of Formula 1 is used as a medicament, or used for medicament or pharmaceutical use, the chroman-2-carboxylic acid amide derivative having the structure of Formula 1 may be prepared according to conventional methods. As an acceptable carrier or excipient, it can be used as a diluent or mixed with.

Examples of the pharmaceutically acceptable carrier, excipient, or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and at least one selected from the group consisting of physiological function, but is not limited thereto, and any conventional carrier, excipient or diluent may be used. In addition, the pharmaceutical composition may further include conventional fillers, extenders, binders, disintegrants, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers or preservatives.

In addition, the composition of the present invention may further include a substance used as an inhibitor of known NF-κB in addition to the active ingredient.

The formulation of the composition may vary depending on the method of use and may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In general, the formulations include PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOULTIONS, AEROSOLS, and OITMENTS. ), FRUIDEXTRACTS, ELIXIR, EMULSIONS, SUSPENSIONS, INFUSIONS, SACHET, TABLETS, PILLS, INJECTIONS, soft or It may be in the form of hard capsules (CAPSULES) and pills (PILLS). Furthermore, the compositions of the present invention may be formulated using suitable methods known in the art or using methods disclosed in Remington's Pharmaceutical Science (Recent Edition, Mack Publishing Company, Easton PA). Can be.

When the composition is used as a medicament, the administration method may be oral or parenteral, and may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular.

The dosage of the composition may be determined in consideration of the method of administration, age, sex, severity, condition of the patient, absorption of the active ingredient in the body, inactivation rate and the drug used in combination, for example, based on the daily effective ingredient 0.0001 mg / kg (body weight) to 1000 mg / kg (body weight), 0.01 mg / kg (body weight) to 100 mg / kg (body weight) or 0.5 mg / kg (body weight) to 50 mg / kg body weight It can be administered, and can be administered once or divided into several times. The dosage does not limit the scope of the invention in any aspect.

The novel chromman-2-carboxylic acid amide derivative compounds of the present invention and pharmaceutical compositions containing the same act as inhibitors of NF-κB and are selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer, a disease associated with NF-κB. It may be used in a composition for the prophylaxis or treatment of one or more diseases.

Hereinafter, preferred embodiments of the present invention are described. However, the following examples are only preferred examples of the present invention, and are not limited to the following examples of the present invention.

Example 1 Preparation of Raw Material

Example 1-1: 6-Methyl-4-oxo-4 H Preparation of -Chroman-2-carboxylic Acid Ethyl Ester (WAL-1111)

Sodium (385 mg, 16.7 mmol) was added to ethanol (35 mL) in a 25 mL round flask to prepare a sodium ethoxide solution, followed by 2-hydroxy-5-methylacetophenone (500 mg, 3.3 mmol) and oxalic acid ethyl ester. (1.47 g, 10 mmol) was added slowly and refluxed under a nitrogen stream for 2 hours. After the reaction was completed, the reaction was cooled at 20 ℃, 5 mL of 6 N -hydrochloric acid was added and stirred at room temperature for 24 hours. After stirring, the mixture was concentrated under reduced pressure, and extracted with water (20 mL) and dichloromethane (30 ml). The extracted solvent was dried, concentrated under reduced pressure, and column chromatography was performed to obtain WAL-1111.

Yield: 99%, 720 mg

¹ H NMR (CDCl ₃ , 300 MHz) d 8.0 (s, 1H, Ar- H ), 7.55 (d, 2H, J = 8.76 Hz, Ar- H ), 7.10 (s, 1H, COC H ), 4.30 ( q, 2H, J = 7.13 Hz, COOC H ₂ CH ₃ ), 1.38 (t, 3H, J = 7.82 Hz, COOCH ₂ C H ₃ )

Example 1-2 Preparation of 6-Methyl-Chroman-2-carboxylic Acid Ethyl Ester (WAL-1145)

6-Methyl-4-oxo- 4H -chroman-2-carboxylic acid ethyl ester (WAL-1111) (500 mg, 2.1 mmol) was dissolved in ethanol (20 mL), followed by Pd / C (150 mg) and acetic acid ( 1 mL) was placed in a 100 mL round flask and stirred for one day under hydrogen stream. The solid was removed by filtration through Celite, the filtrate was concentrated and purified by column chromatography to give the product on the oil (WAL-1145).

Yield: 99%, 460 mg

¹ H NMR (CDCl ₃ , 300 MHz) d 6.93 (d, 1H, J = 8.04 Hz, Ar- H ), 6.84 (s, 1H, Ar- H ), 6.82 (d, 1H, J = 8.13 Hz, Ar -H ), 4.68 (dd, 1H, J = 7.54 Hz, OC H CH ₂ CH ₂ ), 4.25 (q, 2H, J = 7.12 Hz, COOC H ₂ CH ₃ ), 2.84-2.53 (m, 2H, OCHCH ₂ C H ₂ ), 2.30-2.10 (m, 2H, OCHC H ₂ CH ₂ ), 2.45 (s, 3H, Ar-C H ₃ ), 2.25 (s, 3H, Ar-C H ₃ ), 1.29 (t , 3H, J = 7.28 Hz, COOCH ₂ C H ₃ )

Example 1-3 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (WAL-1116)

6-Methyl-chroman-carboxylic acid ethyl ester (WAL-1145) (100 mg, 0.45 mmol) was dissolved in water (10 mL) and potassium hydroxide (122 mg, 2.17 mmol) was stirred at room temperature for 1 hour. After stirring, 6N hydrochloric acid was added to make the pH neutral, and extracted with ethyl acetate. The solvent was concentrated under reduced pressure to obtain WAL-1116.

Yield: 98%, 86 mg

¹ H NMR (CDCl ₃ , 300 MHz) d 6.94 (d, 1H, J = 7.29 Hz, Ar- H ), 6.86 (s, 1H, Hz, Ar- H ), 6.81 (d, 1H, J = 8.26 Hz , Ar- H ), 4.72 (dd, 1H, J = 7.88 Hz, OC H CH ₂ CH ₂ ), 2.84-2.77 (m, 2H, OCHCH ₂ C H ₂ ), 2.38-2.12 (m, 2H, OCHC H ₂ CH ₂ ), 2.50 (s, 3H, Ar-C H ₃ )

Example 1-4: 7-Methyl-4-oxo-4 H Preparation of -Chroman-2-carboxylic Acid Ethyl Ester (TAL-1037)

Sodium ethoxide solution was prepared by adding sodium (77 mg, 3.35 mmol) to ethanol (7 mL) in a 25 mL round flask, followed by 2-hydroxy-4-methylacetophenone (100 mg, 0.67 mmol) and oxalic acid ethyl ester. (293.7 mg, 2.01 mmol) was added slowly and refluxed under a nitrogen stream for 2 hours. After the reaction was over, the reaction was cooled at 20 ℃, 1 mL of 6 N -hydrochloric acid was added and stirred at room temperature for 24 hours. After stirring, the mixture was concentrated under reduced pressure, and extracted with water (10 mL) and dichloromethane (20 ml). The extracted solvent was dried and concentrated under reduced pressure to give TAL-1037 by column chromatography.

Yield: 98%, 154 mg

¹ H NMR (CDCl ₃ , 300 MHz) d 8.25 (d, 1H, J = 8.1 Hz, Ar- H ), 7.59 (s, 1H, Ar- H ) 7.44 (d, 1H, J = 7.6 Hz, Ar- H ), 7.27 (s, 1H, COC H ), 4.64 (q, 2H, J = 7.1 Hz, COOC H ₂ CH ₃ ), 2.68 (s, 3H, Ar-C H ₃ ), 1.61 (t, 3H, J = 7.1 Hz, COOCH ₂ C H ₃ )

Example 1-5 Preparation of 7-Methyl-Chroman-2-carboxylic Acid Ethyl Ester (TAL-1045)

7-Methyl-4-oxo- 4H -chroman-2-carboxylic acid ethyl ester (TAL-1037) (350 mg, 1.15 mmol) was dissolved in ethanol (10 mL), followed by Pd / C (80 mg) and acetic acid ( 1 mL) was placed in a 100 mL round flask and stirred for one day under hydrogen stream. The solid was removed by filtration through Celite, the filtrate was concentrated and purified by column chromatography to give the product on the oil (TAL-1045).

Yield: 98%, 328 mg

¹ H NMR (CDCl ₃ , 300 MHz) d 6.91 (d, 1H, J = 7.6 Hz, Ar- H ), 6.76 (s, 1H, Ar- H ) 6.69 (d, 1H, J = 7.6 Hz, Ar- H ), 4.69 (d, 1H, J = 7.3 Hz, OC H COO), 4.26 (q, 2H, J = 7.1 Hz, COOC H ₂ CH ₃ ), 2.85-2.65 (m, 2H, OCHCH ₂ C H ₂ ), 2.28 (s, 3H, Ar-C H ₃ ), 2.25-2.15 (m, 2H, OCHC H ₂ CH ₂ ), 1.29 (t, 3H, J = 7.1 Hz, COOCH ₂ C H ₃ )

Example 1-6 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (TAL-1046)

7-Methyl-Chroman-2-carboxylic acid ethyl ester (TAL-1045) (360 mg, 1.63 mmol) was dissolved in water (15 mL) and potassium hydroxide (366 mg, 6.52 mmol) was stirred at rt for 1 h. After stirring, 6N hydrochloric acid was added to make the pH neutral, and extracted with ethyl acetate. The solvent was concentrated under reduced pressure to obtain TAL-1046.

