KR101543439B1 - -2- indoline-2-carboxamide derivatives process for preparing the same and pharmaceutical composition comprising it - Google Patents

Abstract

The present invention relates to a novel indoline-2-carboxamide derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. Since the novel chroman-2-carboxylic acid amide derivative has the ability to inhibit NF-κB activity, the pharmaceutical composition containing it as an active ingredient is useful as a therapeutic agent for diseases related to NF-κB, preferably multiple myeloma, rheumatoid arthritis and cancer Or a composition for preventing or treating any one or more diseases selected from the group consisting of:

Indolin-2-carboxamide derivatives, NF-κB

Description

INDOLINE-2-CARBOXAMIDE DERIVATIVES, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING IT BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to indoline-2-carboxamide derivatives,

The present invention relates to a novel indoline-2-carboxamide derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

Most human diseases are caused by the association of abnormal elements with substances produced by gene expression during the onset or progress of the disease. Such diseases include autoimmune diseases including autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease (IBD), septicemia Septic shock, lung fibrosis, carcinogenesis, various cancers, and Acquired Immune Deficiency Syndrome (AIDS).

In general, these genes are either inactive or very insignificant in biological or physical processes. However, the expression of these genes under exponential conditions such as exposure to environmental pollution increases exponentially with pre-existing genetic factors. These genetic elements are essential transcription factors that regulate gene expression in cytokines, chemokines, growth factors, adhesion molecules, and acute phase proteins. And Nuclear Factor-κB (NF-κB).

NF-κB was first identified as a transcription-activating substance specific for B cells of the k-light chain gene of immunoglobulin. Since then, NF-κB has been identified in a variety of cells and is known to be activated by many factors. Such NF-κB has been extensively studied in various fields such as immunology, molecular biology, biochemistry, genetics, cell biology and developmental biology.

NF-κB is mostly found in the cytoplasm of cells and is composed of homo-dimers and hetero-dimers in association with structurally similar protein groups. (Baldwin, AS et al . . Annu . Rev. Immunol. , 14 : 649-683 (1996); Kopp, EB et al . , Adv . Immunol , 58 : 1-27 (1995)). Each element of such a protein family contains a protected amino terminus termed the Rel-Homology Domain (RHD) binding domain, dimerization domain, and nuclear localization signal (NLS). In particular, in mammals, NF-κB is composed 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 from the active protein causing 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 are transformed into p50 and p52, which are the smaller active forms that cause transcription through various processes. Typical NF-κB has a dimer form of p65 (RelA) and p50 / p105 (NF-κB1). However, there are also various dimmer forms that include other Rel (Michael, JM et al . , Immunol . Today , 19: 80-88 (1998)).

In the cytoplasm, NF-κB is present in an inactive form in association with IkBa, IkBb, IkBe, IkBg, and Bcl3, known as inhibitory proteins, and IkB of p100 and p105, the precursor proteins (Simon, TW et al . , Semin . Cancer Biol . 8 : 75-82 (1997)). All known IkBs contain an ankyrin repeat domain with a variety of 30 to 33 amino acid sequences and a specific interaction between the ankyrin repeat domain and RHD is the NF- lt; RTI ID = 0.0 > IkB. < / RTI > The IkB family regulates NF-κB DNA binding and subcellular localization of Rel-NF-κB proteins by blocking the NLS located near the carboxyl terminus of RHD of NF-κB (Thomas, H. et al . , Cell . 68 : 1121-1133 (1992)).

The factor that regulates the binding of NF-κB to IkB is IkB kinase (IKK). Activation of IKK phosphorylates the N - terminus of IkB and regulates the release of IkB. This IKK contains two kinase subunits of IKKa (IKK1) and IKKb (IKK2) and regulatory subunits of NKO (NF-κB essential modifier) or IKKg (Rothwarf, DM et al . , Sci , STKE , 5 : re1. (1999)). In the pathway of general NF-κB, IKKb phosphorylates two N -terminal serine residues of IkB. In particular, IkBa phosphorylates at serine residues 32 and 36 and IkBb phosphorylates at serine residues 19 and 23. The role of IKKa is unclear in the general NF-κB pathway, but recent studies have suggested that it may modulate gene expression by altering the phosphorylation state of histones in the nucleus. However, another pathway for NF-κB is phosphorylation of p100 and is dependent on IKKa, which induces p52.

Thus, each IkB phosphorylated by the IKK complex is ubiquitinated by a ubiquitin ligase, such as an element of SCF (or SCRF), and degraded in the proteasome. When IkB is degraded, NF-κB is activated and is transported into the nucleus by NLS to express the gene. Actually there is a difference in pathway due to very large external signals to activate NF-κB. However, the majority of the pathways are identical in terms of activating IKK and enhancing transcription of NF-κB by liberating IkB. Among the notable studies, there are TNFR, TLR / IL-1R, TCR and BCR pathways that activate IKK by external signals (Matthew, SH et al . , Genes Dev . 18 : 2195-2224 (2004)).

In particular, NF-κB is a cytokine, chemokine, adhesion molecule, acute phase proteins, anti-microbial peptide, cell surface receptor, , Inducible 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, toxic substances, bacteria, viruses, ultraviolet rays, ionizing radiation, etc. Internal substances include cytokines, inflammatory mediators, growth factors, and oxygen deficiency , M. et al . , Nature , 406: 367-8 (2000); Mercurio, F. et al . , curr. Opin . Cell Biol ., 11: 226-32 (1999)).

These genes have been reported to cause many diseases. In particular, abnormal NF-κB activation is known to be involved in inflammatory diseases such as various myeloma, arthritis, various inflammatory diseases such as myeloma, arterial stenosis and asthma, and inflammatory diseases and malignant diseases (Aradhya, S meat al . , Curr. Opin. Genet, Dev, 11: 300-7 (2001); Orlowski, RZ et al . , Trnds Mol. Med., 8: 385-9 (2002)). For example, bortezomib, an inhibitor of the 26S proteasome involved in NF-κB activation, is an anticancer drug for multiple myeloma and has been approved by the US Food and Drug Administration for use in clinical practice (Dispenzieri, AN Engl J. Med ., 352: 2546-8 (2005)).

Therefore, it is necessary to study the development of a substance capable of effectively inhibiting the activation of NF-κB in order to treat refractory diseases such as arthritis, intractable diseases such as autoimmune diseases, multiple myeloma, cancer and the like.

The present invention provides a novel indolin-2-carboxamide derivative compound that effectively inhibits the activation of NF-kB and a method for producing the same.

The present invention also provides a pharmaceutical composition comprising the indolin-2-carboxamide derivative compound as an active ingredient.

The present invention provides an indoline-2-carboxamide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Wherein,

X is H, tert-butoxycarbonyl, or R'CO-, R 'is alkyl having 1 to 9 carbon atoms or arylalkyl having 7 to 12 carbon atoms,

R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents H, a hydroxyl group, a halogen atom, a nitro group, an alkyl group having 1 to 9 carbon atoms, an alkoxy group having 1 to 9 carbon atoms, 9-alkyl, or halogen-substituted alkoxy of 1 to 9 carbons.

The present invention also provides a process for producing the above indolin-2-carboxamide derivative.

The present invention also provides a pharmaceutical composition comprising the indolin-2-carboxamide derivative as an active ingredient.

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

The inventors of the present invention have focused on the fact that inhibition of NF-κB activation can prevent and treat inflammation, multiple myeloma and cancer, and that NF-κB activation inhibitor can be used as a pharmaceutical composition useful for diseases such as inflammation diseases and cancer In the course of developing various chroman derivatives, several kinds of indolinone derivatives having similar structures were synthesized to confirm the effect of inhibiting NF-κB activation. On the basis thereof, novel indoline-2-carboxamide derivatives effective for inhibiting NF-κB activation were derived and their preparation was established, thereby completing the present invention.

In particular, the present invention provides a novel indoline-2-carboxamide derivative compound, a process for producing the same, and an NF-κB inhibitor containing the same as an active ingredient. The inhibitor may be used as a composition for preventing or treating NF-κB-related diseases, and preferably a composition for preventing or treating any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer.

In one aspect of the present invention, the present invention provides a compound having a structure represented by the following formula (I), and pharmaceutically acceptable salts thereof.

[Chemical Formula 1]

Wherein,

X is H, tert-butoxycarbonyl, or R'CO-, R 'is alkyl having 1 to 9 carbon atoms or arylalkyl having 7 to 12 carbon atoms,

R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents H, a hydroxyl group, a halogen atom, a nitro group, an alkyl group having 1 to 9 carbon atoms, an alkoxy group having 1 to 9 carbon atoms, 9-alkyl, or halogen-substituted alkoxy of 1 to 9 carbons.

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

The compounds of the present invention is preferably indoline-2-carboxylic acid N-phenylamide, indoline-2-carboxylic acid N - (2- hydroxy-phenyl) -amide, indoline-2-carboxylic acid N - (3- hydroxy 2-carboxylic acid N - (2-methoxy-phenyl) -amide, indolin-2-carboxylic acid N- (4-hydroxy-phenyl) carboxylic acid N - (3- methoxy-phenyl) -amide, indoline-2-carboxylic acid N - (4- methoxy-phenyl) -amide, indoline-2-carboxylic acid N - (2- methyl-phenyl) -amide , indoline-2-carboxylic acid N - (3- methyl-phenyl) -amide, indoline-2-carboxylic acid N - (4- methyl-phenyl) -amide, indoline-2-carboxylic acid N - (2- tree Carboxylic acid N - (3-trifluoromethyl-phenyl) -amide, indoline-2-carboxylic acid N- (4-trifluoromethyl- phenyl) -amide, indolin- 2-carboxylic acid N - (2- chloro-phenyl) -amide, indoline-2-carboxylic acid N - (3- chloro- Phenyl) -amide, indoline-2-carboxylic acid N - (4- chloro-phenyl) -amide, indoline-2-carboxylic acid N - (2- nitro-phenyl) -amide, indoline-2-carboxylic acid N - ( Carboxylic acid N - (2,5-dichloro-phenyl) -amide, indolin-2-carboxylic acid N- (4-nitro- 2-carboxylic acid N - (3,5- dichloro-phenyl) -amide, indoline-2-carboxylic acid N - (3,4- dichloro-phenyl) -amide, indoline-2-carboxylic acid N - (2,5- Indole-2-carboxylic acid N - (3,4-dimethyl-phenyl) -amide, indolin-2-carboxylic acid N- (3,5- 2-carboxylic acid N - (2,5- dimethoxy-phenyl) -amide, indoline-2-carboxylic acid N - (3,5- dimethoxy-phenyl) -amide, indoline-2-carboxylic acid N - (3, 4-dimethoxy-phenyl) -amide, indoline-2-carboxylic acid N- (3,5-ditrifluoromethyl- phenyl) -amide, tert- butyl 2- (phenylcarbamoyl) indoline (2-hydroxyphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (3-hydroxyphenylcarbamoyl) indoline-1-carboxylate, butyl 2- (4-hydroxyphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (2-methoxyphenylcarbamoyl) indoline- (4-methoxyphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (ortho-tolylcarbamoyl) (Para-tolylcarbamoyl) indoline-1-carboxylate, tert- butyl 2- (meta-tolylcarbamoyl) indoline-1-carboxylate, tert- Butyl 2- (3-trifluoromethylphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (4-trifluoromethylphenylcarbamoyl) indolin- -Trifluoromethylphenylcarbamoyl) indoline-1-carboxylate, tert-butyl Butyl 2- (3-chlorophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (4-chlorophenylcarbamoyl) indoline- Carbamoyl) indolin-1-carboxylate, tert-butyl 2- (2-nitrophenylcarbamoyl) indoline-1-carboxylate, tert- butyl 2- (3-nitrophenylcarbamoyl) indolin- Carboxylate, tert-butyl 2- (4-nitrophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (2,5-dichlorophenylcarbamoyl) indoline- Butyl 2- (3,4-dichlorophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (2, (3,5-dimethylphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (3,4-dimethyl Phenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (2,5-dimethoxyphenylcarbamoyl) indolin- Carboxylate, tert-butyl 2- (3, 4-dimethoxyphenylcarbamoyl) indoline-1-carboxylate , And tert-butyl 2- (3,5-ditrifluoromethylphenylcarbamoyl) indoline-1-carboxylate.

