MDM2/MDMX DOUBLE-TARGET INHIBITOR COMPOUND, PRODRUG, PHARMACEUTICAL COMPOSITION, AND PREPARATION METHOD THEREFOR AND USE THEREOF
20250223307 ยท 2025-07-10
Inventors
Cpc classification
C07D233/96
CHEMISTRY; METALLURGY
A61K31/4178
HUMAN NECESSITIES
A61K31/675
HUMAN NECESSITIES
C07D403/06
CHEMISTRY; METALLURGY
C07F9/6558
CHEMISTRY; METALLURGY
A61K31/4166
HUMAN NECESSITIES
C07F9/65583
CHEMISTRY; METALLURGY
International classification
C07F9/6558
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
A61K31/4178
HUMAN NECESSITIES
A61K31/675
HUMAN NECESSITIES
C07D233/96
CHEMISTRY; METALLURGY
Abstract
The disclosure provides a compound shown in formula (I) and a prodrug thereof, which have a good MDM2 and/or MDMX inhibiting effect and may be used for treating MDM2 and/or MDMX-mediated symptoms and/or diseases such as neoplastic diseases and/or idiopathic pulmonary fibrosis and preparing drugs for such symptoms or diseases. In particular, a compound containing a phosphoric acid (phosphate) structure has higher solubility. As the prodrug, the compound can release an MDM2 and/or MDMX double-target inhibitor compound with high activity in an animal body, which solves the problem that such double-target inhibitors are hardly prepared into drugs.
Claims
1. A compound shown in formula (I), and a raceme, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug compound thereof: ##STR00243## wherein R.sub.1 is selected from H, halogen, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6alkyl, and halogenated C.sub.1-6 alkoxyl; R.sub.2 is selected from H, C.sub.1-6 alkyl, halogen, C.sub.1-6 alkoxyl, C.sub.1-6 alkylthio, halogenated C.sub.1-6 alkyl, and halogenated C.sub.1-6 alkoxyl; R.sub.3 is selected from H, R.sub.3aOC.sub.1-6 alkyl, CH(O), and C(O)NHR.sub.3b; R.sub.3a is selected from H or P(O)(OR.sub.31)(OR.sub.32); R.sub.3b is selected from the following radicals which are unsubstituted or optionally substituted with one, two, three or more R.sub.3c: C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8cycloalkyl-C.sub.1-6 alkyl; R.sub.3c is selected from OH, C.sub.1-6 alkyl-NH, (C.sub.1-6 alkyl).sub.2-N, and OP(O)(OR.sub.31)(OR.sub.32); and R.sub.31 and R.sub.32 are same or different, and are independently selected from H and C.sub.1-6alkyl; R.sub.4 is selected from H and P(O)(OR.sub.41)(OR.sub.42); and R.sub.41 and R.sub.42 are same or different, and are independently selected from H and C.sub.1-6 alkyl; R.sub.5 is selected from H and P(O)(OR.sub.51)(OR.sub.52); and R.sub.51 and R.sub.52 are same or different, and are independently selected from H and C.sub.1-6 alkyl; Y is O or OR.sub.6; R.sub.6 is selected from H and P(O)(OR.sub.61)(OR.sub.62); and R.sub.61 and R.sub.62 are same or different, and are independently selected from H and C.sub.1-6 alkyl; is selected from a single bond or a double bond; m is selected from 0, 1, 2, 3, 4 or 5; and n is selected from 0, 1, 2, 3 or 4.
2. The compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to claim 1, wherein R.sub.1 is selected from H, halogen, CN, C.sub.1-3 alkyl, C.sub.2-3alkynyl, C.sub.1-3 alkoxyl, halogenated C.sub.1-3 alkyl, and halogenated C.sub.1-3alkoxyl; preferably, R.sub.1 is selected from H, F, Cl, CN, acetenyl, methyl, ethyl, and propyl; preferably, R.sub.2 is selected from H, C.sub.1-3 alkyl, halogen, C.sub.1-3 alkoxyl, C.sub.1-3 alkylthio, and halogenated C.sub.1-3 alkoxyl; and preferably, R.sub.2 is selected from H, F, Cl, Br, methyl, methoxyl, fluoromethoxyl, and methylthio.
3. The compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to claim 1, wherein R.sub.3 is selected from H, R.sub.3aOC.sub.1-3 alkyl, CH(O), and C(O)NHR.sub.3b; R.sub.3a is selected from H or P(O)(OH)(OH); R.sub.3b is selected from the following radicals which are unsubstituted or optionally substituted with one, two, three or more R.sub.3c: C.sub.1-3 alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8 cycloalkyl-C.sub.1-3 alkyl; and R.sub.3c is selected from OH, C.sub.1-3 alkyl-NH, (C.sub.1-3 alkyl).sub.2-N, and OP(O)(OH)(OH); preferably, R.sub.3 is selected from H, methyl, ##STR00244## ##STR00245## for example, selected from ##STR00246##
4. The compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to any one of claim 1, wherein R.sub.4 is selected from H and P(O)(OR.sub.41)(OR.sub.42); R.sub.41 and R.sub.42 are same or different, and are independently selected from H and C.sub.1-3 alkyl; preferably, R.sub.4 is selected from H and P(O)(OH)(OH); preferably, R.sub.5 is selected from H and P(O)(OR.sub.51)(OR.sub.52); and R.sub.51 and R.sub.52 are same or different, and are independently selected from H and C.sub.1-3 alkyl; preferably, R.sub.5 is selected from H and P(O)(OH)(OH); preferably, Y is O or OR.sub.6; R.sub.6 is selected from H and P(O)(OR.sub.61)(OR.sub.62); and R.sub.61 and R.sub.62 are same or different, and are independently selected from H and C.sub.1-3 alkyl; preferably, R.sub.6 is selected from H and P(O)(OH)(OH); preferably, m is selected from 1, 2 or 3; and preferably, n is selected from 1 or 2.