Yield: 96%, 301 mg

¹ H NMR (CDCl ₃ , 300 MHz) d 6.95 (d, 1H, J = 7.6 Hz, Ar- H ), 6.76 (s, 1H, Ar- H ) 6.73 (d, 1H, J = 7.8 Hz, Ar- H ), 4.73 (dd, 1H, J = 8.2 Hz, OC H CH ₂ CH ₂ ), 2.85-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.39-2.33 (m, 1H, OCHC H ₂ CH ₂ ), 2.29 (s, 3H, Ar-C H ₃ ), 2.18-2.05 (m, 1H, OCHC H ₂ CH ₂ )

Example 2 Preparation of 6-Methyl-Chroman-2-carboxylic Acid Phenylamide (WAL-1208)

6-Methyl-chroman-carboxylic acid (WAL-1116) (100 mg, 0.52 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and then N, N -carbonyldiimidazole (126 mg, 0.78 mmol, 1.5 Equivalent). After the reaction at room temperature for 1 hour, phenylamine (84 mg, 0.78 mmol, 1.5 equivalents) was added thereto, and the mixture was stirred for 12 hours under room temperature and a nitrogen stream. Then, the mixture was concentrated under reduced pressure, water was added, titrated to pH 3 to 4 with 6 N hydrochloric acid, and extracted with dichloromethane. The organic layer was concentrated under reduced pressure after removing water from the organic layer to obtain the derivative WAL-1208 by column chromatography.

Yield: 90% 119 mg

m. p. 96-98 ℃

IR (KBr): 3461, 1654, 1504, 703 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.60 (d, 2H, J = 7.79 Hz, Ar- H ), 7.35 (t, 2H, J = 7.87 Hz, Ar- H ), 7.15 (t, 1H, J = 7.43 Hz, Ar- H ), 6.98 (d, 1H, J = 7.26 Hz, Ar- H ), 6.91 (s, 1H, Ar- H ), 6.87 (d, 1H, J = 8.24 Hz, Ar- H ), 4.62 (dd, 1H, J = 9.64 Hz, OC H CH ₂ CH ₂ ), 2.97-2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.03 (m, 2H, OCHC H ₂ CH ₂ ) , 2.28 (s, 3H, Ar-C H ₃ )

Example 3 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2-Hydroxy-phenyl) -amide (WAL-1155)

Except for using 60 mg (0.55 mmol) of 2-aminophenol instead of phenylamine, the same equivalent weight as in Example 2 was obtained, to obtain a derivative WAL-1155.

Yield: 47% 50 mg

m. p. 177-179 ℃

IR (KBr): 3089, 1654, 1550, 773 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.15 (t, 1H, J = 6.98 Hz, Ar- H ), 7.06 (d, 1H, J = 6.42 Hz, Ar- H ), 7.05 (t, 1H, J = 5.04 Hz, Ar- H ), 6.98 (d, 1H, J = 8.23 Hz, Ar- H ), 6.94 (s, 1H, Ar- H ), 6.88 (d, 2H, J = 8.38 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.75 Hz, OC H CH ₂ CH ₂ ), 3.00-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.57-2.00 (m, 2H, OCHC H ₂ CH ₂ ) , 2.28 (s, 3H, Ar-C H ₃ )

Example 4 : Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3-hydroxy-phenyl) -amide (WAL-1156)

Derivative WAL-1156 was obtained by the same amount as in Example 2 except that 60 mg (0.55 mmol) of 3-aminophenol was used instead of phenylamine.

Yield: 83% 90 mg

m. p. 177-179 ℃

IR (KBr): 3392, 3214, 1664, 1552 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.70 (s, 1H, Ar- H ), 7.15 (t, 1H, J = 7.56 Hz, Ar- H ), 6.96 (d, 1H, J = 8.16 Hz, Ar- H ), 6.90 (s, 1H, Ar- H ), 6.85 ( d, 1H, J = 8.22, Ar- H ), 6.72 (d, 1H, J = 7.79 Hz, Ar- H ), 4.63 (d, 1H, J = 9.73 Hz), 4.60 (dd, 1H, J = 6.82 Hz, OC H CH ₂ CH ₂ ), 3.00-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.25 (s, 3H, Ar-C H ₃ )

Example 5 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (4-hydroxy-phenyl) -amide (WAL-1157)

Derivative WAL-1157 was obtained by the same equivalent as that of Example 2 except that 60 mg (0.55 mmol) of 4-aminophenol was used instead of phenylamine.

Yield: 56% 60 mg

m. p. 162-165 ℃

IR (KBr): 3264, 1654, 1506, 1224 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.67 (d, 2H, J = 8.79 Hz, Ar- H ), 7.25 (d, 1H, J = 8.25 Hz, Ar- H ), 7.20 (s, 1H, Ar H ), 7.15 (d, 1H, J = 8.34, Ar- H ), 7.05 (d, 2H, J = 8.56 Hz, Ar- H ), 4.75 (dd, 1H, J = 9.71 Hz, OC H CH ₂ CH ₂ ), 3.25-3.00 (m, 2H, OCHCH ₂ C H ₂ ), 2.83-2.30 (m, 2H, OCHC H ₂ CH ₂ ), 2.55 (s, 3H, Ar-C H ₃ )

Example 6 Preparation of 6 -Methyl-Chroman-2-carboxylic Acid (2-Methyl-phenyl) -amide (WAL-1163)

Except for using 84 mg (0.78 mmol) of 2-tolylamine in place of phenylamine, the same amount as in Example 2 was obtained to obtain a derivative WAL-1163.

Yield: 72% 105 mg

m. p. 88-90 ℃

IR (KBr): 3423, 1675, 1521, 628 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.02 (d, 1H, J = 7.94 Hz, Ar- H ), 7.21 (t, 1H, J = 8.49 Hz, Ar- H ), 7.19 (d, 1H, J = 7.16 Hz, Ar- H ), 7.05 (t, 1H, J = 7.38 Hz, Ar- H ), 6.96 (d, 1H, J = 10.07 Hz, Ar- H ), 6.90 (s, 1H, Ar- H ), 6.82 (d, 1H, J = 8.19 Hz, Ar- H ), 4.70 (dd, 1H, J = 8.70 Hz, OC H CH ₂ CH ₂ ), 2.95-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.10 (m, 2H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ ), 2.22 (s, 3H, Ar-C H ₃ )

Example 7 : Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3-Methyl-phenyl) -amide (WAL-1164)

Except for using 84 mg (0.78 mmol) of 3-tolylamine instead of phenylamine, the same amount as in Example 2 was obtained to obtain a derivative WAL-1164.

Yield: 80% 110 mg

m. p. 100-102 ℃

IR (KBr): 3239, 1673, 1554, 769 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.45 (s, 1H, Ar- H ), 7.35 (d, 1H, J = 8.17 Hz, Ar- H ), 7.25 (t, 1H, J = 9.29 Hz, Ar H ), 6.95 (d, 2H, J = 6.03 Hz, Ar- H ), 6.90 (s, 1H, Ar- H ), 6.85 (d, 1H, J = 8.24 Ar- H ), 4.61 (dd, 1H , J = 9.67 Hz, OC H CH ₂ CH ₂ ), 2.95-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.50-2.10 (m, 2H, OCHC H ₂ CH ₂ ), 2.35 (s, 3H, Ar-C H ₃ ), 2.25 (s, 3H, Ar-C H ₃ )

Example 8 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (4-Methyl-phenyl) -amide (WAL-1165)

Except for using 84 mg (0.78 mmol) of 4-tolylamine instead of phenylamine was carried out the same equivalent as in Example 2 to obtain the derivative WAL-1165.

Yield: 92% 130 mg

m. p. 113-116 ℃

IR (KBr): 3318, 1666, 1529, 663 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.35 (d, 2H, J = 9.36 Hz, Ar- H ), 7.15 (d, 2H, J = 8.23 Hz, Ar- H ), 7.03 (d, 1H, J = 8.54 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.84 (d, 1H, J = 8.24 Hz, Ar- H ) 4.60 (dd, 1H, J = 9.67 Hz, OC H CH ₂ CH ₂ ), 2.95-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.05 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ ), 2.28 (s , 3H, Ar-C H ₃ )

Example 9 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2-methoxy-phenyl) -amide (WAL-1160)

Except for using 96 mg (0.78 mmol) of 2-methoxyphenylamine in place of phenylamine was carried out the same equivalent as in Example 2 to obtain the derivative WAL-1160.

Yield: 71% 110 mg

m. p. 119-121 ℃

IR (KBr): 3461, 1683, 1536, 661 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.42 (d, 1H, J = 6.64 Hz, Ar- H ), 7.07 (t, 1H, J = 6.27 Hz, Ar- H ), 6.97 (t, 1H, J = 7.64 Hz, Ar- H ), 6.95 (d, 2H, J = 5.40 Hz, Ar- H ), 6.92 (d, 1H, J = 8.28 Hz, Ar- H ), 6.90 (s, 1H, Ar- H ), 6.85 (d, 1H, J = 8.28, Ar- H ), 4.65 (dd, 1H, J = 9.68 Hz, OC H CH ₂ CH ₂ ), 3.84 (s, 3H, Ar-OCH ₃ ), 2.90- 2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.50-2.04 (m, 2H, OCHC H ₂ CH ₂ ), 2.27 (s, 3H, Ar-C H ₃ )

Example 10 Preparation of 6-Methyl-Chromman-2-carboxylic Acid (3-methoxy-phenyl) -amide (WAL-1161)

Derivative WAL-1161 was obtained in the same equivalent manner as in Example 2 except that 96 mg (0.78 mmol) of 3-methoxyphenylamine was used instead of phenylamine.

Yield: 68% 100 mg

m. p. 101-103 ℃

IR (KBr): 3282, 1677, 1531, 703 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.40 (s, 1H, Ar- H ), 7.25 (t, 1H, J = 8.16 Hz, Ar- H ), 7.07 (d, 1H, J = 8.92 Hz, Ar H ), 6.98 (d, 1H, J = 6.27 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.89 (d, 1H, J = 8.24 Hz, Ar- H ), 6.73 (d , 1H, J = 6.65, Ar- H ), 4.60 (dd, 1H, J = 10.61 Hz, OC H CH ₂ CH ₂ ), 3.82 (s, 3H, Ar-OCH ₃ ), 2.95-2.72 (m, 2H , OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.30 (s, 3H, Ar-C H ₃ )

Example 11 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (4-methoxy-phenyl) -amide (WAL-1170)

Derivative WAL-1170 was obtained by the same amount as in Example 2, except that 96 mg (0.78 mmol) of 4-methoxyphenylamine was used instead of phenylamine.