The indoline-2-carboxamide derivative of the present invention is more preferably tert-butyl 2- (3,5-dichlorophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- 1-carboxylate, tert-butyl 2- (3-nitrophenylcarbamoyl) indolin-1-carboxylate, Indole-1-carboxylate, tert-butyl 2- (3,5-ditrifluoromethylphenylcarbamoyl) indole Carboxylate, and indoline-2-carboxylic acid N - (3,5-ditrifluoromethyl-phenyl) -amide.

According to another aspect of the present invention, there is provided a process for preparing an indoline-2-carboxamide derivative represented by Formula 1 above.

In particular, the present invention provides a process for preparing an indoline-2-carboxamide derivative comprising the step of reacting an indoline-2-carboxylic acid represented by the following formula (2) with an aniline compound represented by the following formula (3).

(2)

(3)

Wherein,

X is H, tert-butoxycarbonyl, or R'CO-, R 'is alkyl having 1 to 9 carbon atoms or arylalkyl having 7 to 12 carbon atoms,

R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents H, a hydroxyl group, a halogen atom, a nitro group, an alkyl group having 1 to 9 carbon atoms, an alkoxy group having 1 to 9 carbon atoms, 9-alkyl, or halogen-substituted alkoxy of 1 to 9 carbons.

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

In addition, the production method of the present invention is characterized in that before the reaction of the indoline-2-carboxylic acid with the aniline compound, the amino group of the indoline-2-carboxylic acid is replaced with a protecting group, and then ethyl (N, Propyl) -carbodiimide, and the like. ≪ / RTI >

In a preferred embodiment, the indolin-2-carboxamide derivatives of the present invention can be prepared by the method shown in Scheme 1 below, but are not limited to these examples. The following Scheme 1 illustrates the preparation of representative compounds of the present invention by stages of preparation and other compounds may be prepared by appropriate modification of reagents and starting materials familiar to those skilled in the art.

The method for preparing the indoline-based derivative represented by the above formula (1) may be as described in the following reaction formula (1).

 [Reaction Scheme 1]

Wherein R < 1 > ^to R & ^{lt ; 4} >

First, the indoline-2-carboxylic acid is dissolved in a mixed solvent of water and dioxane, and then ditert-butyl dicarbonate is used to make N- (tert-butoxycarbonyl) indoline-2-carboxylic acid have. A N- (tert- butoxycarbonyl) indoline-2-carboxylic acid ethyl generated - (N, N-dimethylaminopropyl) into the car after processing the carbodiimide aniline, such as hydroxy-aniline, anisidine N - (tert-butoxycarbonyl) indole-2-carboxylic acid N - (monosubstituted or polysubstituted) phenylamide. Then, the compound prepared by removing the tert-butoxy group of indoline using the above-mentioned product can be prepared.

In another aspect of the present invention, the present invention also provides a composition for inhibiting NF-κB activation comprising the indolin-2-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to provide.

The present inventors measured the amount of secretory alkaline phosphatase (SEAP) produced in association with NF-κB activation by relative fluorescence unit (RFU), and found that by treating the compound with NF lt; RTI ID = 0.0 > activation. < / RTI >

Since the NF-κB induces a transcription process in the nucleus for transferring into the nucleus, the pharmaceutical composition of the present invention for inhibiting NF-κB activation is useful as a cytokine, a chemokine, an adhesion molecule, acute phase proteins, anti-microbial peptides, cell surface receptors, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2 ) Genes, it is possible to prevent or treat any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer which can be affected by the genes.

Accordingly, the composition for inhibiting NF-κB activation comprising the indolin-2-carboxamide derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient is preferably a composition for inhibiting multiple myeloma, rheumatoid arthritis and cancer And a composition for preventing or treating any one or more diseases selected from the group consisting of:

The indolin-2-carboxamide 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 disease, and the other pharmacologically acceptable carrier, excipient Or a diluent. In this case, the content of the indolin-2-carboxamide 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% And the content of the compound may be suitably adjusted in a desired amount depending on the manner of use of the composition and the method of use.

Particularly, when the composition comprising the compound having the structure of Formula 1 is used as a medicine or used for medicinal or pharmaceutical purposes, the indoline-2-carboxamide derivative having the structure of Formula 1 can be produced by a conventional method May be mixed with a pharmaceutically acceptable carrier or excipient or diluted with a diluent.

 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, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin and physiological saline , But it is not limited thereto, and any conventional carrier, excipient or diluent may be used. The pharmaceutical composition may further comprise conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, wetting agents, flavors, emulsifiers or preservatives.

In addition, the composition of the present invention may further comprise a substance used as a known inhibitor of NF-κB in addition to the above-mentioned effective 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 so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. Generally, the formulations will contain one or more of the following ingredients: PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOULTIONS, AEROSOLS, ONITMENTS, SUSPENSIONS, SACHETS, TABLETS, PELLETS, INJECTIONS, FLUIDEXTRACTS, ELIXIR, EMULSIONS, SUSTAINS, INFUSIONS, SACHETS, TABLETS, INJECTIONS, Capsules, and pillars, powders, sachets, and the like. Furthermore, the compositions of the present invention may be formulated using any suitable method known in the art or using methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA .

When the composition is used as a medicine, it can be administered orally or parenterally. In one example, it can be administered through various routes including oral, transdermal, subcutaneous, intravenous or muscular.

The dosage of the composition can be determined in consideration of the administration method, the age, sex, the severity of the patient, the condition of the patient, the degree of absorption of the active ingredient in the body, the inactivation rate and the drug to be used together. Kg body weight to 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, respectively, And may be administered once or several times in divided doses. The dose is not intended to limit the scope of the invention in any way.

In the present invention, matters other than the contents described above can be added or subtracted as needed, and therefore the present invention is not particularly limited thereto.

INDUSTRIAL APPLICABILITY The novel indolinone compound and the pharmaceutical composition containing the same of the present invention act as an inhibitor of NF-κB and prevent or prevent any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer which are diseases associated with NF-κB May be used in therapeutic compositions.

Particularly, the novel indolin-2-carboxamide derivative of the present invention or a pharmaceutically acceptable salt thereof acts as an inhibitor of activation of microglial cells and inhibits the death of neuronal cells, thereby inhibiting the brain such as stroke, Alzheimer's disease, Parkinson's disease, Diseases, rheumatism, and arthritis.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited to the following examples.

Example  One: tert -Butyl 2- ( Phenylcarbamoyl ) Indolin -One- Of the carboxylate (YAL-1093)  Produce

N- ( Rat - Butoxycarbonyl ) Indolin -2- Carboxylic  Produce

2-carboxylic acid (10 mmol, 1 eq.) Was dissolved in 30 mL of a 1: 2 mixed solvent of water: dioxane and then sodium hydroxide (25 mmol, 2.5 eq.) Was added. While stirring at room temperature, a solvent in which sodium hydroxide was dissolved in water and di-tert-butyl dicarbonate (20 mmol, 2 equivalents) were dissolved in dioxane was slowly added dropwise while maintaining a pH of 9-10. The reaction was carried out at room temperature for about 2 hours with stirring. It was then concentrated, dissolved in water and washed with dichloromethane. The remaining water layer was acidified, extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated under reduced pressure to give indolin-2-carboxylic acid, N- (tert-butoxycarbonyl) indoline-2-carboxylic acid.

Yield: 95% 2.5 g

^{1 H NMR (MeOD, 300 MHz} ) d 7.45 ~ 7.85 (Br, 1H, Ar- H), 7.15 (t, 1H, J = 7.47 Hz, Ar- H), 7.14 (d, 1H, J = 7.47 Hz, Ar- H), 6.94 (t, 1H, J = 7.47z, Ar- H), 4.75 ~ 4.85 (m, 1H, NC H CH 2), 3.45 ~ 3.65 (m, 1H, NCHCH 2), 3.05 ~ 3.15 _{(m, 1H, NCHCH 2)} , 1.50 (s, 9H, O (C H 3) 3)

tert -Butyl 2- ( Phenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1093)

1 equivalent of N - (tert-butoxycarbonyl) indoline-2-carboxylic acid and 1.5 equivalents of ethyl- ( N , N -dimethylaminopropyl) carbodiimide prepared above were dissolved in anhydrous tetrahydrofuran, And stirred under a gas. After 1 hour, 1.5 equivalents of aniline was added and reacted for 12 to 14 hours. After concentration, the mixture was extracted with 6 N hydrochloric acid and dichloromethane. The organic layer was dried over sodium sulfate, concentrated, and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to give indolin derivative YAL-1093.

Yield: 93% 120 mg

m.p. 198 ~ 201 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.55 ~ 7.75 (Br, 1H, Ar- H), 7.49 (d, 2H, J = 7.82 Hz, Ar- H), 7.31 (t, 2H, J = 7.82 Hz , Ar- H), 7.21 (d , 1H, J = 7.20 Hz, Ar- H), 7.19 (t, 1H, J = 7.82 Hz, Ar- H), 7.10 (t, 1H, J = 7.20 Hz, Ar - H), 7.01 (t, 1H, J = 7.20 Hz, Ar- H), 4.95 ~ 5.15 (m, 1H, NC H CH 2), 3.35 ~ 3.65 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H ₃ ) ₃ )

Example  2: tert -Butyl 2- (2- Hydrophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1124)

An indoline derivative YAL-1124 was obtained in the same manner as in Example 1 except that aniline was replaced with 2-hydroxy aniline.

Yield: 74% 400 mg

m.p. 185 ~ 186 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.55 ~ 7.75 (Br, 1H, Ar- H), 7.23 (t, 1H, J = 7.66 Hz, Ar- H), 7.21 (d, 1H, J = 7.66 Hz , Ar- H), 7.13 (t , 1H, J = 7.66 Hz, Ar- H), 7.04 (t, 1H, J = 7.67 Hz, Ar- H), 7.02 (d, 1H, J = 7.66 Hz, Ar - H), 6.97 (d, 1H, J = 7.67 Hz, Ar- H), 6.85 (t, 1H, J = 7.67 Hz, Ar- H), 5.05 ~ 5.15 (m, 1H, NC H CH 2), 3.35 to 3.60 (m, 2H, NCHC H ₂ ), 1.59 (s, 9H, O (C H ₃ ) ₃ )

Example  3: tert -Butyl 2- (3- Hydrophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1134)

An indoline derivative YAL-1134 was obtained in the same manner as in Example 1 except that aniline was replaced with 3-hydroxyaniline.