5. The compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to any one of claim 1, wherein the prodrug compound has a structure shown in formula (II): ##STR00247## wherein R.sub.1, R.sub.2, m and n independently have definitions according to any one of claim 1; R.sub.3 has a definition of R.sub.3 according to any one of claim 1; R.sub.4 is selected from H and P(O)(OR.sub.41)(OR.sub.42); R.sub.41 and R.sub.42 are same or different, and are independently selected from H and C.sub.1-3 alkyl; preferably, R.sub.4 is selected from H and P(O)(OR.sub.41)(OR.sub.42); and R.sub.41 and R.sub.42 are same or different, and are independently selected from H and C.sub.1-6alkyl; R.sub.5 is selected from H and P(O)(OR.sub.51)(OR.sub.52); R.sub.51 and R.sub.52 are same or different, and are independently selected from H and C.sub.1-3 alkyl; preferably, R.sub.5 is selected from H and P(O)(OR.sub.51)(OR.sub.52); and R.sub.51 and R.sub.52 are same or different, and are independently selected from H and C.sub.1-6 alkyl; Y is O or OR.sub.6; R.sub.6 is selected from H and P(O)(OR.sub.61)(OR.sub.62); and R.sub.61 and R.sub.62 are same or different, and are independently selected from H and C.sub.1-3 alkyl; preferably, R6 is selected from H and P(O)(OR.sub.61)(OR.sub.62); and R.sub.61 and R.sub.62 are same or different, and are independently selected from H and C.sub.1-6 alkyl; is selected from a single bond or a double bond; preferably, R.sub.3 is selected from H, R.sub.3aOC.sub.1-6 alkyl, CH(O), and C(O)NHR.sub.3b; R.sub.3a is selected from H or P(O)(OH)(OH); R.sub.3b is selected from the following radicals which are unsubstituted or optionally substituted with one, two, three or more R.sub.3c: C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl; R.sub.3c is selected from OH, C.sub.1-6 alkyl-NH, (C.sub.1-6 alkyl).sub.2-N, and OP(O)(OH)(OH); preferably, R.sub.4 is selected from H and P(O)(OH)(OH); preferably, R.sub.5 is selected from H and P(O)(OH)(OH); preferably, Y is O or OR.sub.6; and R.sub.6 is selected from H and P(O)(OH)(OH);
is selected from a single bond or a double bond; and at least one of R.sub.4, R.sub.5, R.sub.6, R.sub.3a, and R.sub.3c is P(O)(OH)(OH).
6. The compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to any one of claim 1, wherein the compound is selected from the following structures: TABLE-US-00004 Number Structure 1
7. A method for preparing the compound according to any one of claim 1, comprising a method I and/or a method II: method I: performing a reaction on a compound a and a compound b to obtain the compound shown in formula (I); ##STR00358## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Y, m, and n independently have definitions according to any one of claim 1; method II: performing a reaction on a compound c and R.sub.3bNH.sub.2 to obtain the compound shown in formula (I); ##STR00359## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.3b, Y, m, and n independently have definitions according to any one of claim 1.
8. A pharmaceutical composition, comprising a therapeutically effective amount of at least one of the compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to any one of claim 1.
9. Use of at least one of the compound, and the raceme, the stereoisomer, the tautomer, the isotopic label, the solvate, the polymorph, the pharmaceutically acceptable salt or the prodrug compound thereof according to any one of claim 1 in preparation of a drug, wherein preferably, the use is use in preparation of a drug for treating an MDM2 and/or MDMX-mediated symptom and/or disease, for example, use in preparation of an MDM2 and/or MDMX inhibitor drug; and preferably, the use is use in preparation of a drug for treating idiopathic pulmonary fibrosis.
10. The use according to claim 9, wherein the disease is a neoplastic disease, and the neoplastic disease comprises at least one of leukemia, chronic myeloid leukemia, acute myelocytic leukemia, lymphocytic leukemia, hairy cell leukemia, T lymphoblastic leukemia, lymphoma, B-cell lymphoma, burkitt lymphoma, hodgkin lymphoma, chondrosarcoma, fibrosarcoma, ewing sarcoma, rhabdomyosarcoma, small cell lung cancer, non-small cell lung cancer, myeloma, glioma, prostatic cancer, breast cancer, bone cancer, neuroblastoma, gastric cancer, ovarian cancer, intestinal cancer, renal cancer, medulloblastoma, pancreatic cancer, thyroid cancer, mesothelioma, cervical cancer, bladder cancer, liver cancer, skin cancer, and tumors in the central system or the peripheral nervous system.
Description
DETAILED DESCRIPTION
[0080] The technical solutions of the disclosure will be further described in detail below in conjunction with specific examples. It should be understood that the examples below merely describe and explain the disclosure exemplarily and should not be explained as a limitation to the protection scope of the disclosure. Technologies realized based on the above content of the disclosure should fall within the scope to be protected by the disclosure.
[0081] Unless otherwise specified, raw materials and reagents used in the examples below all are marketed commodities or may be prepared by known methods.