Yield: 88% 130 mg

m. p. 126-129 ℃

IR (KBr): 3199, 1666, 1506, 524 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.48 (d, 2H, J = 8.92 Hz, Ar- H ), 7.97 (d, 1H, J = 8.38 Hz, Ar- H ), 7.92 (d, 2H, J = 8.99 Hz, Ar- H ), 6.87 (s, 1H, Ar- H ), 6.84 (d, 1H, J = 8.11 Hz, Ar- H ), 4.59 (dd, 1H, J = 9.69 Hz, OC H CH ₂ CH ₂ ), 3.80 (s, 3H, Ar-OCH ₃ ), 2.94-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.28 (s , 3H, Ar-C H ₃ )

Example 12 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2-Trifluoromethyl-phenyl) -amide (WAL-2013)

Except for using 63 mg (0.39 mmol) of 2-trifluoromethylphenylamine in place of phenylamine, the same amount as in Example 2 was obtained to obtain an oil-like derivative WAL-2013.

Yield: 34% 30 mg

IR (KBr): 3436, 1706, 1533, 761 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.38 (d, 1H, J = 8.29 Hz, Ar- H ), 7.63 (d, 1H, J = 8.32 Hz, Ar- H ), 7.58 (t, 1H, J = 8.76 Hz, Ar- H ), 7.25 (t, 1H, J = 7.25 Hz, Ar- H ), 6.97 (d, 1H, J = 8.24 Hz, Ar- H ), 6.90 (d, 1H, J = 8.20 Hz, Ar- H ), 6.87 (s, 1H, Ar- H ), 4.60 (dd, 1H, J = 9.70 Hz, OC H CH ₂ CH ₂ ), 2.95-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ )

Example 13 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3-Trifluoromethyl-phenyl) -amide (WAL-1166)

Derivative WAL-1166 was obtained by following the same equivalent as Example 2 except that 125 mg (0.78 mmol) of 3-trifluoromethylphenylamine was used instead of phenylamine.

Yield: 52% 90 mg

m. p. 89-91 ℃

IR (KBr): 3272, 1675, 1494, 692 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.90 (s, 1H, Ar- H ), 7.80 (d, 1H, J = 7.98 Hz, Ar- H ), 7.47 (t, 1H, J = 7.87 Hz, Ar- H ), 7.40 (d, 1H, J = 7.77 Hz, Ar- H ), 6.96 (d, 1H, J = 8.19 Hz, Ar- H ), 6.92 (s, 1H, Ar- H ), 6.87 (d, 1H, J = 8.25 Hz, Ar- H ), 4.56 (dd, 1H, J = 9.75 Hz, OC H CH ₂ CH ₂ ), 3.00-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.30 (s, 3H , Ar-C H ₃ )

Example 14 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (4-Trifluoromethyl-phenyl) -amide (WAL-1167)

Derivative WAL-1167 was obtained in the same amount as in Example 2 except that 125 mg (0.78 mmol) of 4-trifluoromethylphenylamine was used instead of phenylamine.

Yield: 75% 130 mg

m. p. 143-145 ℃

IR (KBr): 3315, 1679, 1517, 690 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.75 (d, 2H, J = 8.55 Hz, Ar- H ), 7.60 (d, 2H, J = 8.56 Hz, Ar- H ), 6.97 (d, 1H, J = 8.20 Hz, Ar- H ), 6.91 (s, 1H, Ar- H ), 6.88 (d, 1H, J = 4.40 Hz, Ar- H ), 4.63 (dd, 1H, J = 9.77 Hz, OC H CH ₂ CH ₂ ), 2.98-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.20 (m, 2H, OCHC H ₂ CH ₂ ), 2.27 (s, 3H, Ar-C H ₃ )

Example 15 Preparation of 6-Methyl-Chromman-2-carboxylic Acid (2-nitro-phenyl) -amide (WAL-2004)

Derivative WAL-2004 was obtained by the same amount as in Example 2 except for using 54 mg (0.39 mmol) of 2-nitrophenylamine instead of phenylamine.

Yield: 25% 20 mg

m. p. 111-113 ℃

IR (KBr): 3311, 1704, 1594, 736 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.93 (d, 1H, J = 8.56 Hz, Ar- H ), 8.25 (d, 1H, J = 8.50 Hz, Ar- H ), 7.65 (t, 1H, J = 7.84 Hz, Ar- H ), 7.25 (t, 1H, J = 10.44 Hz, Ar- H ), 7.05 (d, 1H, J = 8.38 Hz, Ar- H ), 7.00 (s, 1H, Ar- H ), 6.90 (d, 1H, J = 7.03 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.42 Hz, OC H CH ₂ CH ₂ ), 2.93-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.25 (s, 3H, Ar-C H ₃ )

Example 16 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3-Nitro-phenyl) -amide (WAL-1176)

Derivative WAL-1176 was obtained by the same equivalent as Example 2 except for using 54 mg (0.39 mmol) of 3-nitrophenylamine instead of phenylamine.

Yield: 49% 40 mg

m. p. 175-177 ℃

IR (KBr): 3363, 1693, 1540, 661 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.45 (s, 1H, Ar- H ), 8.03 (d, 1H, J = 6.72 Hz, Ar- H ), 8.01 (d, 1H, J = 7.58 Hz, Ar- H ), 7.51 (t, 1H, J = 8.17 Hz, Ar- H ), 7.00 (d, 1H, J = 8.10 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.89 (d, 1H, J = 8.29 Hz, Ar- H ), 4.63 (dd, 1H, J = 9.78 Hz, OC H CH ₂ CH ₂ ), 2.98-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.29 (s, 3H , Ar-C H ₃ )

Example 17 Preparation of 6-Methyl-Chromman-2-carboxylic Acid (4-nitro-phenyl) -amide (WAL-1183)

Except that 108 mg (0.78 mmol) of 4-nitrophenylamine was used instead of phenylamine, the same amount as in Example 2 was obtained to obtain a derivative WAL-1183.

Yield: 42% 70 mg

m. p. 162-165 ℃

IR (KBr): 3351, 1702, 1600, 655 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.25 (d, 2H, J = 9.06 Hz, Ar- H ), 7.81 (d, 2H, J = 9.06 Hz, Ar- H ), 7.00 (d, 1H, J = 8.28 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.88 (d, 1H, J = 8.24 Hz, Ar- H ), 4.63 (dd, 1H, J = 9.84 Hz, OC H CH ₂ CH ₂ ), 2.90-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ )

Example 18 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2-Chloro-phenyl) -amide (WAL-2006)

Derivative WAL-2006 was obtained in the same equivalent manner as in Example 2 except that 50 mg (0.39 mmol) of 2-chlorophenylamine was used instead of phenylamine.

Yield: 65% 50 mg

m. p. 181-183 ℃

IR (KBr): 3372, 1689, 1531, 646 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.47 (d, 1H, J = 8.24 Hz, Ar- H ), 7.37 (d, 1H, J = 8.02 Hz, Ar- H ), 7.30 (t, 1H, J = 8.85 Hz, Ar- H ), 7.05 (t, 1H, J = 8.02 Hz, Ar- H ), 6.97 (d, 1H, J = 8.28 Hz, Ar- H ), 6.92 (s, 1H, Ar- H ), 6.87 (d, 1H, J = 8.28 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.22 Hz, OC H CH ₂ CH ₂ ), 2.96-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.45-2.05 (m, 2H, OCHC H ₂ CH ₂ ), 2.30 (s, 3H, Ar-C H ₃ )

Example 19 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3-Chloro-phenyl) -amide (WAL-1158)

Derivative WAL-1158 was obtained by the same amount as in Example 2 except that 100 mg (0.78 mmol) of 3-chlorophenylamine was used instead of phenylamine.

Yield: 90% 140 mg

m. p. 81-83 ℃

IR (KBr): 3343, 1675, 1590, 686 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.73 (s, 1H, Ar- H ), 7.45 (d, 1H, J = 7.30 Hz, Ar- H ), 7.26 (t, 1H, J = 8.06 Hz, Ar H ), 7.13 (d, 1H, J = 8.00 Hz, Ar- H ), 6.95 (d, 1H, J = 8.36 Hz, Ar- H ), 6.92 (s, 1H, Ar- H ), 6.86 (d , 1H, J = 10.76 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.66 Hz, OC H CH ₂ CH ₂ ), 2.95-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.07 (m, 2H, OCHC H ₂ CH ₂ ), 2.23 (s, 3H, Ar-C H ₃ )

Example 20 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (4-Chloro-phenyl) -amide (WAL-1159)

Derivative WAL-1159 was obtained in the same equivalent manner as in Example 2 except that 70 mg (0.54 mmol) of 4-chlorophenylamine was used instead of phenylamine.

Yield: 83% 90 mg

m. p. 117-119 ℃

IR (KBr): 3309, 1670, 1500, 674 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.55 (d, 2H, J = 8.69 Hz, Ar- H ), 7.33 (d, 2H, J = 8.80 Hz, Ar- H ), 6.97 (d, 1H, J = 8.20 Hz, Ar- H ), 6.90 (s, 1H, Ar- H ), 6.82 (d, 1H, J = 8.13 Hz, Ar- H ), 4.56 (dd, 1H, J = 9.73 Hz, OC H CH ₂ CH ₂ ), 2.97-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ )

Example 21 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,4-Dichloro-phenyl) -amide (TAL-1092)

Derivative TAL-1092 was obtained by the same equivalent as Example 2 except for using 126 mg (0.78 mmol) of 3,4-dichloroaniline in place of phenylamine.