Yield: 92% 370 mg

m.p. 184 ~ 186 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.68 ~ 7.78 (Br, 1H, Ar- H), 7.12 (s, 1H, Ar- H), 7.09 (t, 1H, J = 7.85 Hz, Ar- H), 7.08 (d, 1H, J = 7.96 Hz, Ar- H), 7.03 (t, 1H, J = 7.96 Hz, Ar- H), 6.88 (d, 1H, J = 7.85 Hz, Ar- H), 6.87 ( t, 1H, J = 7.85 Hz , Ar- H), 6.46 (d, 1H, J = 7.96 Hz, Ar- H), 4.75 ~ 4.85 (m, 1H, NC H CH 2), 3.41 ~ 3.52 (m, _{2H, NCHCH 2), 1.40 (} s, 9H, O (C H 3) 3)

Example  4: tert -Butyl 2- (4- Hydrophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1122)

An indoline derivative YAL-1122 was obtained in the same manner as in Example 1 except that aniline was replaced with 4-hydroxyaniline.

Yield: 78% 400 mg

m.p. 175-178 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.55 ~ 7.75 (Br, 1H, Ar- H), 7.33 (d, 2H, J = 8.79 Hz, Ar- H), 7.21 (t, 1H, J = 7.43 Hz , Ar- H), 7.20 (d , 1H, J = 7.43 Hz, Ar- H), 6.99 (t, 1H, J = 7.43 Hz, Ar- H), 6.68 (d, 2H, J = 8.79 Hz, Ar - H), 4.92 ~ 5.02 ( m, 1H, NC H CH 2), 3.45 ~ 3.54 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H 3) 3)

Example  5: tert -Butyl 2- (2- Methoxyphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1079)

An indoline derivative YAL-1079 was obtained in the same manner as in Example 1 except that aniline was used instead of 2-methoxyaniline.

Yield: 96% 402 mg

m.p. 134 to 135 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.49 (d, 1H, J = 7.78 Hz, Ar- H), 7.65 ~ 7.85 (Br, 1H, Ar- H), 7.22 (t, 1H, J = 7.79 Hz , Ar- H), 7.18 (d , 1H, J = 7.79 Hz, Ar- H), 7.03 (t, 1H, J = 7.79 Hz, Ar- H), 7.01 (t, 1H, J = 7.78 Hz, Ar - H), 6.94 (t, 1H, J = 7.78 Hz, Ar- H), 6.84 (d, 1H, J = 7.78 Hz, Ar- H), 4.85 ~ 5.05 (m, 1H, NC H CH 2), 3.81 (s, 3H, OC H 3), 3.35 ~ 3.70 (m, 2H, NCHC H 2), 1.54 (s, 9H, O (C H 3) 3)

Example  6: tert -Butyl 2- (3- Methoxyphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1075)

An indoline derivative YAL-1075 was obtained in the same manner as in Example 1 except that aniline was used instead of 3-methoxyaniline.

Yield: 91% 260 mg

m.p. 168 ~ 170 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.55 ~ 7.75 (Br, 1H, Ar- H), 7.29 (s, 1H, Ar- H), 7.21 (t, 1H, J = 8.11 Hz, Ar- H) , 7.20 (d, 1H, J = 8.11 Hz, Ar- H), 7.19 (t, 1H, J = 7.69 Hz, Ar- H), 7.02 (t, 1H, J = 7.69 Hz, Ar- H), 6.80 (d, 1H, J = 7.69 Hz, Ar- H), 6.66 (d, 1H, J = 8.11 Hz, Ar- H), 4.90 ~ 5.10 (m, 1H, NC H CH 2), 3.79 (s, 3H _{, OC H 3), 3.35 ~} 3.60 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H 3) 3)

Example  7: tert -Butyl 2- (4- Methoxyphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1074)

An indoline derivative YAL-1074 was obtained in the same manner as in Example 1 except that aniline was replaced with 4-methoxyaniline.

Yield: 71% 200 mg

m.p. 197-199 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.58 ~ 7.74 (Br, 1H, Ar- H), 7.40 (d, 2H, J = 8.89 Hz, Ar- H), 7.24 (t, 1H, J = 7.48 Hz , Ar- H), 7.22 (d , 1H, J = 7.48 Hz, Ar- H), 7.02 (t, 1H, J = 7.48 Hz, Ar- H), 6.84 (d, 2H, J = 8.89 Hz, Ar - H), 4.93 ~ 5.04 ( m, 1H, NC H CH 2), 3.78 (s, 3H, OC H 3), 3.40 ~ 3.58 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H ₃ ) ₃ )

Example  8: tert -Butyl 2- (2- Methylphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1090)

An indoline derivative YAL-1090 was obtained in the same manner as in Example 1 except that aniline was replaced with 2-methylaniline.

Yield: 55% 235 mg

m.p. 157-159 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.93 (d, 1H, J = 7.94 Hz, Ar- H), 7.53 ~ 7.75 (Br, 1H, Ar- H), 7.22 (t, 1H, J = 6.99 Hz , Ar- H), 7.21 (t , 1H, J = 6.99 Hz, Ar- H), 7.13 (t, 1H, J = 7.94 Hz, Ar- H), 7.10 (d, 1H, J = 7.94 Hz, Ar - H), 7.04 (t, 1H, J = 6.99 Hz, Ar- H), 7.02 (t, 1H, J = 7.94 Hz, Ar- H), 5.04 ~ 5.10 (m, 1H, NC H CH 2), 3H, Ar-C H ₃ ), 1.54 (s, 9H, O (C H ₃ ) ₃ ), 3.45-3.62 (m, 2H, NCHC H ₂ )

Example  9: tert -Butyl 2- (3- Methylphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1089)

An indoline derivative YAL-1089 was obtained in the same manner as in Example 1 except that aniline was replaced with 3-methylaniline.

Yield: 81% 323 mg

m.p. 151 to 152 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.58 ~ 7.72 (Br, 1H, Ar- H), 7.36 (s, 1H, Ar- H), 7.26 (d, 1H, J = 7.25 Hz, Ar- H) , 7.21 (t, 1H, J = 7.25 Hz, Ar- H), 7.20 (d, 1H, J = 7.55 Hz, Ar- H), 7.19 (t, 1H, J = 7.55 Hz, Ar- H), 7.02 (t, 1H, J = 7.55 Hz, Ar- H), 6.92 (d, 1H, J = 7.25 Hz, Ar- H), 4.95 ~ 5.05 (m, 1H, NC H CH 2), 3.40 ~ 3.57 (m _{, 2H, NCHCH 2), 2.32} (s, 3H, Ar-C H 3), 1.57 (s, 9H, O (C H 3) 3)

Example  10: tert -Butyl 2- (4- Methylphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1094)

Indoline derivative YAL-1094 was obtained in the same manner as in Example 1 except that aniline was replaced with 4-methylaniline.

Yield: 55% 220 mg

m.p. 199 - 201 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.60 ~ 7.75 (Br, 1H, Ar- H), 7.37 (d, 2H, J = 7.86 Hz, Ar- H), 7.20 (d, 2H, J = 7.86 Hz , Ar- H), 7.12 (t , 1H, J = 8.24 Hz, Ar- H), 7.11 (d, 1H, J = 8.24 Hz, Ar- H), 7.01 (t, 1H, J = 8.24 Hz, Ar - H), 4.95 ~ 5.05 ( m, 1H, NC H CH 2), 3.45 ~ 3.65 (m, 2H, NCHCH 2), 2.30 (s, 3H, Ar-C H 3), 1.57 (s, 9H, O (C H ₃ ) ₃ )

Example  11: tert -Butyl 2- (2- Nitrophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1144)

An indoline derivative YAL-1144 was obtained in the same manner as in Example 1 except that aniline was replaced with 2-nitroaniline.

Yield: 69% 400 mg

m.p. 114 to 116 DEG C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.84 (d, 1H, J = 8.11 Hz, Ar- H), 8.19 (d, 1H, J = 8.11 Hz, Ar- H), 7.55 ~ 7.80 (Br, 1H , Ar- H), 7.65 (t , 1H, J = 8.11 Hz, Ar- H), 7.10 ~ 7.25 (m, 3H, Ar- H), 7.02 (t, 1H, J = 7.40 Hz, Ar- H) , 4.95 ~ 5.10 (m, 1H , NC H CH 2), 3.55 ~ 3.75 (m, 1H, NCHC H 2), 3.23 ~ 3.37 (m, 1H, NCHC H 2), 1.55 (s, 9H, O (C H ₃ ) ₃ )

Example  12: tert -Butyl 2- (3- Nitrophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1143)

An indoline derivative YAL-1143 was obtained in the same manner as in Example 1 except that aniline was replaced with 3-nitroaniline.

Yield: 53% 310 mg

m.p. 193-195 ° C

^{1 H NMR (MeOD, 300 MHz} ) d 8.61 (s, 1H, Ar- H), 7.97 (d, 1H, J = 8.43 Hz, Ar- H), 7.94 (d, 1H, J = 8.43 Hz, Ar- H), 7.77 ~ 7.88 (Br , 1H, Ar- H), 7.57 (t, 1H, J = 8.43 Hz, Ar- H), 7.19 (t, 1H, J = 7.67 Hz, Ar- H), 7.17 ( d, 1H, J = 7.67 Hz , Ar- H), 6.96 (t, 1H, J = 7.67 Hz, Ar- H), 4.77 ~ 4.88 (m, 1H, NC H CH 2), 3.52 ~ 3.64 (m, _{1H, NCHCH 2), 3.10 ~} 3.21 (m, 1H, NCHCH 2), 1.44 (s, 9H, O (C H 3) 3)

Example  13: tert -Butyl 2- (4- Nitrophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1126)

An indoline derivative YAL-1126 was obtained in the same manner as in Example 1 except that aniline was used in place of 4-nitroaniline.

Yield: 42% 370 mg

m.p. 193-195 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.19 (d, 2H, J = 9.11 Hz, Ar- H), 7.69 (d, 2H, J = 9.11 Hz, Ar- H), 7.50 ~ 7.65 (Br, 1H , Ar- H), 7.23 (d , 1H, J = 7.78 Hz, Ar- H), 7.21 (t, 1H, J = 7.78 Hz, Ar- H), 7.04 (t, 1H, J = 7.78 Hz, Ar - H), 5.05 ~ 5.15 ( m, 1H, NC H CH 2), 3.55 ~ 3.70 (m, 1H, NCHCH 2), 3.35 ~ 3.50 (m, 1H, NCHCH 2), 1.60 (s, 9H, O ( C H ₃ ) ₃ )

Example  14: tert -Butyl 2- (2- Trifluoromethylphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1140)

An indoline derivative YAL-1140 was obtained in the same manner as in Example 1 except that aniline was used in place of 2-trifluoromethylaniline.

Yield: 71% 425 mg

m.p. 167 ~ 169 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.28 (d, 1H, J = 7.84 Hz, Ar- H), 7.58 ~ 7.68 (Br, 1H, Ar- H), 7.57 (d, 1H, J = 7.84 Hz , Ar- H), 7.54 (t , 1H, J = 7.84 Hz, Ar- H), 7.23 (t, 1H, J = 7.64 Hz, Ar- H), 7.20 (t, 1H, J = 7.69 Hz, Ar - H), 7.19 (d, 1H, J = 7.69 Hz, Ar- H), 7.02 (t, 1H, J = 7.84 Hz, Ar- H), 5.00 ~ 5.10 (m, 1H, NC H CH 2), 3.35 to 3.65 (m, 2H, NCHC H ₂ ), 1.57 (s, 9H, O (C H ₃ ) ₃ )

Example  15: tert -Butyl 2- (3- Trifluoromethylphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1139)

An indolin derivative YAL-1139 was obtained in the same manner as in Example 1 except that aniline was used in place of 3-trifluoromethylaniline.