INTERMEDIATES
Intermediate I-1: Synthesis of 3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00118##
[0082] At room temperature, 4-(bromomethyl)-1,2-difluorobenzene (2 g, 9.178 mmol) and potassium carbonate (3.17 g, 22.945 mmol) are dissolved in N,N-dimethylformamide (20 mL). Hydantoin (1.35 g, 12.849 mmol) is added in batches into a mixed solution while the mixed solution is stirred. After being stirred at room temperature for 16 h, the mixture is poured into water (30 mL) and extracted with ethyl acetate (30 mL) three times, and organic phases are combined and washed with saturated saline. After being dried with anhydrous sodium sulfate, the organic phases are filtered, a filtrate is concentrated in vacuum to obtain a white solid crude product intermediate I-1 (1 g, 41.72%), and the crude product is not further purified and is directly used for a next reaction.
[0083] LC-MS m/z (ESI): 227.15 [M+H].sup.+.
Intermediate I-2: Synthesis of 3-(4-chlorobenzyl)imidazolidine-2,4-dione
##STR00119##
[0084] By using the method for the intermediate I-1, the white solid crude product intermediate I-2 (500 mg, 92.78%) is prepared by using 1-(bromomethyl)-4-chlorobenzene and hydantoin, and the crude product is not further purified and is directly used for a next reaction.
Intermediate I-3: Synthesis of 4-((2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
##STR00120##
[0085] By using the method for the intermediate I-1, the white solid crude product intermediate I-3 (2.26 g, 84%) is prepared by using 4-(bromomethyl)benzonitrile and hydantoin, and the crude product is not further purified and is directly used for a next reaction.
Intermediate I-4: Synthesis of 4-((2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile
##STR00121##
[0086] By using the method for the intermediate I-1, the white solid crude product intermediate I-4 (500 mg, 81%) is prepared by using 1-(bromomethyl)-4-chlorobenzene and hydantoin, and the crude product is not further purified and is directly used for a next reaction.
[0087] LC-MS m/z (ESI): 232.00 [MH].sup..
Intermediate I-5: Synthesis of 6-chloro-7-methoxyl-1H-indole-3-formaldehyde
##STR00122##
Intermediate I-5-1: 6-chloro-7-methoxyl-1H-indole
[0088] At 20 C., a bromovinyl magnesium bromide-tetrahydrofuran (1N, 160 mL) solution is slowly dropwise added into a solution of 1-chloro-2-methoxyl-3-nitrobenzene (10 g, 53.31 mmol) in tetrahydrofuran (200 mL). After being stirred at room temperature for 3 h, the mixture is poured into ice water (200 ml) and extracted with ethyl acetate (500 ml) twice. Organic phases are combined, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated in vacuum. The mixture is purified by flash chromatography to obtain the white solid I-5-1 (2.1 g, 19.52%).
[0089] LC-MS m/z (ESI): 182.1 [M+H].sup.+.
[0090] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.39 (s, 1H), 7.30 (dd, J=8.4, 0.5 Hz, 1H), 7.19 (dd, J=3.1, 2.5 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.53 (dd, J=3.1, 2.2 Hz, 1H), 4.02 (s, 3H).
I-5: 6-chloro-7-methoxyl-1H-indole-3-formaldehyde
[0091] At 0 C., phosphorus oxychloride (2.12 g, 13.87 mmol) is added into dimethylformamide (20 ml). The mixture is stirred at 0 C. for 10 min. Then, a solution of 6-chloro-7-methoxyl-1H-indole (2.1 g, 11.56 mmol) in dichloromethane (5 mL) is added. A mixed solution is stirred at room temperature for 1 h, sodium hydroxide (1N, 30 ml) is added into the mixed solution, and the mixed solution is stirred for 30 min. The mixed solution is extracted with ethyl acetate (30 ml) three times. Organic phases are combined, washed with anhydrous sodium sulfate, and concentrated in vacuum. The mixture is purified by flash chromatography to obtain the white solid I-5 (0.9 g, 37.1%).
[0092] LC-MS m/z (ESI): 210.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 12.57 (s, 1H), 9.94 (s, 1H), 8.35 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).
Intermediate I-6: Synthesis of 3-[(4-acetenyl phenyl)methyl]imidazolidine-2,4-dione
##STR00123##
[0093] By using the method for the intermediate I-1, the white solid intermediate I-6 (122 mg, 26%) is prepared by using 1-(bromomethyl)-4-acetylenylbenzene and hydantoin.
[0094] LC-MS m/z (ESI): 215.1 [M+H].sup.+.
Intermediate I-7: Synthesis of 3-[4-(8-amino octyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione
##STR00124##
[0095] By using the method for the intermediate I-1, the brown solid intermediate I-7 (129 mg, 29%) is prepared by using 3-(bromomethyl)benzonitrile and hydantoin.
[0096] LC-MS m/z (ESI): 214.0 [MH].sup..
Intermediate I-8: Synthesis of 6-chloro-7-methyl-1H-indole-3-formaldehyde
##STR00125##
I-8-1: 6-chloro-7-methyl-1H-indole
[0097] Under nitrogen protection, 1-chloro-2-methyl-3-nitrobenzene (2.0 g, 11.656 mmol) is dissolved in a tetrahydrofuran (20 ml) solution, the temperature of the solution is decreased to 78 C., vinyl magnesium bromide (1N, 46.6 ml, 46.626 mmol) is slowly dropwise added, and the mixture is continuously stirred for 2 h. A saturated ammonium chloride (100 ml) solution is slowly added into the mixture and the temperature of the system is maintained not higher than 60 C. A reaction is performed to raise the temperature to room temperature, the mixture is extracted with ethyl acetate (100 ml) three times, and combined organic phases are washed with saturated saline (100 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum. A residue is purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (5:1) to obtain the brown oily I-8-1 (1.08 g, 56%).