Yield: 75% 131 mg

m. p 138-140 ℃

IR (KBr): 3323, 1678, 1585, 1234 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.75 (s, 1H, Ar- H ), 7.33 (d, 1H, J = 8.8 Hz, Ar- H ) 7.28 (d, 1H, J = 8.7 Hz, Ar- H ), 6.87 (d, 1H, J = 8.3 Hz, Ar- H ), 6.81 (s, 1H, Ar- H ), 6.75 (d, 1H, J = 8.2 Hz, Ar- H ), 4.48 (dd, 1H, J = 9.8 Hz, OC H CH ₂ CH ₂ ), 2.80-2.68 (m, 2H, OCHCH ₂ C H ₂ ), 2.39-2.34 (m, 1H, OCHC H ₂ CH ₂ ), 2.17 (s, 3H , Ar-C H ₃ ), 2.03-1.90 (m, 1H, OCHC H ₂ CH ₂ )

Example 22 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,5-Dichloro-phenyl) -amide (TAL-1093)

Derivative TAL-1093 was obtained by the same amount as in Example 2 except that 190 mg (1.17 mmol) of 3,5-dichloroaniline was used instead of phenylamine.

Yield: 24% 63 mg

m. p 141-143 ° C

IR (KBr): 3313, 1670, 1583, 1227 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.59 (s, 2H, Ar- H ), 7.13 (s, 1H, Ar- H ) 6.98 (d, 1H, J = 8.2 Hz, Ar- H ), 6.91 ( s, 1H, Ar- H ), 6.86 (d, 1H, J = 8.2 Hz, Ar- H ), 4.59 (dd, 1H, J = 9.8 Hz, OC H CH ₂ CH ₂ ), 2.90-2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.49-2.43 (m, 1H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ ), 2.13-2.00 (m, 1H, OCHC H ₂ CH ₂ )

Example 23 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2,5-Dichloro-phenyl) -amide (TAL-1091)

Derivative TAL-1091 was obtained by following the same equivalent as Example 2 except for using 128 mg (0.78 mmol) of 2,5-dichloroaniline instead of phenylamine.

Yield: 77% 134 mg

m. p 159-161 ℃

IR (KBr): 3365, 1695, 1583, 1213 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.54 (s, 1H, Ar- H ), 7.25 (d, 1H, J = 8.6 Hz, Ar- H ), 6.99 (d, 1H, J = 8.6 Hz, Ar -H ), 6.92 (d, 1H, J = 8.3 Hz, Ar- H ), 6.86 (s, 1H, Ar- H ), 6.83 (d, 1H, J = 8.3 Hz, Ar- H ), 4.62 (dd , 1H, J = 9.3 Hz, OC H CH ₂ CH ₂ ), 2.88-2.69 (m, 2H, OCHCH ₂ C H ₂ ), 2.47-2.41 (m, 1H, OCHC H ₂ CH ₂ ), 2.22 (s, 3H, Ar-C H ₃ ), 2.15-2.02 (m, 1H, OCHC H ₂ CH ₂ )

Example 24 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,4-Dimethyl-phenyl) -amide (TAL-1087)

Except for using 142 mg (1.17 mmol) of 3,4-dimethylaniline in place of phenylamine, the same amount as in Example 2 was obtained to obtain a derivative TAL-1087.

Yield: 65% 150 mg

m. p 117-119 ° C

IR (KBr): 3259, 1666, 1496, 1217 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.42 (s, 1H, Ar- H ), 7.36 (d, 1H, J = 8.1 Hz, Ar- H ) 7.12 (d, 1H, J = 8.1 Hz, Ar- H ), 6.99 (d, 1H, J = 8.2 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.90 (d, 1H, J = 8.4 Hz, Ar- H ), 4.61 (dd, 1H, J = 9.7 Hz, OC H CH ₂ CH ₂ ), 2.94-2.77 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.46 (m, 1H, OCHC H ₂ CH ₂ ), 2.31 (s, 3H , Ar-C H ₃ ), 2.29 (s, 3H, Ar-C H ₃ ), 2.26 (s, 3H, Ar-C H ₃ ), 2.17-2.08 (m, 1H, OCHC H ₂ CH ₂ )

Example 25 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,5-Dimethyl-phenyl) -amide (TAL-1086)

Except for using 142 mg (1.17 mmol) of 3,5-dimethylaniline in place of phenylamine, the same amount as in Example 2 was obtained to obtain a derivative TAL-1086.

Yield: 86% 199 mg

m. p 150-152 ℃

IR (KBr): 3273, 1662, 1545, 1221 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.26 (s, 2H, Ar- H ), 6.99 (d, 1H, J = 8.2 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.90 (d, 1H, J = 8.3 Hz, Ar- H ), 6.81 (s, 1H, Ar- H ), 4.61 (dd, 1H, J = 9.6 Hz, OC H CH ₂ CH ₂ ), 2.92-2.81 (m , 2H, OCHCH ₂ C H ₂ ), 2.55-2.46 (m, 1H, OCHC H ₂ CH ₂ ), 2.34 (s, 9H, Ar-C H ₃ ), 2.16-2.08 (m, 1H, OCHC H ₂ CH ₂ )

Example 26 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2,5-Dimethyl-phenyl) -amide (TAL-1085)

Derivative TAL-1085 was obtained by following the same equivalent as Example 2 except for using 47 mg (0.39 mmol) of 2,5-dimethylaniline in place of phenylamine.

Yield: 78% 60 mg

m. p 115-117 ° C

IR (KBr): 3305, 1664, 1539, 1228 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.90 (s, 1H, Ar- H ), 7.08 (d, 1H, J = 7.7 Hz, Ar- H ) 6.98 (d, 1H, J = 8.2 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.91 (d, 1H, J = 9.4 Hz, Ar- H ), 6.87 (d, 1H, J = 8.2 Hz, Ar- H ), 4.71 (dd, 1H, J = 8.7 Hz, OC H CH ₂ CH ₂ ), 2.92-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.43 (m, 1H, OCHC H ₂ CH ₂ ), 2.36 (s, 3H , Ar-C H ₃ ), 2.30 (s, 3H, Ar-C H ₃ ), 2.27-2.22 (m, 1H, OCHC H ₂ CH ₂ ), 2.19 (s, 3H, Ar-C H ₃ )

Example 27 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,4-Dimethoxy-phenyl) -amide (TAL-1090)

Derivative TAL-1090 was obtained by following the same equivalent as Example 2 except for using 119 mg (0.78 mmol) of 3,4-dimethoxyaniline instead of phenylamine.

Yield: 71% 121 mg

m. p 119-121 ℃

IR (KBr): 3194, 1664, 1508, 1232 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.41 (s, 1H, Ar- H ), 6.97 (d, 2H, J = 8.6 Hz, Ar- H ) 6.91 (s, 1H, Ar- H ), 6.87 ( d, 1H, J = 8.3 Hz, Ar- H ), 6.82 (d, 1H, J = 8.6 Hz, Ar- H ), 4.59 (dd, 1H, J = 9.7 Hz, OC H CH ₂ CH ₂ ), 3.90 (s, 3H, Ar-OC H ₃ ), 3.87 (s, 3H, Ar-OC H ₃ ), 2.90-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.44 (m, 1H, OCHC H ₂ CH ₂ ), 2.27 (s, 3H, Ar-C H ₃ ), 2.15-2.04 (m, 1H, OCHC H ₂ CH ₂ )

Example 28 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,5-dimethoxy-phenyl) -amide (TAL-1108)

Derivative TAL-1108 was obtained by the same amount as in Example 2 except that 180 mg (1.17 mmol) of 3,5-dimethoxyaniline was used instead of phenylamine.

Yield: 72% 185 mg

m. p 93-95 ℃

IR (KBr): 3317, 1674, 1543, 1153 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 6.97 (d, 1H, J = 8.2 Hz, Ar- H ), 6.90 (s, 1H, Ar- H ), 6.88 (d, 1H, J = 9.8 Hz, Ar - H), 6.85 (s, 2H, Ar- H), 6.28 (s, 1H, Ar- H), 4.58 (dd, 1H, J = 9.7 Hz, OC H CH 2 CH 2), 3.79 (s, 6H , OC H ₃ ), 2.89-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.50-2.45 (m, 1H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ ), 2.12 2.05 (m, 1H, OCHC H ₂ CH ₂ )

Example 29 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (2,5-dimethoxy-phenyl) -amide (TAL-1070)

Derivative TAL-1070 was obtained by following the same equivalent as Example 2 except that 37 mg (0.24 mmol) of 2,5-dimethoxyaniline was used instead of phenylamine.

Yield: 62% 33 mg

m. p 102-104 ℃

IR (KBr): 3317, 1674, 1543, 1217 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.17 (s, 1H, Ar- H ), 6.98 (d, 1H, J = 8.3 Hz, Ar- H ) 6.90 (s, 1H, Ar- H ), 6.89 ( d, 1H, J = 8.4 Hz, Ar- H ), 6.80 (d, 1H, J = 8.5 Hz, Ar- H ), 6.60 (d, 1H, J = 8.8 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.1 Hz, OC H CH ₂ CH ₂ ), 3.82 (s, 3H, Ar-OC H ₃ ), 3.80 (s, 3H, Ar-OC H ₃ ), 2.93-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.49-2.43 (m, 1H, OCHC H ₂ CH ₂ ), 2.28 (s, 3H, Ar-C H ₃ ), 2.21-2.06 (m, 1H, OCHC H ₂ CH ₂ )

Example 30 Preparation of 6-Methyl-Chroman-2-carboxylic Acid (3,5-Ditrifluoromethyl-phenyl) -amide (TAL-1088)

Except for using 178 mg (0.78 mmol) of 3,5-bistrifluoromethylaniline instead of phenylamine, the same amount as in Example 2 was obtained to obtain a derivative TAL-1088.