Yield: 39% 237 mg

m.p. 177-178 ° C

^{1 H NMR (MeOD, 300 MHz} ) d 8.01 (s, 1H, Ar- H), 7.80 (d, 1H, J = 7.64 Hz, Ar- H), 7.75 ~ 7.85 (Br, 1H, Ar- H), 7.52 (t, 1H, J = 7.64 Hz, Ar- H), 7.40 (d, 1H, J = 7.64 Hz, Ar- H), 7.18 (t, 1H, J = 7.56 Hz, Ar- H), 7.16 ( d, 1H, J = 7.56 Hz , Ar- H), 6.96 (t, 1H, J = 7.56 Hz, Ar- H), 4.85 ~ 5.00 (m, 1H, NC H CH 2), 3.50 ~ 3.63 (m, _{1H, NCHCH 2), 3.12 ~} 3.21 (m, 1H, NCHCH 2), 1.44 (s, 9H, O (C H 3) 3)

Example  16: tert -Butyl 2- (4- Trifluoromethylphenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1128)

An indoline derivative YAL-1128 was obtained in the same manner as in Example 1 except that aniline was used in place of 4-trifluoromethylaniline.

Yield: 65% 300 mg

m.p. 188-190 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.63 (d, 2H, J = 8.64 Hz, Ar- H), 7.54 ~ 7.63 (Br, 1H, Ar- H), 7.54 (d, 2H, J = 8.64 Hz , Ar- H), 7.22 (d , 1H, J = 6.91 Hz, Ar- H), 7.21 (t, 1H, J = 6.91 Hz, Ar- H), 7.03 (t, 1H, J = 6.91 Hz, Ar - H), 5.00 ~ 5.10 ( m, 1H, NC H CH 2), 3.35 ~ 3.65 (m, 2H, NCHCH 2), 1.59 (s, 9H, O (C H 3) 3)

Example  17: tert -Butyl 2- (2- Chlorophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1110)

An indoline derivative YAL-1110 was obtained in the same manner as in Example 1 except that 2-chloroaniline was used instead of 2-chloroaniline.

Yield: 70% 296 mg

m.p. 144 to 146 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.42 (d, 1H, J = 8.25 Hz, Ar- H), 7.65 ~ 7.85 (Br, 1H, Ar- H), 7.18 ~ 7.40 (m, 4H, Ar- H), 7.03 ~ 7.11 (m , 2H, Ar- H), 5.00 ~ 5.15 (m, 1H, NC H CH 2), 3.40 ~ 3.70 (m, 2H, NCHC H 2), 1.59 (s, 9H, O (C H ₃ ) ₃ )

Example  18: tert -Butyl 2- (3- Chlorophenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1106)

An indoline derivative YAL-1106 was obtained in the same manner as in Example 1 except that aniline was replaced with 3-chloroaniline.

Yield: 61% 259 mg

m.p. 188 ~ 189 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.67 (s, 1H, Ar- H), 7.55 ~ 7.70 (Br, 1H, Ar- H), 7.34 (d, 1H, J = 8.11 Hz, Ar- H) , 7.15 ~ 7.27 (m, 3H , Ar- H), 7.09 (d, 1H, J = 8.11 Hz, Ar- H), 7.04 (t, 1H, J = 7.54 Hz, Ar- H), 4.95 ~ 5.08 ( _{m, 1H, NC H CH 2} ), 3.40 ~ 3.65 (m, 2H, NCHCH 2), 1.60 (s, 9H, O (C H 3) 3)

Example  19: tert -Butyl 2- (4- Chlorophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1115)

Indolin derivative YAL-1115 was obtained in the same manner as in Example 1 except that the aniline was replaced with 4-chloroaniline.

Yield: 83% 400 mg

m.p. 204 to 205 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.56 ~ 7.70 (Br, 1H, Ar- H), 7.46 (d, 2H, J = 8.68 Hz, Ar- H), 7.27 (d, 1H, J = 8.68 Hz , Ar- H), 7.15 ~ 7.25 (m, 2H, Ar- H), 7.02 (t, 1H, J = 7.44Hz, Ar- H), 4.95 ~ 5.01 (m, 1H, NC H CH 2), 3.35 ~ 3.65 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H 3) 3)

Example  20: tert Butyl 2- (2,5- Dichlorophenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1111)

An indoline derivative YAL-1111 was obtained in the same manner as in Example 1 except that aniline was used instead of 2,5-dichloroaniline.

Yield: 69% 426 mg

m.p. 143 ~ 144 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.50 (s, 1H, Ar- H), 7.55 ~ 7.80 (Br, 1H, Ar- H), 7.15 ~ 7.27 (m, 3H, Ar- H), 6.98 ~ 7.06 (m, 2H, Ar- H ), 5.00 ~ 5.10 (m, 1H, NC H CH 2), 3.35 ~ 3.65 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H 3) 3 )

Example  21: tert -Butyl 2- (3,5- Dichlorophenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1112)

An indoline derivative YAL-1112 was obtained in the same manner as in Example 1 except that aniline was replaced with 3,5-dichloroaniline.

Yield: 65% 400 mg

m.p. 147 ~ 149 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.50 ~ 7.65 (Br, 1H, Ar- H), 7.47 (s, 2H, Ar- H), 7.22 (d, 1H, J = 7.32 Hz, Ar- H) , 7.20 (t, 1H, J = 7.32 Hz, Ar- H), 7.08 (s, 1H, Ar- H), 7.03 (t, 1H, J = 7.32 Hz, Ar- H), 4.95 ~ 5.08 (m, _{1H, NC H CH 2),} 3.30 ~ 3.65 (m, 2H, NCHCH 2), 1.60 (s, 9H, O (C H 3) 3)

Example  22: tert -Butyl 2- (3,4- Dichlorophenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1116)

An indoline derivative YAL-1116 was obtained in the same manner as in Example 1 except that aniline was used in place of 3,4-dichloroaniline.

Yield: 68% 330 mg

m.p. 206 to 207 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.78 (s, 1H, Ar- H), 7.55 ~ 7.65 (Br, 1H, Ar- H), 7.36 (d, 1H, J = 8.74 Hz, Ar- H) , 7.31 (d, 1H, J = 8.74 Hz, Ar- H), 7.22 (d, 1H, J = 7.57 Hz, Ar- H), 7.18 (t, 1H, J = 7.57 Hz, Ar- H), 7.03 (t, 1H, J = 7.57 Hz, Ar- H), 4.95 ~ 5.07 (m, 1H, NC H CH 2), 3.30 ~ 3.65 (m, 2H, NCHCH 2), 1.58 (s, 9H, O (C H ₃ ) ₃ )

Example  23: tert Butyl 2- (2,5- Dimethylphenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1101)

Indolin derivative YAL-1101 was obtained in the same manner as in Example 1 except that aniline was used in place of 2,5-dimethylaniline.

Yield: 98% 410 mg

m.p. 147 ~ 149 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.78 (s, 1H, Ar- H), 7.15 ~ 7.25 (m, 2H, Ar- H), 6.95 ~ 7.17 (m, 2H, Ar- H), 6.85 ( d, 1H, J = 6.99 Hz , Ar- H), 4.96 ~ 5.10 (m, 1H, NC H CH 2), 3.38 ~ 3.64 (m, 2H, NCHCH 2), 2.29 (s, 3H, Ar-C H ₃ ), 2.12 (s, 3H, Ar-C H ₃ ), 1.54 (s, 9H, O (C H ₃ ) ₃ )

Example  24: tert -Butyl 2- (3,5- Dimethylphenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1100)

An indoline derivative YAL-1100 was obtained in the same manner as in Example 1 except that aniline was used in place of 3,5-dimethylaniline.

Yield: 86% 357 mg

m.p. 170-171 C

^{1 H NMR (MeOD, 300 MHz} ) d 7.72 ~ 7.88 (Br, 1H, Ar- H), 7.20 (s, 2H, Ar- H), 7.17 (t, 1H, J = 7.61 Hz, Ar- H), 7.16 (d, 1H, J = 7.61 Hz, Ar- H), 6.95 (t, 1H, J = 7.61 Hz, Ar- H), 6.77 (s, 1H, Ar- H), 4.85 ~ 4.95 (m, 1H _{, NC H CH 2), 3.50} ~ 3.62 (m, 2H, NCHCH 2), 2.27 (s, 6H, Ar-C H 3), 1.46 (s, 9H, O (C H 3) 3)

Example  25: tert -Butyl 2- (3,4- Dimethylphenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1099)

An indoline derivative YAL-1099 was obtained in the same manner as in Example 1 except that aniline was used in place of 3,4-dimethylaniline.

Yield: 62% 260 mg

m.p. 175-177 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.55 ~ 7.76 (Br, 1H, Ar- H), 7.29 (s, 1H, Ar- H), 7.15 ~ 7.25 (m, 3H, Ar- H), 7.05 ( d, 1H, J = 8.32 Hz , Ar- H), 7.01 (t, 1H, J = 7.45 Hz, Ar- H), 4.90 ~ 5.05 (m, 1H, NC H CH 2), 3.35 ~ 3.60 (m, _{2H, NCHCH 2), 2.22 (} s, 3H, Ar-C H 3), 2.21 (s, 3H, Ar-C H 3), 1.56 (s, 9H, O (C H 3) 3)

Example  26: tert Butyl 2- (2,5- Dimethoxyphenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1080)

An indoline derivative YAL-1080 was obtained in the same manner as in Example 1, except that aniline was used in place of 2,5-dimethoxyaniline.

Yield: 99% 454 mg

m.p. 91 ~ 93 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.09 (s, 1H, Ar- H), 7.65 ~ 7.85 (Br, 1H, Ar- H), 7.22 (t, 1H, J = 7.39 Hz, Ar- H) , 7.18 (d, 1H, J = 7.39 Hz, Ar- H), 7.00 (t, 1H, J = 7.39 Hz, Ar- H), 6.75 (d, 1H, J = 8.90 Hz, Ar- H), 6.56 (d, 1H, J = 8.90 Hz, Ar- H), 4.92 ~ 5.06 (m, 1H, NC H CH 2), 3.76 (s, 6H, OC H 3), 3.32 ~ 3.62 (m, 2H, NCHCH 2 ), 1.54 (s, 9H, O (C H 3) 3)

Example  27: tert -Butyl 2- (3,5- Dimethoxyphenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1084)

An indoline derivative YAL-1084 was obtained in the same manner as in Example 1 except that aniline was used in place of 3,5-dimethoxyaniline.

Yield: 79% 360 mg

m.p. 186 ~ 188 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.50 ~ 7.68 (Br, 1H, Ar- H), 7.21 (t, 1H, J = 6.49 Hz, Ar- H), 7.20 (d, 1H, J = 6.49 Hz , Ar- H), 7.02 (t , 1H, J = 6.49 Hz, Ar- H), 6.75 (s, 2H, Ar- H), 6.23 (s, 1H, Ar- H), 4.95 ~ 5.05 (m, _{1H, NC H CH 2),} 3.76 (s, 6H, OC H 3), 3.40 ~ 3.58 (m, 2H, NCHCH 2), 1.57 (s, 9H, O (C H 3) 3)

Example  28: tert -Butyl 2- (3,4- Dimethoxyphenylcarbamoyl ) Indolin -One- Carboxylate  (YAL-1085)

An indoline derivative YAL-1085 was obtained in the same manner as in Example 1 except that aniline was used in place of 3,4-dimethoxyaniline.