[0098] LC-MS m/z (ESI): 166.2 [M+H].sup.+.
I-8: 6-chloro-7-methyl-1H-indole-3-formaldehyde
[0099] At 0 C., phosphorus oxychloride (2.4 g, 16.094 mol) is dropwise added into a dimethylformamide (2.5 ml) solution. The obtained mixed solution is continuously stirred under nitrogen protection for 30 min and maintained at 0 C. A solution of 6-chloro-7-methyl-1H-indole (540 mg, 3.260 mmol) in dimethylformamide (2.5 ml) is added into the solution. After being stirred at 40 C. for 1 h, the mixture is cooled to room temperature and water (20 ml) is added to quench the reaction. The pH value of the system is adjusted to 8 with a sodium hydroxide (30%) solution. The obtained mixture is extracted with ethyl acetate (50 ml) three times, and combined organic phases are washed with saturated saline (50 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum. A residue is purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (1:1) to obtain the brown oily I-8 (623 mg, 96%).
[0100] LC-MS m/z (ESI): 194.1 [M+H].sup.+.
Intermediate I-9: Synthesis of 6-chloro-7-(methyl sulfonyl)-1H-indole-3-formaldehyde
##STR00126##
I-9-1: 1-chloro-2-methylthio-3-nitrobenzene
[0101] Under nitrogen protection at room temperature, 1-chloro-2-fluoro-3-nitrobenzene (2 g, 10.824 mmol) is dissolved in a DMF (40 mL) solution, sodium thiomethoxide (0.88 g, 11.906 mmol) is added into the solution, and the mixed solution is maintained stirred. The mixture is heated to 120 C. and stirred for 12 h, and after the reaction is completed, the mixture is cooled to room temperature. The obtained mixed solution is concentrated in vacuum. A residue is purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (5/95) to obtain the reddish brown oily I-9-1 (770 mg, 29%).
[0102] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.68-7.60 (m, 1H), 7.55-7.47 (m, 1H), 7.41-7.38 (m, 1H), 2.46 (s, 3H).
I-9-2: 6-chloro-7-(methyl sulfonyl)-1H-indole
[0103] Under nitrogen protection, 1-chloro-2-methylthio-3-nitrobenzene (230 mg, 0.932 mol) is dissolved in a tetrahydrofuran (5 ml) solution, the temperature of the solution is decreased to 78 C., vinyl magnesium bromide (1N, 3.7 ml, 3.7 mmol) is slowly dropwise added, and the mixture is continuously stirred for 3 h. A saturated ammonium chloride (50 ml) solution is slowly added into the mixture and the temperature of the system is maintained not higher than 60 C. A reaction is performed to raise the temperature to room temperature, the mixture is extracted with ethyl acetate (50 ml) twice, and combined organic phases are washed with saturated saline (50 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum. A residue is purified by preparative high performance liquid chromatography to obtain the brown oily I-9-2 (180 mg, 81%).
[0104] LC-MS m/z (ESI): 198.1 [M+H].sup.+.
I-9: 6-chloro-7-(methylsulfonyl)-1H-indole-3-formaldehyde
[0105] At 0 C., phosphorus oxychloride (0.178 g, 1.115 mol) is dropwise added into a dimethylformamide (1.5 ml) solution. The obtained mixed solution is continuously stirred under nitrogen protection for 30 min and maintained at 0 C. A solution of 6-chloro-7-(methylsulfonyl)-1H-indole (180 mg, 0.76 mmol) in dimethylformamide (1.5 ml) is added into the solution. After being stirred at 40 C. for 1 h, the mixture is cooled to room temperature and water (5 ml) is added to quench the reaction. The pH value of the system is adjusted to 8 with a sodium hydroxide (30%) solution. The obtained mixture is extracted with ethyl acetate (20 ml) three times, and combined organic phases are washed with saturated saline (30 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum to obtain the light yellow solid I-9 (160 mg, 89%). A crude product is directly left for a next step without further purification.
[0106] LC-MS m/z (ESI): 226.0 [M+H].sup.+.
Intermediate I-10: Synthesis of 6-chloro-7-fluoro-1H-indole-3-formaldehyde
##STR00127##
[0107] At 0 C., phosphorus oxychloride (0.18 ml, 1.117 mol) is dropwise added into a dimethylformamide (1.5 ml) solution. The obtained mixed solution is continuously stirred under nitrogen protection for 30 min and maintained at 0 C. A solution of 6-chloro-7-fluoro-1H-indole (75 mg, 0.44 mmol) in dimethylformamide (1.5 ml) is added into the solution. After being stirred at 40 C. for 1 h, the mixture is cooled to room temperature and water (5 ml) is added to quench the reaction. The pH value of the system is adjusted to 8 with a sodium hydroxide (30%) solution. The obtained mixture is extracted with ethyl acetate (50 ml) three times, and combined organic phases are washed with saturated saline (30 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum to obtain the white-like solid I-10 (75 mg, 44.07%). A crude product is directly left for a next step without further purification.