Yield: 57% 119 mg

m. p 152-154 ℃

IR (KBr): 3373, 1682, 1558, 1282 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.14 (s, 2H, Ar- H ), 7.65 (s, 1H, Ar- H ), 6.99 (d, 1H, J = 8.3 Hz, Ar- H ), 6.93 (s, 1H, Ar- H ), 6.90 (d, 1H, J = 8.3 Hz, Ar- H ), 4.64 (dd, 1H, J = 9.9 Hz, OC H CH ₂ CH ₂ ), 2.99-2.76 (m , 2H, OCHCH ₂ C H ₂ ), 2.55-2.46 (m, 1H, OCHC H ₂ CH ₂ ), 2.29 (s, 3H, Ar-C H ₃ ), 2.16-2.03 (m, 1H, OCHC H ₂ CH ₂ )

Example 31 Preparation of 7-methyl-chroman-2-carboxylic acid phenylamide (WAL-1220)

7-Methyl-Chroman-2-carboxylic acid (TAL-1046) (100 mg, 0.52 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and then N, N -carbonyldiimidazole (126 mg, 0.78 mmol, 1.5 Equivalent). After the reaction at room temperature for 1 hour, phenylamine (84 mg, 0.78 mmol, 1.5 equivalents) was added thereto, and the mixture was stirred for 12 hours under room temperature and a nitrogen stream. Then, the mixture was concentrated under reduced pressure, water was added, titrated to pH 3 to 4 with 6 N hydrochloric acid, and extracted with dichloromethane. The organic layer was concentrated under reduced pressure after removing water from the organic layer to obtain the derivative WAL-1220 by column chromatography.

Yield: 92% 131 mg

m. p. 130-133 ℃

IR (KBr): 3309, 1670, 1529, 682 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.02 (s, 1H, J = 7.84 Hz, Ar- H ), 7.60 (d, 1H, J = 7.84 Hz, Ar- H ), 7.33 (t, 1H, J = 7.87 Hz, Ar- H ), 7.14 (t, 1H, J = 7.41 Hz, Ar- H ), 6.98 (d, 1H, J = 7.67 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.74 (d, 1H, J = 7.67 Hz, Ar- H ), 4.62 (dd, 1H, J = 11.23 Hz, OC H CH ₂ CH ₂ ), 2.15-2.72 (m, 2H, OCHCH ₂ C H ₂ ) 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.45 (s, 3H, Ar-C H ₃ )

Example 32 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (2-hydroxy-phenyl) -amide (WAL-1186)

Derivative WAL-1186 was obtained by the same equivalent as that of Example 31 except that 85 mg (0.78 mmol) of 2-aminophenol was used instead of phenylamine.

Yield: 70% 99 mg

m. p. 173-175 ℃

IR (KBr): 2921, 1641, 1550, 742 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.16 (t, 1H, J = 7.63 Hz, Ar- H ), 7.04 (d, 2H, J = 7.98 Hz, Ar- H ), 6.98 (d, 1H, J = 7.62 Hz, Ar- H ), 6.90 (t, 1H, J = 7.70 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 8.27 Hz, Ar- H ), 4.70 (dd, 1H, J = 6.85 Hz, OC H CH ₂ CH ₂ ), 3.00-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.58-2.00 (m, 2H, OCHC H ₂ CH ₂ ) , 2.33 (s, 3H, Ar-C H ₃ )

Example 33: Preparation of 7-methyl-chroman-2-carboxylic acid (3-hydroxy-phenyl) -amide (WAL-1206)

Derivative WAL-1206 was obtained by the same equivalent as that of Example 31 except that 85 mg (0.78 mmol) of 3-aminophenol was used instead of phenylamine.

Yield: 94% 139 mg

m. p. 200-203 ℃

IR (KBr): 3156, 1660, 1550, 740 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.56 (s, 1H, Ar- H ), 7.20 (t, 1H, J = 8.00 Hz, Ar- H ), 6.98 (d, 1H, J = 7.60 Hz, Ar- H ), 6.87 (d, 1H, J = 8.00 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 7.90 Hz, Ar- H ), 6.61 (d, 1H, J = 8.40 Hz), 4.60 (dd, 1H, J = 6.82 Hz, OC H CH ₂ CH ₂ ), 2.89-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.51-2.20 (m, 2H, OCHC H ₂ CH ₂ ), 2.38 (s, 3H, Ar-C H ₃ )

Example 34 Preparation of 7-Methyl-Chromman-2-carboxylic Acid (4-hydroxy-phenyl) -amide (WAL-1207)

Derivative WAL-1207 was obtained by the same equivalent as Example 31 except that 85 mg (0.78 mmol) of 4-aminophenol was used instead of phenylamine.

Yield: 70% 99 mg

m. p. 200-203 ℃

IR (KBr): 3295, 1662, 1542, 520 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.43 (d, 2H, J = 8.78 Hz, Ar- H ), 6.98 (d, 1H, J = 7.61 Hz, Ar- H ), 6.83 (d, 1H, J = 8.93 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 6.6 Hz, Ar- H ), 6.75 (d, 1H, J = 7.89 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.70 Hz, OC H CH ₂ CH ₂ ), 2.94-2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.52-2.00 (m, 2H, OCHC H ₂ CH ₂ ) , 2.32 (s, 3H, Ar-C H ₃ )

Example 35 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (2-Methyl-phenyl) -amide (WAL-1184)

Derivative WAL-1184 was obtained by the same equivalent as that of Example 31 except that 84 mg (0.78 mmol) of 2-tolylamine was used instead of phenylamine.

Yield: 86% 120 mg

m. p. 90-93 ℃

IR (KBr): 3424, 1668, 1527, 656 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.02 (d, 1H, J = 8.07 Hz, Ar- H ), 7.22 (d, 1H, J = 10.7 Hz, Ar- H ), .9.17 (t, 1H, J = 9.17 Hz, Ar- H ), 7.08 (t, 1H, J = 7.40 Hz, Ar- H ), 7.00 (d, 1H, J = 7.57 Hz, Ar- H ), 6.78 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 8.43 Hz, Ar- H ), 4.70 (dd, 1H, J = 10.5 Hz, OC H CH ₂ CH ₂ ), 2.90-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.10 (m, 2H, OCHC H ₂ CH ₂ ), 2.32 (s, 3H, Ar-C H ₃ ), 2.22 (s, 3H, Ar-C H ₃ )

Example 36 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (3-Methyl-phenyl) -amide (WAL-1181)

Except for using 84 mg (0.78 mmol) of 3-tolylamine in place of phenylamine, the same amount as in Example 31 was obtained to obtain the derivative WAL-1181.

Yield: 98% 140 mg

m. p. 106-108 ℃

IR (KBr): 3197, 1671, 1554, 767 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.45 (s, 1H, Ar- H ), 7.38 (d, 1H, J = 7.94 Hz, Ar- H ), 7.23 (t, 1H, J = 7.84 Hz, Ar H ), 6.99 (d, 1H, J = 7.03 Hz, Ar- H ), 6.95 (d, 1H, J = 6.21 Hz, Ar- H ), 6.81 (s, 1H, Ar- H ), 6.76 (d , 1H, J = 7.59 Hz, Ar- H ), 4.61 (dd, 1H, J = 9.50 Hz, OC H CH ₂ CH ₂ ), 2.95-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.35 (s, 3H, Ar-C H ₃ ), 2.35 (s, 3H, Ar-C H ₃ ), 2.30 (s, 3H, Ar-C H ₃ )

Example 37 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (4-Methyl-phenyl) -amide (WAL-1182)

Except for using 84 mg (0.78 mmol) of 4-tolylamine in place of phenylamine, the same amount as in Example 31 was obtained to obtain the derivative WAL-1182.

Yield: 98% 140 mg

m. p. 139-141 ℃

IR (KBr): 3320, 1664, 1531, 661 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.47 (d, 2H, J = 8.31 Hz, Ar- H ), 7.15 (d, 2H, J = 8.20 Hz, Ar- H ), 6.98 (d, 1H, J = 7.75 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 2.76 (d, 1H, J = 7.69 Hz, Ar- H ) 4.60 (dd, 1H, J = 9.73 Hz, OC H CH ₂ CH ₂ ), 2.95-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 6H, Ar-C H ₃ )

Example 38 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (2-methoxy-phenyl) -amide (WAL-1185)

Derivative WAL-1160 was obtained by the same equivalent as Example 31 except that 96 mg (0.78 mmol) of 2-methoxyphenylamine was used instead of phenylamine.

Yield: 98% 147 mg

m. p. 81-83 ℃

IR (KBr): 3369, 1675, 1535, 636 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.42 (d, 1H, J = 8.85 Hz, Ar- H ), 7.08 (t, 1H, J = 7.69 Hz, Ar- H ), 7.99 (t, 1H, J = 3.7 Hz, Ar- H ), 6.97 (d, 2H, J = 4.26 Hz, Ar- H ), 6.88 (d, 1H, J = 7.99 Hz, Ar- H ), 6.83 (s, 1H, Ar- H ), 6.75 (d, 1H, J = 7.61, Ar- H ), 4.65 (dd, 1H, J = 10.67 Hz, OC H CH ₂ CH ₂ ), 3.88 (s, 3H, Ar-OCH ₃ ), 2.90- 2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.56-2.04 (m, 2H, OCHC H ₂ CH ₂ ), 2.34 (s, 3H, Ar-C H ₃ )

Example 39 Preparation of 7-methyl-chroman-2-carboxylic acid (3-methoxy-phenyl) -amide (WAL-1177)

Derivative WAL-1177 was obtained in the same amount as in Example 31 except that 96 mg (0.78 mmol) of 3-methoxyphenylamine was used instead of phenylamine.