Yield: 88% 400 mg

m.p. 97 ~ 99 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.55 ~ 7.75 (Br, 1H, Ar- H), 7.33 (s, 1H, Ar- H), 7.21 (t, 1H, J = 6.99 Hz, Ar- H) , 7.20 (d, 1H, J = 6.99 Hz, Ar- H), 7.02 (t, 1H, J = 6.99 Hz, Ar- H), 6.86 (d, 1H, J = 8.62 Hz, Ar- H), 6.78 (d, 1H, J = 8.62 Hz, Ar- H), 4.95 ~ 5.05 (m, 1H, NC H CH 2), 3.86 (s, 3H, OC H 3), 3.85 (s, 3H, OC H 3) , 3.43 ~ 3.58 (m, 2H , NCHCH 2), 1.58 (s, 9H, O (C H 3) 3)

Example  29: tert -Butyl 2- (3,5- Di (trifluoromethyl) phenylcarbamoyl ) Indolin -One- Carboxylate  ( YAL -1152)

An indoline derivative YAL-1152 was obtained in the same manner as in Example 1 except that aniline was used in place of 3,5-di (trifluoromethyl) aniline.

Yield: 63% 452 mg

m.p. 76 ~ 80 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.01 (s, 2H, Ar- H), 7.58 (s, 1H, Ar- H), 7.47 ~ 7.62 (Br, 1H, Ar- H), 7.23 (d, 1H, J = 7.84 Hz, Ar- H), 7.18 (t, 1H, J = 7.84 Hz, Ar- H), 7.04 (t, 1H, J = 7.84 Hz, Ar- H), 5.05 ~ 5.15 (m, _{1H, NC H CH 2),} 3.56 ~ 3.73 (m, 1H, NCHCH 2), 3.32 ~ 3.50 (m, 1H, NCHCH 2), 1.61 (s, 9H, O (C H 3) 3)

Example  30: Indolin -2- Carboxylic acid N - Phenylamide  ( YAL -1076)

YAL-1093 (1 equivalent) obtained in Example 1 was dissolved in 30 mL of dichloromethane. Trifluoroacetic acid (10 equivalents) was added thereto and stirred for 6 hours. After neutralization with sodium hydrogen carbonate, the organic layer was dried over sodium sulfate, concentrated, and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to give indolin derivative YAL-1076.

Yield: 80% 95 mg

m.p. 120 ~ 125 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.59 (d, 2H, J = 7.90 Hz, Ar- H), 7.33 (t, 2H, J = 7.90 Hz, Ar- H), 7.15 (d, 1H, J = 7.39 Hz, Ar- H), 7.13 (t, 1H, J = 7.90 Hz, Ar- H), 7.12 (t, 1H, J = 7.39 Hz, Ar- H), 6.88 (t, 1H, J = 7.39 Hz, Ar- H), 6.84 ( t, 1H, J = 7.39 Hz, Ar- H), 4.55 (dd, 1H, J = 8.77, 10.80 Hz, NC H CH 2), 3.65 ~ 3.75 (m, 1H, NCHC H ₂ ), 3.15-3.30 (m, 1H, NCHC H ₂ )

Example  31: Indolin -2- Carboxylic acid N -(2- Hydroxyphenyl ) Amide  ( YAL -1131)

In the same manner as in Example 30, the indoline-based derivative YAL-1131 was obtained by using the material obtained in Example 2 instead of YAL-1093.

Yield: 71% 153 mg

m.p. 180 ~ 183 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 8.01 (d, 1H, J = 7.72 Hz, Ar- H), 6.99 (d, 1H, J = 7.20 Hz, Ar- H), 6.95 (t, 1H, J = 7.72 Hz, Ar- H), 6.86 (t, 1H, J = 7.72 Hz, Ar- H), 6.75 (d, 1H, J = 7.72 Hz, Ar- H), 6.73 (t, 1H, J = 7.20 Hz , Ar- H), 6.69 (d , 1H, J = 7.20 Hz, Ar- H), 6.66 (t, 1H, J = 7.20 Hz, Ar- H), 4.38 (dd, 1H, J = 8.96, 10.72 Hz _{, NC H CH 2), 3.43} ~ 3.55 (m, 1H, NCHC H 2), 2.95 ~ 3.08 (m, 1H, NCHC H 2)

Example  32: Indolin -2- Carboxylic acid N - (3- Hydroxyphenyl ) Amide  ( YAL -1137)

In the same manner as in Example 30, the indoline-based derivative YAL-1137 was obtained by using the material obtained in Example 3 instead of YAL-1093.

Yield: 83% 160 mg

m.p. 212 to 214 ° C

^{1 H NMR (MeOD, 500 MHz} ) d 7.39 ~ 7.45 (m, 4H, Ar- H), 7.17 (s, 1H, Ar- H), 7.11 (t, 1H, J = 8.09 Hz, Ar- H), 6.98 (d, 1H, J = 8.09 Hz, Ar- H), 6.55 (d, 1H, J = 8.09 Hz, Ar- H), 4.93 (dd, 1H, J = 7.31, 9.61 Hz, NC H CH 2) , 3.74 ~ 3.81 (m, 1H , NCHC H 2), 3.38 ~ 3.46 (m, 1H, NCHC H 2)

Example  33: Indolin -2- Carboxylic acid N -(4- Hydroxyphenyl ) Amide  ( YAL -1135)

In the same manner as in Example 30, the indoline-based derivative YAL-1135 was obtained by using the material obtained in Example 4 instead of YAL-1093.

Yield: 99% 287 mg

m.p. 198 ~ 200 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.28 (d, 2H, J = 8.88 Hz, Ar- H), 6.98 (d, 1H, J = 7.67 Hz, Ar- H), 6.94 (t, 1H, J = 7.67 Hz, Ar- H), 6.60 ~ 6.70 (m, 4H, Ar- H), 4.34 (dd, 1H, J = 8.72, 10.46 Hz, NC H CH 2), 4.30 ~ 4.38 (m, 1H, NCHC H ₂ ), 2.98-3.07 (m, 1H, NCHC H ₂ )

Example  34: Indolin -2- Carboxylic acid N -(2- Methoxyphenyl ) Amide  ( YAL -1082)

In the same manner as in Example 30, the indoline-based derivative YAL-1082 was obtained by using the material obtained in Example 5 instead of YAL-1093.

Yield: 77% 180 mg

m.p. 135-137 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.43 (d, 1H, J = 7.88 Hz, Ar- H), 7.14 (d, 1H, J = 7.58 Hz, Ar- H), 7.12 (t, 1H, J = 7.88 Hz, Ar- H), 7.06 (t, 1H, J = 7.58 Hz, Ar- H), 6.97 (t, 1H, J = 7.88 Hz, Ar- H), 6.87 (d, 1H, J = 7.88 Hz, Ar- H), 6.85 ( t, 1H, J = 7.58 Hz, Ar- H), 6.82 (t, 1H, J = 7.58 Hz, Ar- H), 4.55 (dd, 1H, J = 9.09, 10.53 _{Hz, NC H CH 2),} 3.81 (s, 3H, OC H 3), 3.58 ~ 3.72 (m, 1H, NCHC H 2), 3.15 ~ 3.28 (m, 1H, NCHC H 2)

Example  35: Indolin -2- Carboxylic acid N - (3- Methoxyphenyl ) Amide  ( YAL -1078)

In the same manner as in Example 30, the indolinone derivative YAL-1078 was obtained by using the substance obtained in Example 6 instead of YAL-1093.

Yield: 73% 90 mg

m.p. 145-160 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.36 (s, 1H, Ar- H), 7.22 (t, 1H, J = 7.88 Hz, Ar- H), 7.14 (d, 1H, J = 7.88 Hz, Ar - H), 7.13 (t, 1H, J = 7.92 Hz, Ar- H), 7.05 (d, 1H, J = 7.92 Hz, Ar- H), 6.87 (t, 1H, J = 7.92 Hz, Ar- H ), 6.84 (d, 1H, J = 7.88 Hz, Ar- H), 6.67 (d, 1H, J = 7.92 Hz, Ar- H), 4.54 (dd, 1H, J = 8.96, 10.62 Hz, NC H CH _{2), 3.81 (s, 3H} , OC H 3), 3.63 ~ 3.75 (m, 1H, NCHC H 2), 3.15 ~ 3.28 (m, 1H, NCHC H 2)

Example  36: Indolin -2- Carboxylic acid N -(4- Methoxyphenyl ) Amide  ( YAL -1077)

In the same manner as in Example 30, the indolinone derivative YAL-1077 was obtained by using the substance obtained in Example 7 instead of YAL-1093.

Yield: 65% 70 mg

m.p. 171-172 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.50 (d, 2H, J = 8.94 Hz, Ar- H), 7.14 (d, 1H, J = 8.34 Hz, Ar- H), 7.13 (t, 1H, J = 8.34 Hz, Ar- H), 6.88 (t, 1H, J = 8.34 Hz, Ar- H), 6.87 (d, 2H, J = 8.94 Hz, Ar- H), 6.83 (d, 1H, J = 8.34 Hz, Ar- H), 4.48 ~ 4.59 (m, 1H, NC H CH 2), 3.79 (s, 3H, OC H 3), 3.60 ~ 3.85 (m, 1H, NCHC H 2), 3.15 ~ 3.28 (m , 1H, NCHC H ₂ )

Example  37: Indolin -2- Carboxylic acid N -(2- Methylphenyl ) Amide  ( YAL -1092)

In the same manner as in Example 30, the indoline-based derivative YAL-1092 was obtained by using the material obtained in Example 8 instead of YAL-1093.

Yield: 60% 68 mg

m.p. 157-159 ° C

^{1 H NMR (MeOD, 300 MHz} ) d 7.61 (d, 1H, J = 7.93 Hz, Ar- H), 7.20 (t, 1H, J = 7.93 Hz, Ar- H), 7.17 (d, 1H, J = 7.93 Hz, Ar- H), 7.10 (t, 1H, J = 7.93 Hz, Ar- H), 7.08 (d, 1H, J = 7.55 Hz, Ar- H), 7.01 (t, 1H, J = 7.55 Hz , Ar- H), 6.76 (d , 1H, J = 7.55 Hz, Ar- H), 6.74 (t, 1H, J = 7.55 Hz, Ar- H), 4.48 (dd, 1H, J = 8.43, 10.61 Hz _{, NC H CH 2), 3.51} ~ 3.63 (m, 1H, NCHC H 2), 3.08 ~ 3.20 (m, 1H, NCHC H 2), 2.23 (s, 3H, Ar-C H 3)

Example  38: Indolin -2- Carboxylic acid N - (3- Methylphenyl ) Amide  ( YAL -1091)

In the same manner as in Example 30, the indoline-based derivative YAL-1091 was obtained by using the material obtained in Example 9 instead of YAL-1093.