Intermediate I-11: Synthesis of 6-chloro-7-(fluoromethoxyl)-1H-indole-3-formaldehyde
##STR00128##
I-11-1: 1-chloro-2-(fluoromethoxyl)-3-nitrobenzene
[0108] At room temperature, 6-chloro-2-nitrophenol (1 g, 5.474 mmol) and potassium carbonate (1.59 g, 10.929 mmol) are added into a dimethylformamide (15 ml) solution and are maintained stirred, and bromofluoromethane (6.51 g, 54.764 mmol) is added into the mixture. The mixture is stirred overnight under nitrogen protection at room temperature, and after the reaction is completed, the mixed solution is poured into water (50 ml). The obtained mixture is extracted with ethyl acetate (30 ml) three times and washed with saturated saline (20 ml), and organic phases are combined and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum. A residue is purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (5:1) to obtain the yellow oily I-11-1 (430 mg, 38.14%).
[0109] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.02-7.95 (m, 2H), 7.52 (d, J=8.1 Hz, 1H), 5.87 (s, 1H), 5.70 (s, 1H).
I-11-2: 6-chloro-7-(fluoromethoxyl)-1H-indole
[0110] Under nitrogen protection, 1-chloro-2-(fluoromethoxyl)-3-nitrobenzene (590 mg, 2.864 mol) is dissolved in a tetrahydrofuran (8 ml) solution, the temperature of the solution is decreased to 78 C., vinyl magnesium bromide (1N, 8 ml, 8 mmol) is slowly dropwise added, and the mixture is continuously stirred for 3 h. A saturated ammonium chloride (50 ml) solution is slowly added into the mixture and the temperature of the system is maintained not higher than 60 C. A reaction is performed to raise the temperature to room temperature, the mixture is extracted with ethyl acetate (50 ml) twice, and combined organic phases are washed with saturated saline (50 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum. A residue is purified by preparative high performance liquid chromatography to obtain the gray oily I-11-2 (690 mg, 81%).
[0111] LC-MS m/z (ESI): 198.0 [MH].sup..
I-11: 6-chloro-7-(fluoromethoxyl)-1H-indole-3-formaldehyde
[0112] At 0 C., phosphorus oxychloride (1.25 g, 7.848 mol) is dropwise added into a dimethylformamide (13 ml) solution. The obtained mixed solution is continuously stirred under nitrogen protection for 30 min and maintained at 0 C. A solution of 6-chloro-7-(fluoromethoxyl)-1H-indole (640 mg, 3.2 mmol) in dimethylformamide (13 ml) is added into the solution. After being stirred at 40 C. for 1 h, the mixture is cooled to room temperature and water (4 ml) is added to quench the reaction. The pH value of the system is adjusted to 8 with a sodium hydroxide (30%) solution. The obtained mixture is extracted with ethyl acetate (30 ml) three times, and combined organic phases are washed with saturated saline (30 ml) and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated in vacuum to obtain the brown oily I-11 (380 mg, 51.56%). A crude product is directly left for a next step without further purification.
[0113] LC-MS m/z (ESI): 228.2 [M+H].sup.+.
Intermediate I-12: Synthesis of 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidine-1-yl)acetic acid
##STR00129##
I-12-1: Methyl 2-bromo-2(4-chlorophenyl)acetate
[0114] N-bromosuccinimide (1.93 g, 10.83 mmol) and azodiisobutyronitrile (1.78 g, 10.83 mmol) are added into a solution of methyl 2-(4-chlorophenyl)acetate (2 g, 10.83 mmol) in carbon tetrachloride (20 mL). A mixed solution is stirred at 80 C. for 5 h. The mixture is dried in vacuum to obtain the yellow oily I-12-1 (1.7 g, 56%).
[0115] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.50-7.47 (m, 2H), 7.36-7.33 (m, 2H), 5.32 (s, 1H), 3.79 (s, 3H).
I-12-2: Methyl 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate
[0116] At room temperature, hydantoin (0.89 g, 8.55 mmol) and potassium carbonate (1.63 g, 11.8 mmol) are respectively added into a solution of methyl 2-bromo-2(4-chlorophenyl)acetate (1.56 g, 5.9 mmol) in dimethylformamide (20 mL). A mixture is stirred at 25 C. for 16 h. After the reaction is finished, the mixture is diluted with water and extracted with ethyl acetate (50 mL) three times. Organic phases are combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The organic phases are purified by liquid chromatography to obtain the yellow solid I-12-2 (1.85 g, 88%).
[0117] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.45 (d, J=8.5 Hz, 2H), 7.34-7.26 (m, 2H), 5.75 (s, 1H), 5.71 (s, 1H), 4.01 (s, 2H), 3.80 (s, 3H).
I-12: (4-chlorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid
[0118] At room temperature, methyl 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (1.17 g, 4.139 mmol) is added into 2.5 mL of concentrated hydrochloric acid and maintained stirred, and acetic acid (7.5 mL) is dropwise added into a mixed solution. The obtained mixture is heated to 120 C. and then stirred for 3 h. After the reaction is finished, the reaction mixture is cooled to room temperature. The obtained mixture is concentrated at a reduced pressure to obtain a crude product I-12 (1.1 g, 86.7%) in a white solid form. The purified crude product is used for a next step.
[0119] LC-MS m/z (ESI): 269.0 [M+H].sup.+.