Yield: 94% 140 mg

m. p. 93-96 ℃

IR (KBr): 3229, 1666, 1535, 674 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.38 (s, 1H, Ar- H ), 7.25 (t, 1H, J = 7.83 Hz, Ar- H ), 7.05 (d, 1H, J = 8.07 Hz, Ar H ), 7.98 (d, 1H, J = 7.64 Hz, Ar- H ), 6.81 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 7.77 Hz, Ar- H ), 6.70 (d , 1H, J = 7.05, Ar- H ), 4.60 (dd, 1H, J = 10.6 Hz, OC H CH ₂ CH ₂ ), 3.82 (s, 3H, Ar-OCH ₃ ), 2.95-2.72 (m, 2H , OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.23 (s, 3H, Ar-C H ₃ )

Example 40 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (4-methoxy-phenyl) -amide (WAL-1178)

Derivative WAL-1178 was obtained by the same equivalent as Example 31 except that 96 mg (0.78 mmol) of 4-methoxyphenylamine was used instead of phenylamine.

Yield: 98% 147 mg

m. p. 127-130 ℃

IR (KBr): 3448, 1683, 1519, 800 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.50 (d, 2H, J = 8.68 Hz, Ar- H ), 6.98 (d, 1H, J = 7.66 Hz, Ar- H ), 6.88 (d, 2H, J = 8.67 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.75 (d, 1H, J = 7.61 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.57 Hz, OC H CH ₂ CH ₂ ), 3.80 (s, 3H, Ar-OCH ₃ ), 2.94-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.32 (s , 3H, Ar-C H ₃ )

Example 41 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (2-Trifluoromethyl-phenyl) -amide (WAL-2026)

Derivative WAL-2026 was obtained by following the same equivalent as Example 31 except for using 125 mg (0.78 mmol) of 2-trifluoromethylphenylamine instead of phenylamine.

Yield: 25% 40 mg

m. p. 82-84 ℃

IR (KBr): 3421, 1710, 1535, 634 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.38 (d, 2H, J = 8.28 Hz, Ar- H ), 7.61 (d, 1H, J = 7.99 Hz, Ar- H ), 7.58 (t, 1H, J = 9.37 Hz, Ar- H ), 7.22 (t, 1H, J = 6.45 Hz, Ar- H ), 6.98 (d, 1H, J = 7.51 Hz, Ar- H ), 6.78 (s, 1H, Ar- H ), 6.75 (d, 1H, J = 8.21 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.80 Hz, OC H CH ₂ CH ₂ ), 2.95-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.34 (s, 3H, Ar-C H ₃ )

Example 42 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (3-Trifluoromethyl-phenyl) -amide (WAL-1209)

Derivative WAL-1209 was obtained by the same equivalent as Example 31 except that 125 mg (0.78 mmol) of 3-trifluoromethylphenylamine was used instead of phenylamine.

Yield: 96% 162 mg

m. p. 104-106 ℃

IR (KBr): 3407, 1668, 1531, 661 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.91 (s, 1H, Ar- H ), 7.82 (d, 1H, J = 7.90 Hz, Ar- H ), 7.48 (t, 1H, J = 7.86 Hz, Ar- H ), 7.40 (d, 1H, J = 7.70 Hz, Ar- H ), 7.00 (d, 1H, J = 7.63 Hz, Ar- H ), 6.83 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 7.67 Hz, Ar- H ), 4.61 (dd, 1H, J = 9.84 Hz, OC H CH ₂ CH ₂ ), 2.97-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.56-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H , Ar-C H ₃ )

Example 43 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (4-Trifluoromethyl-phenyl) -amide (WAL-1179)

Derivative WAL-1179 was obtained by the same equivalent as Example 31 except that 125 mg (0.78 mmol) of 4-trifluoromethylphenylamine was used instead of phenylamine.

Yield: 98% 171 mg

m. p. 156-158 ℃

IR (KBr): 3328, 1689, 1518 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.55 (d, 2H, J = 8.32 Hz, Ar- H ), 7.80 (d, 2H, J = 8.37 Hz, Ar- H ), 7.00 (d, 1H, J = 7.55 Hz, Ar- H ), 6.84 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 7.74 Hz, Ar- H ), 4.63 (dd, 1H, J = 9.76 Hz, OC H CH ₂ CH ₂ ), 2.98-2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.34 (s, 3H, Ar-C H ₃ )

Example 44 Preparation of 7-Methyl-Chromman-2-carboxylic Acid (2-nitro-phenyl) -amide (WAL-1190)

Except for using 54 mg (0.39 mmol) of 2-nitrophenylamine in place of phenylamine was carried out the same equivalent as in Example 31 to obtain the derivative WAL-1190.

Yield: 88% 70 mg

m. p. 82-84 ℃

IR (KBr): 3461, 1724, 1587, 730 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.91 (d, 1H, J = 8.57 Hz, Ar- H ), 8.27 (d, 1H, J = 8.43 Hz, Ar- H ), 7.68 (t, 1H, J = 7.72 Hz, Ar- H ), 7.23 (t, 1H, J = 9.32 Hz, Ar- H ), 6.98 (d, 1H, J = 7.73 Hz, Ar- H ), 6.91 (s, 1H, Ar- H ), 6.75 (d, 1H, J = 7.86 Hz, Ar- H ), 4.67 (dd, 1H, J = 9.86 Hz, OC H CH ₂ CH ₂ ), 3.00-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.50-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ )

Example 45 Preparation of 7-methyl-chroman-2-carboxylic acid (3-nitro-phenyl) -amide (WAL-1189)

Except for using 11 mg (0.08 mmol) of 3-nitrophenylamine in place of phenylamine was carried out the same equivalent as in Example 31 to obtain the derivative WAL-1189.

Yield: 60% 10 mg

m. p. 147-149 ℃

IR (KBr): 3450, 1675, 1531, 628 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.47 (s, 1H, Ar- H ), 8.04 (d, 1H, J = 8.23 Hz, Ar- H ), 8.01 (d, 1H, J = 8.25 Hz, Ar- H ), 7.51 (t, 1H, J = 8.18 Hz, Ar- H ), 7.00 (d, 1H, J = 7.67 Hz, Ar- H ), 6.83 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 8.66 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.83 Hz, OC H CH ₂ CH ₂ ), 2.98-2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H , Ar-C H ₃ )

Example 46 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (4-nitro-phenyl) -amide (WAL-1180)

Except for using 108 mg (0.78 mmol) of 4-nitrophenylamine in place of phenylamine was carried out the same equivalent as in Example 31 to obtain the derivative WAL-1180.

Yield: 81% 130 mg

m. p. 136-138 ℃

IR (KBr): 3363, 1695, 1504, 647 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.25 (d, 2H, J = 9.06 Hz, Ar- H ), 7.81 (d, 2H, J = 9.07 Hz, Ar- H ), 7.00 (d, 1H, J = 7.61 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.79 (d, 1H, J = 7.90 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.95 Hz, OC H CH ₂ CH ₂ ), 3.00-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ )

Example 47 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (2-Chloro-phenyl) -amide (WAL-1195)

Derivative WAL-1195 was obtained in the same equivalent manner as in Example 31 except that 30 mg (0.23 mmol) of 2-chlorophenylamine was used instead of phenylamine.

Yield: 62% 30 mg

m. p. 76-79 ℃

IR (KBr): 3365, 1689, 1529, 634 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.48 (d, 1H, J = 8.22 Hz, Ar- H ), 7.38 (d, 1H, J = 7.98 Hz, Ar- H ), 7.30 (t, 1H, J = 7.89 Hz, Ar- H ), 7.05 (t, 1H, J = 7.71 Hz, Ar- H ), 6.97 (d, 1H, J = 7.66 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 7.35 Hz, Ar- H ), 4.68 (dd, 1H, J = 10.13 Hz, OC H CH ₂ CH ₂ ), 2.95-2.70 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ )

Example 48 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (3-Chloro-phenyl) -amide (WAL-1204)

Derivative WAL-1204 was obtained by the same equivalent as that of Example 31 except that 100 mg (0.78 mmol) of 3-chlorophenylamine was used instead of phenylamine.

Yield: 85% 133 mg

m. p. 84-87 ℃

IR (KBr): 3330, 1671, 1529, 646 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.73 (s, 1H, Ar- H ), 7.47 (d, 1H, J = 9.79 Hz, Ar- H ), 7.28 (t, 1H, J = 10.2 Hz, Ar H ), 7.13 (d, 1H, J = 7.99 Hz, Ar- H ), 7.00 (d, 1H, J = 7.64 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.70 (d , 1H, J = 6.88 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.74 Hz, OC H CH ₂ CH ₂ ), 2.95-2.50 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.32 (s, 3H, Ar-C H ₃ )

Example 49 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (4-Chloro-phenyl) -amide (WAL-1205)

Derivative WAL-1205 was obtained in the same equivalent manner as in Example 31 except that 100 mg (0.78 mmol) of 4-chlorophenylamine was used instead of phenylamine.

Yield: 77% 120 mg

m. p. 140-142 ℃

IR (KBr): 3301, 1666, 1523, 690 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.56 (d, 2H, J = 8.78 Hz, Ar- H ), 7.32 (d, 2H, J = 8.75 Hz, Ar- H ), 7.00 (d, 1H, J = 7.69 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.77 (d, 1H, J = 7.70 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.78 Hz, OC H CH ₂ CH ₂ ), 2.98-2.61 (m, 2H, OCHCH ₂ C H ₂ ), 2.55-2.00 (m, 2H, OCHC H ₂ CH ₂ ), 2.32 (s, 3H, Ar-C H ₃ )

Example 50 Preparation of 7-methyl-chroman-2-carboxylic acid (3,4-dichloro-phenyl) -amide (TAL-1084)

Derivative TAL-1084 was obtained by the same amount as in Example 31 except that 39 mg (0.24 mmol) of 3,4-dichloroaniline was used instead of phenylamine.