Yield: 89% 170 mg

m.p. 113 ~ 114 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.44 (s, 1H, Ar- H), 7.37 (d, 1H, J = 8.08 Hz, Ar- H), 7.21 (t, 1H, J = 7.61 Hz, Ar - H), 7.14 (d, 1H, J = 7.61 Hz, Ar- H), 7.12 (t, 1H, J = 8.08 Hz, Ar- H), 6.93 (d, 1H, J = 7.61 Hz, Ar- H ), 6.87 (t, 1H, J = 7.61 Hz, Ar- H), 6.83 (d, 1H, J = 8.08 Hz, Ar- H), 4.53 (dd, 1H, J = 8.77, 10.80 Hz, NC H CH _{2), 3.62 ~ 3.73 (m} , 1H, NCHC H 2), 3.15 ~ 3.27 (m, 1H, NCHC H 2), 2.34 (s, 3H, Ar-C H 3)

Example  39: Indolin -2- Carboxylic acid N -(4- Methylphenyl ) Amide  ( YAL -1096)

In the same manner as in Example 30, the indoline-based derivative YAL-1096 was obtained by using the material obtained in Example 10 instead of YAL-1093.

Yield: 74% 90 mg

m.p. 202 to 205 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.47 (d, 2H, J = 8.23 Hz, Ar- H), 7.13 (d, 2H, J = 8.23 Hz, Ar- H), 7.12 (t, 1H, J = 7.04 Hz, Ar- H), 7.11 (d, 1H, J = 7.04 Hz, Ar- H), 6.87 (t, 1H, J = 7.04 Hz, Ar- H), 6.83 (d, 1H, J = 7.04 Hz, Ar- H), 4.48 ~ 4.58 (m, 1H, NC H CH 2), 3.63 ~ 3.73 (m, 1H, NCHC H 2), 3.16 ~ 3.26 (m, 1H, NCHC H 2), 2.31 (s , 3H, Ar - C H ₃ )

Example  40: Indolin -2- Carboxylic acid N -(2- Nitrophenyl ) Amide  ( YAL -1148)

In the same manner as in Example 30, the indoline-based derivative YAL-1148 was obtained by using the material obtained in Example 11 instead of YAL-1093.

Yield: 25% 50 mg

m.p. 164 to 165 ° C

^{1 H NMR (MeOD, 300 MHz} ) d 8.66 (d, 1H, J = 8.12 Hz, Ar- H), 8.19 (d, 1H, J = 8.12 Hz, Ar- H), 7.70 (t, 1H, J = 8.12 Hz, Ar- H), 7.28 (t, 1H, J = 8.12 Hz, Ar- H), 7.07 (d, 1H, J = 7.77 Hz, Ar- H), 7.05 (t, 1H, J = 7.77 Hz , Ar- H), 6.82 (d , 1H, J = 7.77 Hz, Ar- H), 6.75 (t, 1H, J = 7.77 Hz, Ar- H), 4.49 (dd, 1H, J = 8.21, 10.98 Hz _{, NC H CH 2), 3.54} ~ 3.66 (m, 1H, NCHC H 2), 3.09 ~ 3.19 (m, 1H, NCHC H 2)

Example  41: Indolin -2- Carboxylic acid N - (3- Nitrophenyl ) Amide  ( YAL -1147)

In the same manner as in Example 30, the indoline-based derivative YAL-1147 was obtained by using the material obtained in Example 12 instead of YAL-1093.

Yield: 90% 140 mg

m.p. 181 ~ 183 ° C

^{1 H NMR (MeOD, 300 MHz} ) d 8.69 (s, 1H, Ar- H), 7.92 ~ 8.00 (m, 2H, Ar- H), 7.55 (t, 1H, J = 8.21 Hz, Ar- H), 7.07 (d, 1H, J = 7.60 Hz, Ar- H), 7.03 (t, 1H, J = 7.60 Hz, Ar- H), 6.76 (d, 1H, J = 7.60 Hz, Ar- H), 6.72 ( t, 1H, J = 7.60 Hz , Ar- H), 4.49 (dd, 1H, J = 8.46, 10.54 Hz, NC H CH 2), 3.48 ~ 3.60 (m, 1H, NCHC H 2), 3.10 ~ 3.21 ( m, 1H, NCHC H ₂ )

Example  42: Indolin -2- Carboxylic acid N -(4- Nitrophenyl ) Amide  ( YAL -1130)

In the same manner as in Example 30, the indoline-based derivative YAL-1130 was obtained by using the material obtained in Example 13 instead of YAL-1093.

Yield: 68% 150 mg

m.p. 195-197 ° C

^{1 H NMR (MeOD, 300 MHz} ) d 8.14 (d, 2H, J = 9.26 Hz, Ar- H), 7.82 (d, 2H, J = 9.26 Hz, Ar- H), 6.99 (d, 1H, J = 7.32 Hz, Ar- H), 6.95 (t, 1H, J = 7.32 Hz, Ar- H), 6.68 (d, 1H, J = 7.32 Hz, Ar- H), 6.65 (t, 1H, J = 7.62 Hz , Ar- H), 4.40 (dd , 1H, J = 8.33, 10.51 Hz, NC H CH 2), 3.40 ~ 3.50 (m, 1H, NCHC H 2), 3.02 ~ 3.13 (m, 1H, NCHC H 2)

Example  43: Indolin -2- Carboxylic acid N -(2- Trifluoromethylphenyl ) Amide  ( YAL -1146)

In the same manner as in Example 30, a substance obtained in Example 14 was used instead of YAL-1093 to obtain an indoline-based derivative YAL-1146 in the form of a caramel.

Yield: 63% 100 mg

^{1 H NMR (MeOD, 300 MHz} ) d 8.10 (d, 1H, J = 7.97 Hz, Ar- H), 7.68 (d, 1H, J = 7.97 Hz, Ar- H), 7.63 (t, 1H, J = 7.97 Hz, Ar- H), 7.34 (t, 1H, J = 7.97 Hz, Ar- H), 7.08 (d, 1H, J = 7.65 Hz, Ar- H), 7.04 (t, 1H, J = 7.65 Hz , Ar- H), 6.78 (d , 1H, J = 7.65 Hz, Ar- H), 6.77 (t, 1H, J = 7.65 Hz, Ar- H), 4.47 (dd, 1H, J = 8.02, 10.86 Hz _{, NC H CH 2), 3.54} ~ 3.64 (m, 1H, NCHC H 2), 3.08 ~ 3.18 (m, 1H, NCHC H 2)

Example  44: Indolin -2- Carboxylic acid N - (3- Trifluoromethylphenyl ) Amide  ( YAL -1153)

In the same manner as in Example 30, the indoline-based derivative YAL-1153 was obtained by using the material obtained in Example 15 instead of YAL-1093.

Yield: 50% 135 mg

m.p. 97 ~ 100 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 8.08 (s, 1H, Ar- H), 7.79 (d, 1H, J = 7.96 Hz, Ar- H), 7.49 (t, 1H, J = 7.96 Hz, Ar- H), 7.37 (d, 1H , J = 7.96 Hz, Ar- H), 7.05 (d, 1H, J = 7.73 Hz, Ar- H), 7.01 (t, 1H, J = 7.73 Hz, Ar- H) , 6.73 (d, 1H, J = 7.73 Hz, Ar- H), 6.70 (t, 1H, J = 7.73 Hz, Ar- H), 4.45 (dd, 1H, J = 8.53, 10.51 Hz, NC H CH 2 ), 3.45 ~ 3.57 (m, 1H, NCHC H 2), 3.07 ~ 3.18 (m, 1H, NCHC H 2)

Example  45: Indolin -2- Carboxylic acid N -(4- Trifluoromethylphenyl ) Amide  ( YAL -1138)

In the same manner as in Example 30, the indoline-based derivative YAL-1138 was obtained by using the substance obtained in Example 16 instead of YAL-1093.

Yield: 51% 154 mg

m.p. 153 ~ 155 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.80 (d, 2H, J = 8.55 Hz, Ar- H), 7.60 (d, 2H, J = 8.55 Hz, Ar- H), 7.28 (d, 1H, J = 7.62 Hz, Ar- H), 7.25 (t, 1H, J = 7.62 Hz, Ar- H), 7.16 (d, 1H, J = 7.62 Hz, Ar- H), 7.14 (t, 1H, J = 7.62 Hz, Ar- H), 4.80 ( dd, 1H, J = 7.62, 10.01 Hz, NC H CH 2), 3.65 ~ 3.74 (m, 1H, NCHC H 2), 3.29 ~ 3.37 (m, 1H, NCHC H 2 )

Example  46: Indolin -2- Carboxylic acid N -(2- Chlorophenyl ) Amide  ( YAL -1114)

In the same manner as in Example 30, the indoline-based derivative YAL-1114 was obtained by using the material obtained in Example 17 instead of YAL-1093.

Yield: 68% 102 mg

m.p. 118 ~ 120 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 8.23 (d, 1H, J = 7.97 Hz, Ar- H), 7.43 (d, 1H, J = 7.97 Hz, Ar- H), 7.31 (t, 1H, J = 7.97 Hz, Ar- H), 7.12 (t, 1H, J = 7.97 Hz, Ar- H), 7.08 (d, 1H, J = 7.57 Hz, Ar- H), 7.04 (t, 1H, J = 7.57 Hz , Ar- H), 6.79 (d , 1H, J = 7.57 Hz, Ar- H), 6.76 (t, 1H, J = 7.57 Hz, Ar- H), 4.48 (dd, 1H, J = 8.34, 9.94 Hz _{, NC H CH 2), 3.54} ~ 3.66 (m, 1H, NCHC H 2), 3.08 ~ 3.18 (m, 1H, NCHC H 2)

Example  47: Indolin -2- Carboxylic acid N - (3- Chlorophenyl ) Amide  ( YAL -1113)

In the same manner as in Example 30, the indoline-based derivative YAL-1113 was obtained by using the material obtained in Example 18 instead of YAL-1093.

Yield: 69% 90 mg

m.p. 103 ~ 105 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.82 (s, 1H, Ar- H), 7.47 (d, 1H, J = 8.12 Hz, Ar- H), 7.28 (t, 1H, J = 8.12 Hz, Ar- H), 7.10 (d, 1H , J = 8.12 Hz, Ar- H), 7.06 (d, 1H, J = 7.93 Hz, Ar- H), 7.02 (t, 1H, J = 7.93 Hz, Ar- H) , 6.74 (d, 1H, J = 7.93 Hz, Ar- H), 6.69 (t, 1H, J = 7.93 Hz, Ar- H), 4.44 (dd, 1H, J = 8.55, 10.47 Hz, NC H CH 2 ), 3.45 ~ 3.57 (m, 1H, NCHC H 2), 3.07 ~ 3.18 (m, 1H, NCHC H 2)

Example  48: Indolin -2- Carboxylic acid N -(4- Chlorophenyl ) Amide  ( YAL -1120)

In the same manner as in Example 30, the indoline-based derivative YAL-1120 was obtained by using the material obtained in Example 19 instead of YAL-1093.