Intermediate I-13: Synthesis of (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetic acid
##STR00130##
[0120] methyl 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (1.56 g, 5.5 mmol) is added into an ethyl acetate (10 mL) solution, and then concentrated hydrochloric acid (3 mL) is then added. The obtained mixture is reflowed till it is completely dissolved. The mixture is concentrated to obtain an intermediate. The intermediate is dissolved in ethyl acetate (15 mL) and piperidine (2 mL) for being further reflowed for 2 h, and then 6-chloro-1H-indole-3-formaldehyde (0.99 g, 5.5 mmol) is added. The mixture is stirred and reflowed for 16 h. After the reaction is finished, the reaction mixture is cooled to room temperature. The mixture is filtered to collect a yellow precipitant, so as to obtain a crude product in a piperidine salt form. The crude product is dissociated with hydrochloric acid to obtain the I-13 (0.56 g, 21.82%). The purified crude product is used for a next step.
[0121] LC-MS m/z (ESI): 429.9 [M+H].sup.+.
Intermediate I-14: Synthesis of [(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-chlorophenyl)acetic acid
##STR00131##
I-14-1: Methyl 2-bromo-2-(4-chlorophenyl)acetate
[0122] At room temperature, hydrobromic acid in acetic acid (7.04 g, 35.208 mmol) is dropwise added into a stirred solution of methyl 2-(4-chlorophenyl)acetate (5 g, 27.083 mmol) and NBS (6.27 g, 35.208 mmol) in DCE (50 mL). The obtained mixture is then stirred at 85 C. for 12 h. After being cooled to room temperature, the obtained mixture is concentrated in vacuum to obtain a white solid crude product I-14-1 (8 g), and the crude product is directly used for a next step without further purification.
I-14-2: Methyl 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate
[0123] At room temperature, methyl 2-bromo-2-(4-chlorophenyl)acetate (2 g) and potassium carbonate (13.1 g, 9.488 mmol) are respectively added into a DMF (15 mL) solution, and then hydantoin (570 mg, 5.692 mmol) is added. The obtained mixture is then stirred at room temperature for 12 h. The obtained mixture is concentrated in vacuum. A residue is purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (5:1) to obtain the I-14-2 (1.17 g, 93.45%) in a white solid form.
[0124] LC-MS m/z (ESI): 283.1 [M+H].sup.+.
I-14-3: (4-chlorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid
[0125] At room temperature, methyl 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (1.17 g, 4.139 mmol) is added into 2.5 mL of concentrated hydrochloric acid and maintained stirred, and acetic acid (7.5 mL) is continuously dropwise added into a mixed solution. The obtained mixture is heated to 120 C. and then stirred for 3 h. A product is cooled to room temperature. The obtained mixture is concentrated in vacuum to obtain a white solid crude product I-14-3 (1.1 g), and the crude product is directly used for a next step without further purification.
[0126] LC-MS m/z (ESI): 269 [M+H].sup.+.
I-14: [(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-chlorophenyl)acetic acid
[0127] At room temperature, (4-chlorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (400 mg, 1.487 mmol) and 6-chloro-7-fluoro-1H-indole-3-formaldehyde (294 mg, 1.489 mmol) are respectively added into ethanol (6 mL), and then piperidine (0.54 mL) is added into a mixed solution. The obtained mixture is heated to 100 C. and stirred for 12 h. After the product is cooled to room temperature, a residue is purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (2:1) to obtain the yellow solid I-14 (196 mg, 31%).
[0128] LC-MS m/z (ESI): 446.0 [MH].sup..
Intermediate I-15: Synthesis of (4-cyanophenyl)(2,5-dioxypyrimidin-1-yl)acetic acid
##STR00132##
I-15-1: Methyl 2-bromo-2(4-cyanophenyl)acetate
[0129] At room temperature, methyl 2-(4-cyanophenyl)acetate (1200 mg, 6.507 mmol) and NBS (1552 mg, 8.719 mmol) are respectively added into a DCE (12 mL) solution, and a hydrobromic acid solution (0.27 mL, 8.784 mmol) is continuously dropwise added into a mixed system and maintained stirred. After the obtained mixture is heated to 85 C. and stirred for 12 h, the mixture is cooled to room temperature. The obtained mixture is concentrated in vacuum. A residue is dissolved in ethyl acetate (50 mL). The residue is washed with saturated saline (30 mL) three times and dried with anhydrous sodium sulfate. After the residue is filtered, a filtrate is concentrated at a reduced pressure to obtain a light yellow solid crude product I-15-1 (1.46 g), and the crude product may be used for a next step without purification.
I-15-2: Methyl 2-(4-cyanophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate
[0130] At room temperature, methyl 2-bromo-2-(4-cyanophenyl)acetate (1.46 g) and hydantoin (1.52 g, 14.429 mmol) are respectively added into a dimethylformamide (20 mL) solution, and potassium carbonate (2.10 g, 14.471 mmol) is continuously added into the solution. A mixture is stirred under nitrogen protection at room temperature for 12 h, reacted, and poured into a saturated ammonium chloride solution (150 mL). The mixture is extracted with ethyl acetate (100) three times. Organic phases are combined, washed with saturated saline (100 mL) twice, and dried with anhydrous sodium sulfate. After the organic phases are filtered, a filtrate is concentrated at a reduced pressure. A residue is purified by reversed-phase chromatography to obtain the I-15-2 (400 mg, 24.3%) in a light yellow solid form.
[0131] LC-MS m/z (ESI): 274.2 [M+H].sup.+.