Yield: 91% 49 mg

m. p 141-143 ° C

IR (KBr): 3311, 1670, 1518, 1379 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.86 (s, 1H, Ar- H ), 7.45 (d, 1H, J = 8.7 Hz, Ar- H ) 7.40 (d, 1H, J = 8.7 Hz, Ar- H ), 7.00 (d, 1H, J = 7.6 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.78 (d, 1H, J = 8.2 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.9 Hz, OC H CH ₂ CH ₂ ), 2.95-2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.44 (m, 1H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H , Ar-C H ₃ ), 2.13-2.00 (m, 1H, OCHC H ₂ CH ₂ )

Example 51 Preparation of 7-methyl-chroman-2-carboxylic acid (3,5-dichloro-phenyl) -amide (TAL-1083)

Derivative TAL-1083 was obtained by following the same equivalent as Example 31 except that 190 mg (1.17 mmol) of 3,5-dichloroaniline was used instead of phenylamine.

Yield: 52% 135 mg

m. p 118-120 ℃

IR (KBr): 3325, 1684, 1585, 1117 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.60 (s, 2H, Ar- H ), 7.13 (s, 1H, Ar- H ) 6.99 (d, 1H, J = 7.6 Hz, Ar- H ), 6.80 ( s, 1H, Ar- H ), 6.78 (d, 1H, J = 8.5 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.8 Hz, OC H CH ₂ CH ₂ ), 2.89-2.79 (m, 2H, OCHCH ₂ C H ₂ ), 2.51-2.45 (m, 1H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ ), 2.10-2.05 (m, 1H, OCHC H ₂ CH ₂ )

Example 52 Preparation of 7-methyl-chroman-2-carboxylic acid (2,5-dichloro-phenyl) -amide (TAL-1082)

Derivative TAL-1082 was obtained by following the same equivalent as Example 31 except that 190 mg (1.17 mmol) of 2,5-dichloroaniline was used instead of phenylamine.

Yield: 86% 225 mg

m. p 128-130 ℃

IR (KBr): 3363, 1709, 1581, 1254 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.59 (s, 1H, Ar- H ), 7.31 (d, 1H, J = 8.6 Hz, Ar- H ), 7.05 (d, 1H, J = 8.6 Hz, Ar H ), 6.98 (d, 1H, J = 7.6 Hz, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 7.7 Hz, Ar- H ), 4.67 (dd , 1H, J = 9.6 Hz, OC H CH ₂ CH ₂ ), 2.90-2.80 (m, 2H, OCHCH ₂ C H ₂ ), 2.49-2.46 (m, 1H, OCHC H ₂ CH ₂ ), 2.32 (s, 3H, Ar-C H ₃ ), 2.14-2.10 (m, 1H, OCHC H ₂ CH ₂ )

Example 53 Preparation of 7-methyl-chroman-2-carboxylic acid (3,4-dimethyl-phenyl) -amide (TAL-1052)

Derivative TAL-1052 was obtained by following the same equivalent as Example 31 except that 29 mg (0.24 mmol) of 3,4-dimethylaniline was used instead of phenylamine.

Yield: 91% 43 mg

m. p 142-144 ℃

IR (KBr): 3076, 1672, 1537, 1240 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.39 (s, 1H, Ar- H ), 7.32 (d, 1H, J = 8.1 Hz, Ar- H ) 7.11 (d, 1H, J = 8.1 Hz, Ar- H ), 6.99 (d, 1H, J = 7.7 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 7.7 Hz, Ar- H ), 4.61 (dd, 1H, J = 9.7 Hz, OC H CH ₂ CH ₂ ), 2.94 to 2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.54-2.45 (m, 1H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H , Ar-C H ₃ ), 2.27 (s, 3H, Ar-C H ₃ ), 2.24 (s, 3H, Ar-C H ₃ ), 2.18-2.02 (m, 1H, OCHC H ₂ CH ₂ )

Example 54 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (3,5-Dimethyl-phenyl) -amide (TAL-1050)

Except that 29 mg (0.24 mmol) of 3,5-dimethylaniline was used instead of phenylamine, the same amount as in Example 31 was obtained to obtain the derivative TAL-1050.

Yield: 98% 47 mg

m. p 129-131 ° C

IR (KBr): 3311, 1670, 1541, 1244 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.25 (s, 2H, Ar- H ), 6.99 (d, 1H, J = 7.6 Hz, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.80 (s, 1H, Ar- H ), 6.77 (d, 1H, J = 7.7 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.7 Hz, OC H CH ₂ CH ₂ ), 2.95-2.74 (m , 2H, OCHCH ₂ C H ₂ ), 2.53-2.42 (m, 1H, OCHC H ₂ CH ₂ ), 2.33 (s, 9H, Ar-C H ₃ ), 2.15-2.02 (m, 1H, OCHC H ₂ CH ₂ )

Example 55 Preparation of 7-methyl-chroman-2-carboxylic acid (2,5-dimethyl-phenyl) -amide (TAL-1049)

Derivative TAL-1049 was obtained by following the same equivalent as Example 31 except that 29 mg (0.24 mmol) of 2,5-dimethylaniline was used instead of phenylamine.

Yield: 94% 44 mg

m. p 127-129 ° C

IR (KBr): 3267, 1664, 1533, 1255 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.87 (s, 1H, Ar- H ), 7.07 (d, 1H, J = 7.7 Hz, Ar- H ) 6.99 (d, 1H, J = 7.5 Hz, Ar- H ), 6.90 (d, 1H, J = 7.5 Hz, Ar- H ), 6.78 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 8.2 Hz, Ar- H ), 4.69 (dd, 1H, J = 8.9 Hz, OC H CH ₂ CH ₂ ), 2.93-2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.52-2.43 (m, 1H, OCHC H ₂ CH ₂ ), 2.34 (s, 3H , Ar-C H ₃ ), 2.32 (s, 3H, Ar-C H ₃ ), 2.18 (s, 3H, Ar-C H ₃ ), 2.23-2.11 (m, 1H, OCHC H ₂ CH ₂ )

Example 56 Preparation of 7-methyl-chroman-2-carboxylic acid (3,4-dimethoxy-phenyl) -amide (TAL-1047)

Derivative TAL-1047 was obtained by the same amount as in Example 31 except that 23 mg (0.15 mmol) of 3,4-dimethoxyaniline was used instead of phenylamine.

Yield: 80% 26 mg

m. p 118-120 ℃

IR (KBr): 3290, 1662, 1525, 1242 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 7.41 (s, 1H, Ar- H ), 6.99 (d, 1H, J = 5.3 Hz, Ar- H ) 6.97 (d, 1H, J = 6.0 Hz, Ar- H ), 6.83 (d, 1H, J = 9.0 Hz, Ar- H ), 6.81 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 7.8 Hz, Ar- H ), 4.60 (dd, 1H, J = 9.8 Hz, OC H CH ₂ CH ₂ ), 3.91 (s, 3H, Ar-OC H ₃ ), 3.87 (s, 3H, Ar-OC H ₃ ), 2.89-2.76 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.45 (m, 1H, OCHC H ₂ CH ₂ ), 2.32 (s, 3H, Ar-C H ₃ ), 2.14-2.03 (m, 1H, OCHC H ₂ CH ₂ )

Example 57 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (3,5-dimethoxy-phenyl) -amide (TAL-1106)

Derivative TAL-1106 was obtained by the same equivalent as Example 31 except that 180 mg (1.17 mmol) of 3,5-dimethoxyaniline was used instead of phenylamine.

Yield: 62% 203 mg

m. p 115-117 ° C

IR (KBr): 3392, 1685, 1539, 1151 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 6.99 (d, 1H, J = 7.7 Hz, Ar- H ), 6.86 (s, 2H, Ar- H ), 6.82 (s, 1H, Ar- H ), 6.76 (d, 1H, J = 7.7 Hz, Ar- H ), 6.28 (s, 1H, Ar- H ), 4.59 (dd, 1H, J = 9.8 Hz, OC H CH ₂ CH ₂ ), 3.80 (s, 6H , OC H ₃ ), 2.89-2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.53-2.44 (m, 1H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ ), 2.13 2.05 (m, 1H, OCHC H ₂ CH ₂ )

Example 58 Preparation of 7-methyl-chroman-2-carboxylic acid (2,5-dimethoxy-phenyl) -amide (TAL-1048)

Derivative TAL-1048 was obtained by the same amount as in Example 31 except that 23 mg (0.15 mmol) of 2,5-dimethoxyaniline was used instead of phenylamine.

Yield: 68% 22 mg

m. p 109-111 ° C

IR (KBr): 3386, 1678, 1541, 1248 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.16 (s, 1H, Ar- H ), 6.98 (d, 1H, J = 7.7 Hz, Ar- H ) 6.81 (d, 1H, J = 8.9 Hz, Ar- H ), 6.81 (s, 1H, Ar- H ), 6.75 (d, 1H, J = 7.8 Hz, Ar- H ), 6.08 (d, 1H, J = 8.9 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.3 Hz, OC H CH ₂ CH ₂ ), 3.83 (s, 3H, Ar-OC H ₃ ), 3.80 (s, 3H, Ar-OC H ₃ ), 2.93-2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.51-2.42 (m, 1H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ ), 2.19-2.05 (m, 1H, OCHC H ₂ CH ₂ )

Example 59 Preparation of 7-Methyl-Chroman-2-carboxylic Acid (3,5-Ditrifluoromethyl-phenyl) -amide (TAL-1081)

Derivative TAL-1081 was obtained by the same amount as in Example 31 except that 268 mg (1.17 mmol) of 3,5-bistrifluoromethylaniline was used instead of phenylamine.