Yield: 70% 210 mg

m.p. 166 ~ 169 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.53 (d, 2H, J = 8.72 Hz, Ar- H), 7.23 (d, 2H, J = 8.72 Hz, Ar- H), 7.17 (t, 1H, J = 7.75 Hz, Ar- H), 7.15 (d, 1H, J = 7.75 Hz, Ar- H), 7.02 (d, 1H, J = 7.75 Hz, Ar- H), 7.01 (t, 1H, J = 7.75 Hz, Ar- H), 4.83 ( dd, 1H, J = 8.40, 10.44 Hz, NC H CH 2), 3.68 ~ 3.79 (m, 1H, NCHC H 2), 3.20 ~ 3.29 (m, 1H, NCHC H 2 )

Example  49: Indolin -2- Carboxylic acid N - (2,5- Dichlorophenyl ) Amide  ( YAL -1117)

In the same manner as in Example 30, the indoline derivative YAL-1117 was obtained by using the substance obtained in Example 20 instead of YAL-1093.

Yield: 64% 135 mg

m.p. 155 to 156 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.42 (s, 1H, Ar- H), 7.95 (d, 1H, J = 8.46 Hz, Ar- H), 7.28 ~ 7.38 (m, 2H, Ar- H) , 7.19 (t, 1H, J = 7.08 Hz, Ar- H), 7.02 ~ 7.12 (m, 2H, Ar- H), 5.29 (dd, 1H, J = 8.11, 10.70 Hz, NC H CH 2), 3.65 (M, 1H, NCHC H ₂ ), 3.30 ~ 3.45 (m, 1H, NCHC H ₂ )

Example  50: Indolin -2- Carboxylic acid N - (3,5- Dichlorophenyl ) Amide  ( YAL -1118)

YAL-1118 was obtained in the same manner as in Example 30, except that the material obtained in Example 21 was used instead of YAL-1093.

Yield: 97% 220 mg

m.p. 125 ~ 127 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.70 (s, 2H, Ar- H), 7.15 (s, 1H, Ar- H), 7.06 (d, 1H, J = 7.78 Hz, Ar- H), 7.02 ( t, 1H, J = 7.78 Hz , Ar- H), 6.74 (d, 1H, J = 7.78 Hz, Ar- H), 6.71 (t, 1H, J = 7.78 Hz, Ar- H), 4.44 (dd, 1H, J = 8.50, 10.52 Hz , NC H CH 2), 3.45 ~ 3.56 (m, 1H, NCHC H 2), 3.06 ~ 3.17 (m, 1H, NCHC H 2)

Example  51: Indolin -2- Carboxylic acid N - (3,4- Dichlorophenyl ) Amide  ( YAL -1121)

In the same manner as in Example 30, the indoline-based derivative YAL-1121 was obtained by using the material obtained in Example 22 instead of YAL-1093.

Yield: 71% 160 mg

m.p. 220 to 222 DEG C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.84 (s, 1H, Ar- H), 7.42 (d, 1H, J = 8.69 Hz, Ar- H), 7.36 (d, 1H, J = 8.69 Hz, Ar - H), 7.15 (d, 1H, J = 7.52 Hz, Ar- H), 7.13 (t, 1H, J = 7.52 Hz, Ar- H), 6.89 (t, 1H, J = 7.52 Hz, Ar- H ), 6.84 (d, 1H, J = 7.52 Hz, Ar- H), 4.53 (dd, 1H, J = 8.46, 10.90 Hz, NC H CH 2), 3.62 ~ 3.73 (m, 1H, NCHC H 2), 3.15-3.25 (m, 1H, NCHC H ₂ )

Example  52: Indolin -2- Carboxylic acid N - (2,5- Dimethylphenyl ) Amide  ( YAL -1104)

In the same manner as in Example 30, the indoline-based derivative YAL-1104 was obtained by using the material obtained in Example 23 instead of YAL-1093.

Yield: 62% 118 mg

m.p. 147 ~ 149 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.44 (s, 1H, Ar- H), 6.97 ~ 7.12 (m, 3H, Ar- H), 6.92 (d, 1H, J = 7.05 Hz, Ar- H), 6.76 (d, 1H, J = 8.25 Hz, Ar- H), 6.74 (t, 1H, J = 8.25 Hz, Ar- H), 4.47 (dd, 1H, J = 8.47, 10.63 Hz, NC H CH 2) , 3.52 ~ 3.65 (m, 1H , NCHC H 2), 3.09 ~ 3.18 (m, 1H, NCHC H 2), 2.29 (s, 3H, Ar-C H 3), 2.17 (s, 3H, Ar-C H ₃ )

Example  53: Indolin -2- Carboxylic acid N - (3,5- Dimethylphenyl ) Amide  ( YAL -1102)

In the same manner as in Example 30, the indoline-based derivative YAL-1102 was obtained by using the material obtained in Example 24 instead of YAL-1093.

Yield: 50% 130 mg

m.p. 149 ~ 150 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.21 (s, 2H, Ar- H), 7.06 (d, 1H, J = 7.73 Hz, Ar- H), 7.02 (t, 1H, J = 7.73 Hz, Ar- H), 6.77 (s, 1H , Ar- H), 6.74 (d, 1H, J = 7.73 Hz, Ar- H), 6.72 (t, 1H, J = 7.73 Hz, Ar- H), 4.42 (dd, 1H, J = 8.59, 10.49 Hz , NC H CH 2), 3.47 ~ 3.57 (m, 1H, NCHC H 2), 3.06 ~ 3.15 (m, 1H, NCHC H 2), 2.27 (s, 6H, Ar-C H ₃ )

Example  54: Indolin -2- Carboxylic acid N - (3,4- Dimethylphenyl ) Amide  ( YAL -1103)

In the same manner as in Example 30, the indoline-based derivative YAL-1103 was obtained by using the material obtained in Example 25 instead of YAL-1093.

Yield: 66% 97 mg

m.p. 116 ~ 118 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 7.34 (s, 1H, Ar- H), 7.29 (d, 1H, J = 8.18 Hz, Ar- H), 7.06 (d, 2H, J = 8.14 Hz, Ar- H), 7.02 (t, 1H , J = 7.67 Hz, Ar- H), 6.74 (d, 1H, J = 7.67 Hz, Ar- H), 6.72 (t, 1H, J = 7.67 Hz, Ar- H) , 4.43 (dd, 1H, J = 8.52, 10.47 Hz, NC H CH 2), 3.45 ~ 3.57 (m, 1H, NCHC H 2), 3.05 ~ 3.15 (m, 1H, NCHC H 2), 2.24 (s, 3H, Ar - C H ₃ ), 2.21 (s, 3H, Ar - C H ₃ )

Example  55: Indolin -2- Carboxylic acid N - (2,5- Dimethoxyphenyl ) Amide  ( YAL -1083)

In the same manner as in Example 30, the indoline-based derivative YAL-1083 was obtained by using the substance obtained in Example 26 instead of YAL-1093.

Yield: 73% 200 mg

m.p. 137 ~ 139 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 8.17 (s, 1H, Ar- H), 7.13 (d, 1H, J = 7.76 Hz, Ar- H), 7.12 (t, 1H, J = 7.76 Hz, Ar - H), 6.85 (t, 1H, J = 7.76 Hz, Ar- H), 6.84 (d, 1H, J = 7.76 Hz, Ar- H), 6.79 (d, 1H, J = 8.92 Hz, Ar- H ), 6.58 (d, 1H, J = 8.92 Hz, Ar- H), 4.47 ~ 4.59 (m, 1H, NC H CH 2), 3.81 (s, 3H, OC H 3), 3.80 (s, 3H, OC _{H 3), 3.58 ~ 3.71 (} m, 1H, NCHC H 2), 3.15 ~ 3.28 (m, 1H, NCHC H 2)

Example  56: Indolin -2- Carboxylic acid N - (3,5- Dimethoxyphenyl ) Amide  ( YAL -1086)

In the same manner as in Example 30, the indoline-based derivative YAL-1086 was obtained by using the substance obtained in Example 27 instead of YAL-1093.

Yield: 99% 170 mg

m.p. 117 to 119 ° C

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.50 (d, 1H, J = 7.51 Hz, Ar- H), 7.13 (t, 1H, J = 7.51 Hz, Ar- H), 6.89 (d, 1H, J = 7.51 Hz, Ar- H), 6.85 (t, 1H, J = 7.51 Hz, Ar- H), 6.84 (s, 2H, Ar- H), 6.25 (s, 1H, Ar- H), 4.53 (dd , 1H, J = 8.80, 10.75 Hz, NC H CH 2), 3.78 (s, 6H, OC H 3), 3.61 ~ 3.76 (m, 1H, NCHC H 2), 3.15 ~ 3.27 (m, 1H, NCHC H ₂ )

Example  57: Indolin -2- Carboxylic acid N - (3,4- Dimethoxyphenyl ) Amide  ( YAL -1087)

In the same manner as in Example 30, the indoline-based derivative YAL-1087 was obtained by using the material obtained in Example 28 instead of YAL-1093.

Yield: 75% 240 mg

m.p. 168 ~ 169 ℃

_{^{1 H NMR (CDCl 3, 300}} MHz) d 7.39 (s, 1H, Ar- H), 7.14 (d, 1H, J = 8.67 Hz, Ar- H), 7.13 (t, 1H, J = 8.67 Hz, Ar - H), 6.97 (d, 1H, J = 7.79 Hz, Ar- H), 6.88 (t, 1H, J = 8.67 Hz, Ar- H), 6.84 (d, 1H, J = 7.79 Hz, Ar- H ), 6.81 (d, 1H, J = 8.67 Hz, Ar- H), 4.54 (dd, 1H, J = 8.93, 10.64 Hz, NC H CH 2), 3.89 (s, 3H, OC H 3), 3.86 ( _{s, 3H, OC H 3)} , 3.62 ~ 3.75 (m, 1H, NCHC H 2), 3.15 ~ 3.30 (m, 1H, NCHC H 2)

Example  58: Indolin -2- Carboxylic acid N - (3,5- Di (trifluoromethyl) phenyl ) Amide  (YAL-1154)

In the same manner as in Example 30, the indoline-based derivative YAL-1154 was obtained by using the substance obtained in Example 29 instead of YAL-1093.

Yield: 57% 159 mg

m.p. 198 ~ 200 ℃

^{1 H NMR (MeOD, 300 MHz} ) d 8.33 (s, 2H, Ar- H), 7.65 (s, 1H, Ar- H), 7.07 (d, 1H, J = 7.45 Hz, Ar- H), 7.03 ( t, 1H, J = 7.45 Hz , Ar- H), 6.76 (d, 1H, J = 7.45 Hz, Ar- H), 6.72 (t, 1H, J = 7.45 Hz, Ar- H), 4.51 (dd, 1H, J = 8.47, 10.51 Hz , NC H CH 2), 3.45 ~ 3.59 (m, 1H, NCHC H 2), 3.10 ~ 3.22 (m, 1H, NCHC H 2)

The indoline-based derivatives prepared according to Examples 1 to 58 can be represented by the following Formula 1, and the respective substituents are shown in Table 1 and Table 2.

In addition, regarding the biological effects of the indolinone derivatives prepared according to Examples 1 to 58 above, the inhibitory effect of NF-κB was measured through Test Example 1 as described below, and 50% Concentration (IC ₅₀ ).

Test Example  One: NF Inhibitory effect on -KB activation

The samples were pretreated with macrophage RAW264.7 cells transfected with pNF-κB-SEAP-NPT, which is a plasmid capable of detecting expression of a reporter gene dependent on NF-κB activation, for 2 hours, and subjected to glycolysis (LPS, 1 ug / ml) And stimulated for 24 hours. The amount of secretory alkaline phosphatase (abbreviated as SEAP) generated in association with the activation of NF-κB using a supernatant obtained by centrifuging the cell culture was measured using a relative fluorescence unit (RFU) ≪ / RTI >

The measurement results are shown in Tables 1 and 2 below, and the effect of each sample was calculated by a concentration (IC ₅₀ ) showing a 50% inhibitory effect.