I-15: (4-cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid
[0132] methyl 2-(4-cyanophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (400 mg, 1421 mmol) is dissolved in a mixed solution of tetrahydrofuran (15 mL) and water (15 mL), and a lithium hydroxide aqueous solution (2.1 mL, 2.100 mmol) is dropwise added into the solution. The obtained mixture is then stirred at room temperature under nitrogen protection for 0.5 h. A reside is acidized with hydrochloric acid till the pH value is equal to 5. The obtained mixture is concentrated in vacuum. A residue is purified by reversed-phase chromatography to obtain the I-15 (380 mg, 42%) in a white solid form.
[0133] LC-MS m/z (ESI): 260.1 [M+H].sup.+.
Intermediate I-16: Synthesis of [(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyanophenyl)acetic acid
##STR00133##
[0134] At room temperature, (4-cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (200 mg, 0.734 mmol) is added into ethanol (4 mL), and piperidine (263 mg, 2.936 mmol) is continuously added into a solution. The obtained mixture is heated to 80 C. under nitrogen protection and stirred for 0.5 h. The reaction is reduced to room temperature, 6-chloro-7-fluoro-1H-indole-3-formaldehyde (137 mg, 0.661 mmol) is added in batches into the mixture, and the obtained mixture is heated to 80 C. and then stirred for 12 h. The mixture is concentrated at a reduced pressure. A residue is purified by reversed-phase chromatography to obtain the yellow solid I-16 (60 mg, 24%).
[0135] LC-MS m/z (ESI): 439.1 [M+H].sup.+.
Intermediate I-17: Synthesis of [(4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](3,4-difluorophenyl)acetic acid
##STR00134##
I-17-1: Methyl 2-(3,4-difluorophenyl)acetate
[0136] (3,4-difluorophenyl)acetic acid (10 g, 58 mmol) is added into a methanol (100 mL) solution, and sulfuric acid (10 mL) is slowly dropwise added into the mixed solution. The mixed solution is reacted and reflowed overnight, cooled to room temperature, and poured into ice water (100 mL). The mixture is extracted with ethyl acetate (100 mL) three times. Organic phases are combined and dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to obtain a crude product. The crude product is purified by column chromatography (petroleum ether/ethyl acetate) to obtain the yellow oily I-17-1 (10 g, 88%).
[0137] LC-MS m/z (ESI): 187.0 [M+H].sup.+.
I-17-2: Methyl 2-bromo-2-(3,4-difluorophenyl)acetate
[0138] methyl 2-(3,4-difluorophenyl)acetate (3.0 g, 16 mmol) is added into a carbon tetrachloride (30 mL) solution, and NBS (2.6 g, 14 mmol) and 12 drops of a solution of hydrobromic acid in acetic acid are added into the mixed solution. A reaction mixture is heated to 70 C. and stirred for 10 min. The temperature of the reaction is raised to 85 C. and the mixture is continuously stirred for 2.5 h till thin-layer chromatographic tracking shows that raw materials are consumed completely. After being cooled to room temperature, the mixture is concentrated in vacuum to obtain a crude product. The crude product is purified by column chromatography (petroleum ether/ethyl acetate) to obtain the yellow oily I-17-2 (1.1 g, 72%).
[0139] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.49-7.44 (m, 1H), 7.28-7.24 (m, 1H), 7.18-7.11 (m, 1H), 5.31 (s, 1H), 3.80 (s, 3H).
I-17-3: Methyl 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate
[0140] Imidazolidine-2,4-dione (1.71 g, 17 mmol) and potassium carbonate (3.93 g, 28.4 mmol) are added into a solution of methyl 2-bromo-2-(3,4-difluorophenyl)acetate (3.8 g, 14 mmol) in dimethylformamide (37 mL). A reaction mixture is then stirred at room temperature for 14 h. After the reaction is completed, the reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate (50 mL) three times. Organic phases are combined, washed with anhydrous sodium sulfate, filtered and concentrated in vacuum. A crude product is purified by column chromatography (petroleum ether: ethyl acetate=2:1) to obtain the brown solid I-17-3 (1.6 g, 37%).
[0141] LC-MS m/z (ESI): 285.0 [M+H].sup.+.
I-17-4: 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid
[0142] methyl 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (0.85 g, 3.0 mmol) is added into a mixed solution of concentrated hydrochloric acid (26 mL) and ethyl acetate (85 mL), and the mixed solution is heated to 120 C. and stirred for 1 h. A mixture is concentrated in vacuum to obtain the yellow oily crude product I-17-4 (0.80 g, 94%), and the crude product is directly used for a next step without further purification.
[0143] LC-MS m/z (ESI): 271.0 [M+H].sup.+.
I-17: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetic acid
[0144] 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid (0.60 g, 2.2 mmol) is added into ethanol (20 mL), and piperidine (1.9 g, 22 mmol) is added into a mixed system. A mixture is heated and reflowed for 2 h, and then 6-chloro-7-methyl-1H-indole-3-formaldehyde (0.43 g, 2.2 mmol) is added. The mixture is continuously reflowed and stirred for 24 h. The mixture is filtered and extracted with ethyl acetate (2 mL). A solid is dried in vacuum to obtain the yellow solid I-17 (0.7 g, 71%), and the solid is directly used for a next step without further purification.
[0145] LC-MS m/z (ESI): 446.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.95 (brs, 1H), 8.75 (brs, 1H), 8.16 (brs, 1H), 7.62-7.58 (m, 2H), 7.33-7.19 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 6.67 (s, 1H), 5.31 (s, 1H), 2.49 (s, 3H).