Yield: 53% 213 mg

m. p 133-135 ℃

IR (KBr): 3273, 1682, 1556, 1279 cm ^-1

¹ H NMR (CDCl ₃ , 300 MHz) d 8.14 (s, 2H, Ar- H ), 7.65 (s, 1H, Ar- H ), 7.01 (d, 1H, J = 7.7 Hz, Ar- H ), 6.84 (s, 1H, Ar- H ), 6.79 (d, 1H, J = 7.7 Hz, Ar- H ), 4.65 (dd, 1H, J = 9.9 Hz, OC H CH ₂ CH ₂ ), 2.83-2.77 (m , 2H, OCHCH ₂ C H ₂ ), 2.54-2.47 (m, 1H, OCHC H ₂ CH ₂ ), 2.34 (s, 3H, Ar-C H ₃ ), 2.16-2.03 (m, 1H, OCHC H ₂ CH ₂ )

As described below for the biological efficacy of the target compound obtained from the above production method, the inhibitory effect of NF-κB was measured through Example 60, and was calculated as a concentration (IC ₅₀ ) showing a 50% inhibitory effect accordingly.

Example 60 Inhibitory Effect on NF-κB Activation

As described below, the inhibitory effect of NF-κB was measured and calculated as a concentration (IC ₅₀ ) indicating 50% inhibitory effect.

Macrophage introduced pNF-κB-SEAP-NPT (Moon, KY et al. , Anal. Biochem. 292; 17-21 (2001)), a plasmid capable of detecting expression of reporter genes dependent on NF-κB activation RAW264.7 cells (TIB-71, ATCC (American Type Culture Collection)) were pretreated for 2 hours with the sample (compound obtained in Example) and stimulated with glycolipid (LPS, 1 ug / ml) for 24 hours. After centrifugation of the cell culture, the supernatant obtained was used to determine the amount of secreted alkaline phosphatase (SEAP) produced in association with the activation of NF-κB in relative fluorescence units (RFU). (Moon, KY et al. , Anal. Biochem. 292; 17-21 (2001)). From the measured results, the effect of the sample was calculated as a concentration (IC ₅₀ ) showing a 50% inhibitory effect and is shown in Table 3 below.

As shown in Table 3, the sample, that is, the compound prepared in the above example, has an IC ₅₀ value of 50 μM or less, and in most cases, 20 μM to 40 μM, and thus has a very good effect of inhibiting NF-κB activation. It was confirmed.

No. IC ₅₀ (μM) ₎ WAL-1155 22.2 WAL-1157 34.3 WAL-1183 45.7 WAL-1159 24.0 TAL-1092 60.0 WAL-1207 49.3 WAL-1177 55.0 WAL-1178 23.1 WAL-2026 32.7 WAL-1190 35.5 WAL-1180 45.3 WAL-1195 64.6 WAL-1205 20.2 TAL-1083 67.3 TAL-1081 33.6

Claims (11)

Chromman-2-carboxylic acid amide derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof: (Formula 1)

In the above formula, R ¹ and R ² are each alkyl wherein R ¹ is C1 to C4 and R ² is H or R ¹ is H and R ² is C1 to C4 alkyl, R ³ to R ⁷ are each independently H, hydroxy, alkoxy of C1 to C4, alkyl of C1 to C4, nitro, trifluoromethyl or halogen. The method of claim 1, The chroman-2-carboxylic acid amide derivative 6-Methyl-Chroman-2 -carboxylic acid phenylamide, 6-Methyl-Chroman-2 -carboxylic acid (2-hydroxy-phenyl) -amide, 6-Methyl-Chroman-2 -carboxylic acid (3-hydroxy- Phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4-hydroxy-phenyl) -amide, 6-methyl-chroman-carboxylic acid (2-methoxy-phenyl) -amide, 6-methyl -Croman-2-carboxylic acid (3-methoxy-phenyl) -amide, 6-methyl-chromen-2-carboxylic acid (4-methoxy-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid ( 2-methyl-phenyl) amide, 6-methyl-chroman-2-carboxylic acid (3-methyl-phenyl) -amide, 6-methyl-chroman-carboxylic acid (4-methyl-phenyl) amide, 6-methyl -Chroman-2-carboxylic acid (2-nitro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3-nitro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4- Nitro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (2-trifluoromethyl-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3-Trifluoromethyl-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4-trifluoromethyl-phenyl) -amide, 6-methyl-chroman-carboxylic acid (2-chloro -Phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3-chloro-phenyl) -amide, 6-methyl-chroman-carboxylic acid (4-chloro-phenyl) -amide, 6-methyl- Chromman-2-carboxylic acid (3,4-dichloro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3,5-dichloro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (2,5-Dichloro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (3,4-dimethyl-phenyl) -amide, 6-methyl-chroman-carboxylic acid (3,5-dimethyl -Phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (2,5-dimethyl-phenyl) -amide, 6-methyl-chroman-carboxylic acid (3,4-dimethoxy-phenyl) -amide , 6-Methyl-chroman-carboxylic acid (3,5-dimethoxy-phenyl) -amide, 6-methyl-chroman-carboxylic acid (2,5-dimethoxy-phenyl) -amide, 6-Methyl-Chroman-2-carboxylic acid (3,5-ditrifluoromethyl-phenyl) -amide, 7-methyl-Chroman-carboxylic acid phenylamide, 7-methyl-chroman-2-carboxylic acid ( 2-hydroxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3-hydroxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-hydroxy-phenyl)- Amide, 7-methyl-chroman-2-carboxylic acid (2-methoxy-phenyl) -amide, 7-methyl-chroman-carboxylic acid (3-methoxy-phenyl) -amide, 7-methyl-chroman 2-carboxylic acid (4-methoxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2-methyl-phenyl) amide, 7-methyl-chroman-2-carboxylic acid (3-methyl-phenyl ) -Amide, 7-methyl-chroman-2-carboxylic acid (4-methyl-phenyl) amide, 7-methyl-chroman-2-carboxylic acid (2-nitro-phenyl) -amide, 7-methyl-chroman- 2-carboxylic acid (3-nitro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-nitro-phenyl) -amide, 7-methyl-chroman-2-carboxy Acid (2-Trifluoromethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3-trifluoromethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4- Trifluoromethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2-chloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3-chloro-phenyl) -amide, 7-Methyl-Chroman-2-carboxylic acid (4-chloro-phenyl) -amide, 7-methyl-Chroman-2-carboxylic acid (3,4-dichloro-phenyl) -amide, 7-methyl-chromane-2 -Carboxylic acid (3,5-dichloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2,5-dichloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,4 -Dimethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (3,5-dimethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2,5-dimethyl-phenyl)- Amide, 7-methyl-chroman-2-carboxylic acid (3,4-dimethoxy-phenyl) -amide, 7-methyl-chroman-carboxylic acid (3,5-dimethoxy-phenyl ) -Amide, 7-methyl-chroman-2-carboxylic acid (2,5-dimethoxy-phenyl) -amide and 7-methyl-chroman-2-carboxylic acid (3,5-ditrifluoromethyl-phenyl )-Any one selected from the group consisting of amides Chromman-2-carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof. The method of claim 2, The chroman-2-carboxylic acid amide derivative 6-Methyl-Chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, 6-methyl-Chroman-carboxylic acid (4-hydroxy-phenyl) -amide, 6-methyl-chromane-2 -Carboxylic acid (4-nitro-phenyl) -amide, 6-methyl-chroman-2-carboxylic acid (4-chloro-phenyl) -amide, 6-methyl-chroman-carboxylic acid (3,4-dichloro-phenyl ) -Amide, 7-methyl-chroman-2-carboxylic acid (4-hydroxy-phenyl) -amide, 7-methyl-chroman-carboxylic acid (3-methoxy-phenyl) -amide, 7-methyl- Chromman-2-carboxylic acid (4-methoxy-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2-trifluoromethyl-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (2-nitro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-nitro-phenyl) -amide, 7-methyl-chroman-carboxylic acid (2-chloro-phenyl) -amide, 7-methyl-chroman-2-carboxylic acid (4-chloro-phenyl) -amide, 7-methyl-chroman-carboxylic acid (3,5-dichloro-phenyl) -amide 7-methyl-chroman-2-carboxylic acid (3,5-Oro triple-phenyl) - is any one selected from the group consisting of amide Chromman-2-carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof. (a) reacting a 2-hydroxy-acetophenone derivative with an oxalic acid diester to prepare a compound having the structure of Formula 2; (b) reducing the compound having the structure of Formula 2 to prepare a compound having the structure of Formula 3; (c) hydrolyzing the compound having the structure of Formula 3 to produce a compound having the structure of Formula 4; And (d) reacting the compound having the structure of Formula 4 and the amine compound to prepare a chroman-2-carboxylic acid amide derivative having the structure of Formula 1 Method for producing a chroman-2-carboxylic acid amide derivative, comprising a. (Formula 1)

(Formula 2)

(Formula 3)

(Formula 4)

In Formula 2 to Formula 4, R ¹ and R ² are each alkyl wherein R ¹ is C1 to C4, R ² is H or R ¹ is H and R ² is alkyl from C1 to C4. The method of claim 4, wherein the amine compound is selected from phenylamine, aminophenol, methoxyphenylamine, tolylamine, trifluoromethylphenylamine, nitrophenylamine, chlorophenylamine, dichlorophenylamine, dimethylamine, dimethoxyphenylamine and A method for producing a chroman-2-carboxylic acid amide derivative, which is any one selected from the group consisting of ditrifluoromethylphenylamine. A composition for inhibiting NF-κB comprising the chromman-2-carboxylic acid amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A composition for the prophylaxis or treatment of multiple myeloma comprising the chromman-2-carboxylic acid amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A composition for the prophylaxis or treatment of rheumatoid arthritis, comprising the chromoman-2-carboxylic acid amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Chromman-2-carboxylic acid amide derivatives according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient comprising a composition for preventing or treating cancer. The method according to any one of claims 6 to 9, The composition is a composition of the chromaman-2-carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof is 0.001 to 99.9% by weight relative to the total composition. The method according to any one of claims 6 to 9, The formulation of the composition is any one selected from the group consisting of warning agents, granules, lotions, powders, syrups, solutions, aerosols, ointments, liquid extracts, emulsions, suspensions, acupuncture, tablets, injections, capsules and pills Composition.