[Chemical Formula 1]

division Compound No. X R ¹ R ² R ³ R ⁴ R ⁵ % inhibition
at 100uM IC50 (uM) Example 1 YAL-1093 Boc H H H H H 30 ± 5 > 100 Example 2 YAL-1124 Boc OH H H H H 93 ± 1 - Example 3 YAL-1134 Boc H OH H H H 75 ± 8 58.7 Example 4 YAL-1122 Boc H H OH H H 42 ± 4 > 100 Example 5 YAL-1079 Boc OCH ₃ H H H H 76 ± 2 - Example 6 YAL-1075 Boc H OCH ₃ H H H 38 ± 3 > 100 Example 7 YAL-1074 Boc H H OCH ₃ H H 29 ± 3 > 100 Example 8 YAL-1090 Boc CH ₃ H H H H 68 ± 1 62.5 Example 9 YAL-1089 Boc H CH ₃ H H H 87 ± 2 - Example 10 YAL-1094 Boc H H CH ₃ H H 37 ± 6 > 100 Example 11 YAL-1144 Boc NO ₂ H H H H 63 ± 1 - Example 12 YAL-1143 Boc H NO ₂ H H H 94 ± 2 14.1 Example 13 YAL-1126 Boc H H NO ₂ H H > 100 - Example 14 YAL-1140 Boc CF ₃ H H H H 38 ± 4 > 100 Example 15 YAL-1139 Boc H CF ₃ H H H > 100 - Example 16 YAL-1128 Boc H H CF ₃ H H > 100 12 Example 17 YAL-1110 Boc Cl H H H H 50 ± 1 - Example 18 YAL-1106 Boc H Cl H H H > 100 - Example 19 YAL-1115 Boc H H Cl H H 31 ± 3 > 100 Example 20 YAL-1111 Boc Cl H H Cl H 71 ± 4 45.9 Example 21 YAL-1112 Boc H Cl H Cl H - 10.1 Example 22 YAL-1116 Boc H Cl Cl H H 97 ± 3 12.6 Example 23 YAL-1101 Boc Me H H Me H 75 ± 4 50 Example 24 YAL-1100 Boc H Me H Me H 78 ± 9 16.6 Example 25 YZL-1099 Boc H Me Me H H 64 ± 3 - Example 26 YAL-1080 Boc OCH ₃ H H OCH ₃ H 76 ± 1 - Example 27 YAL-1084 Boc H OCH ₃ H OCH ₃ H 88 ± 1 - Example 28 YAL-1085 Boc H OCH ₃ OCH ₃ H H 65 ± 1 52.2 Example 29 YAL-1152 Boc H CF ₃ H CF ₃ H - 14.9

division Compound No. X R ¹ R ² R ³ R ⁴ R ⁵ % inhibition
at 100uM IC50 (uM) Example 30 YAL-1076 H H H H H H 65 ± 6 71.6 Example 31 YAL-1131 H OH H H H H 37 ± 5 > 100 Example 32 YAL-1137 H H OH H H H 30 ± 5 > 100 Example 33 YAL-1135 H H H OH H H 63 ± 3 66.2 Example 34 YAL-1082 H OCH ₃ H H H H 60 ± 5 79.2 Example 35 YAL-1078 H H OCH ₃ H H H 64 ± 3 - Example 36 YAL-1077 H H H OCH ₃ H H 37 ± 9 > 100 Example 37 YAL-1092 H CH ₃ H H H H 39 ± 5 > 100 Example 38 YAL-1091 H H CH ₃ H H H 29 ± 3 > 100 Example 39 YAL-1096 H H H CH ₃ H H 41 ± 8 > 100 Example 40 YAL-1148 H NO ₂ H H H H 41 ± 6 > 100 Example 41 YAL-1147 H H NO ₂ H H H 49 ± 5 > 100 Example 42 YAL-1130 H H H NO ₂ H H 41 ± 4 > 100 Example 43 YAL-1146 H CF ₃ H H H H 61 ± 2 79.4 Example 44 YAL-1153 H H CF ₃ H H H 99 ± 1 46 Example 45 YAL-1138 H H H CF ₃ H H 56 ± 5 79.2 Example 46 YAL-1114 H Cl H H H H 62 ± 10 69.7 Example 47 YAL-1113 H H Cl H H H 63 ± 3 - Example 48 YAL-1120 H H H Cl H H 62 ± 4 70.7 Example 49 YAL-1117 H Cl H H Cl H 34 ± 9 > 100 Example 50 YAL-1118 H H Cl H Cl H 98 ± 3 - Example 51 YAL-1121 H H Cl Cl H H 72 ± 3 - Example 52 YAL-1104 H Me H H Me H 47 ± 7 > 100 Example 53 YAL-1102 H H Me H Me H 56 ± 3 85 Example 54 YAL-1103 H H Me Me H H 87 ± 2 43.3 Example 55 YAL-1083 H OCH ₃ H H OCH ₃ H 47 ± 2 > 100 Example 56 YAL-1086 H H OCH ₃ H OCH ₃ H 41 ± 4 > 100 Example 57 YAL-1087 H H OCH ₃ OCH ₃ H H 15 ± 8 > 100 Example 58 YAL_1154 H H CF ₃ H CF ₃ H 96 ± 3 12

As shown in Tables 1 and 2, the indolin derivatives of Examples 1 to 58 prepared according to the present invention effectively inhibit the activation of NF-κB.

The present invention provides a novel indolin-based derivative that effectively inhibits the activation of NF-κB, thereby preventing the prevention of any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis, and cancer known to be invented by activation of NF-κB Or may be useful for treatment.

In particular, the indolin-based compound of the present invention acts as an inhibitor of activation of microglial cells, minimizing adverse effects by inhibiting the death of nerve cells, and being useful for treating brain diseases such as stroke, Alzheimer's disease, Parkinson's disease and rheumatism and arthritis have.

Claims (10)

delete delete delete delete A pharmaceutical composition for preventing or treating multiple myeloma comprising an indoline-2-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier: [Chemical Formula 1]

Wherein, X is H or tert-butoxycarbonyl, R ¹ , R ² , R ³ and R ⁴ are the same or different and each is H, hydroxy, chloro, nitro, methyl, methoxy or trifluoromethyl. A pharmaceutical composition for preventing or treating rheumatoid arthritis comprising an indoline-2-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier: [Chemical Formula 1]

Wherein, X is H or tert-butoxycarbonyl, R ¹ , R ² , R ³ and R ⁴ are the same or different and each is H, hydroxy, chloro, nitro, methyl, methoxy or trifluoromethyl. A pharmaceutical composition for preventing or treating cancer, comprising an indoline-2-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier: [Chemical Formula 1]

Wherein, X is H or tert-butoxycarbonyl, R ¹ , R ² , R ³ and R ⁴ are the same or different and each is H, hydroxy, chloro, nitro, methyl, methoxy or trifluoromethyl. 8. The method according to any one of claims 5 to 7, Wherein the composition comprises the indolin-2-carboxamide derivative or a pharmaceutically acceptable salt thereof in an amount of 0.001 to 99.9% by weight based on the total composition. 8. The method according to any one of claims 5 to 7, The formulation of the composition is selected from the group consisting of an agent, a granule, a lotion, a powder, a syrup, a liquid, an aerosol, an ointment, a fluid excrement, an oil, a suspension, an infiltrant, a tablet, an injection, a capsule, A pharmaceutical composition. 8. The method according to any one of claims 5 to 7, The indoline-2-carboxamide derivative is indoline-2-carboxylic acid N-phenylamide, indoline-2-carboxylic acid N - (2- hydroxy-phenyl) -amide, indoline-2-carboxylic acid N - ( 2-carboxylic acid N - (2-methoxy-phenyl) -amide, indolin-2-carboxylic acid N- (4-hydroxy- phenyl) 2-carboxylic acid N - (3- methoxy-phenyl) -amide, indoline-2-carboxylic acid N - (4- methoxy-phenyl) -amide, indoline-2-carboxylic acid N - (2- methyl-phenyl ) -amide, indoline-2-carboxylic acid N - (3- methyl-phenyl) -amide, indoline-2-carboxylic acid N - (4- methyl-phenyl) -amide, indoline-2-carboxylic acid N - (2 -trifluoromethyl-phenyl) -amide, indoline-2-carboxylic acid N - (3- trifluoromethyl-phenyl) -amide, indoline-2-carboxylic acid N - (4- trifluoromethyl-phenyl) -amide, indoline-2-carboxylic acid N - (2- chloro-phenyl) -amide, indoline-2-carboxylic acid N - (3- claw -Phenyl) -amide, indoline-2-carboxylic acid N - (4- chloro-phenyl) -amide, indoline-2-carboxylic acid N - (2- nitro-phenyl) -amide, indoline-2-carboxylic acid N Indole-2-carboxylic acid N- (2,5-dichloro-phenyl) -amide, indole-2-carboxylic acid N - (4-nitro- lin-2-carboxylic acid N - (3,5- dichloro-phenyl) -amide, indoline-2-carboxylic acid N - (3,4- dichloro-phenyl) -amide, indoline-2-carboxylic acid N - (2, 5-dimethyl-phenyl) -amide, indoline-2-carboxylic acid N - (3,5- dimethyl-phenyl) -amide, indoline-2-carboxylic acid N - (3,4- dimethyl-phenyl) -amide, indole lin-2-carboxylic acid N - (2,5- dimethoxy-phenyl) -amide, indoline-2-carboxylic acid N - (3,5- dimethoxy-phenyl) -amide, indoline-2-carboxylic acid N - ( 3,4-dimethoxy-phenyl) -amide, indoline-2-carboxylic acid N - (3,5- di triple-phenyl) -amide, tert- butyl 2- (phenylcarbamoyl) of (2-hydroxyphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (3-hydroxyphenylcarbamoyl) indoline-1-carboxylate (2-methoxyphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (4-hydroxyphenylcarbamoyl) indoline- (3-methoxyphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (4-methoxyphenylcarbamoyl) indoline- (Para-tolylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (meta-tolylcarbamoyl) indoline-1-carboxylate, butyl 2- (3-trifluoromethylphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (2-trifluoromethylphenylcarbamoyl) indoline- 4-trifluoromethylphenylcarbamoyl) indoline-1-carboxylate, tert Butyl 2- (3-chlorophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (4-chlorophenylcarbamoyl) indole- (2-nitrophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (3-nitrophenylcarbamoyl) indolin-1-carboxylate (2,5-dichlorophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (4-nitrophenylcarbamoyl) indoline-1-carboxylate, tert- Butyl 2- (3,5-dichlorophenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (3,4-dichlorophenylcarbamoyl) indoline- 1-carboxylate, tert-butyl 2- (3,4-dimethylphenylcarbamoyl) indolin-1-carboxylate, Dimethylphenylcarbamoyl) indoline-1-carboxylate, tert-butyl 2- (2,5-dimethoxyphenylcarbamoyl) indoline 1-carboxylate, tert-butyl 2- (3,4-dimethoxyphenylcarbamoyl) indolin-1-carboxylate, -Carboxylate, and tert-butyl 2- (3,5-ditrifluoromethylphenylcarbamoyl) indoline-1-carboxylate.