Intermediate I-18: Synthesis of [(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyanophenyl)acetic acid
##STR00135##
[0146] At room temperature, (4-cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (200 mg, 0.772 mmol) and piperazine (279.82 mg, 3.088 mmol) are added into an ethanol (3 mL) solution. The obtained mixture is heated to 65 C. and stirred for 20 min. 6-chloro-1H-indole-3-formaldehyde (102 mg, 0.540 mmol) is added in batches into the mixture. The mixture is then stirred at 65 C. for 12 h. Through vacuum concentration, a residue is purified by reversed-phase chromatography to obtain the yellow solid I-18 (102 mg, 31%).
[0147] LC-MS m/z (ESI): 419.0 [MH].sup..
Intermediate I-19: Synthesis of [(4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyanophenyl)acetic acid
##STR00136##
[0148] At room temperature, (4-cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (300 mg, 1.157 mmol) and piperazine (420 mg, 4.628 mmol) are added into an ethanol (3 mL) solution, and the mixture is heated to 65 C. and stirred for 20 min. After the mixture is cooled to room temperature, 6-chloro-7-methyl-1H-indole-3-formaldehyde (157 mg, 0.810 mmol) is added in batches, and the obtained mixture is heated to 65 C. and then stirred for 12 h. Through vacuum concentration, a residue is purified by reversed-phase chromatography to obtain the yellow solid I-19 (270 mg, 59%).
[0149] LC-MS m/z (ESI): 433.0 [MH].sup..
I-20: Synthesis of (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetic acid
##STR00137##
[0150] By using the method for the intermediate I-19, the red solid I-20 (1.5 g, 84.77%) is prepared by using the I-17-4 and corresponding aldehyde.
[0151] LC-MS m/z (ESI): 432.1 [M+H].sup.+.
I-21: Synthesis of 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid
##STR00138##
I-21-1: Methyl 2-bromo-2-(4-bromo-3-fluorophenyl)acetate
[0152] At room temperature, a solution of HBr in AcOH (2.3 mL, 16.261 mmol) is added into a solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (3 g, 11.536 mmol) and NBS (2.81 g, 14.997 mmol) in DCE (30 mL), and the obtained mixture is stirred at 85 C. for 12 h. The mixture is concentrated in vacuum, and a residue is diluted with water (100 mL). The obtained mixture is extracted with EtOAc (100 mL3), and combined organic layers are washed with saline and dried with anhydrous Na.sub.2SO.sub.4. After the organic layers are filtered, a filtrate is concentrated in vacuum. A residue is purified by silica gel column chromatography and eluted with petroleum PE/EA (8:1) to obtain the yellow oily I-21-1 (3.2 g, 77%).
I-21-2: Methyl 2-(4-bromo-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate
[0153] At room temperature, hydantoin (4.36 g, 41.388 mmol) is added in batches into a stirred solution of methyl 2-bromo-2-(4-bromo-3-fluorophenyl)acetate (10 g, 27.611 mmol) and potassium carbonate (8.03 g, 55.222 mmol) in DMF (100 mL), and the obtained mixture is stirred under nitrogen protection at room temperature for 12 h. The obtained mixture is diluted with water (100 mL) and extracted with EtOAc (100 mL3), and combined organic layers are washed with saline and dried with anhydrous Na.sub.2SO.sub.4. After the organic layers are filtered, a filtrate is concentrated in vacuum. A residue is purified by fast reversed-phase chromatography to obtain the white solid I-21-2 (3.9 g, 36.38%).
[0154] LC-MS m/z (ESI): 344.9 [M+H].sup.+.
I-21-3: Methyl 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate
[0155] At room temperature, zinc cyanide (318 mg, 2.576 mmol) is added in batches into a stirred solution of methyl 2-(4-bromo-3-fluorophenyl)-2-(2,5-dioxopyrrolidin-1-yl)acetate (1000 mg, 2.576 mmol) and tetrakis(triphenylphosphine)palladium (313 mg, 0.258 mmol) in DMF (10 mL), and the obtained mixture is stirred under nitrogen protection at 120 C. for 16 h. The obtained mixture is concentrated in vacuum, and a residue is purified by fast reversed-phase chromatography to obtain the yellow solid I-21-3 (600 mg, 79%).
[0156] LC-MS m/z (ESI): 290.0 [MH].sup..
I-21: (4-cyano-3-fluorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid
[0157] At room temperature, HCl (2 mL, 4N) is added in batches into a solution of methyl 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxopyrrolidin-1-yl)acetate (800 mg, 2.747 mmol) in AcOH (6 mL), and the obtained mixture is stirred under nitrogen protection at 100 C. for 1 h. A reaction solution is concentrated to obtain white solid I-21 (700 mg, 92%). A crude product is directly used for a next step without further purification.
[0158] LC-MS m/z (ESI): 278.1 [M+H].sup.+.
EXAMPLES
Example 1
[0159] Compound 1: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00139##
[0160] At room temperature, an intermediate I-1 (119 mg, 0.505 mmol) and 6-chloro-1H-indole-3-formaldehyde (90 mg, 0.476 mmol) were dissolved in ethanol (5 ml). Under stirring, acetic acid (150 mg, 2.370 mmol) and piperidine (0.5 ml) were slowly added into the mixture, and a reaction solution was heated under nitrogen protection to 100 C. and stirred for 2 h. After being cooled to room temperature, the reaction solution was concentrated in vacuum. A crude product was purified by a preparative liquid chromatography to obtain a yellow solid compound 1 (33.5 mg, 17.61%).
[0161] LC-MS m/z (ESI): 385.75 [MH]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.99 (brs, 1H), 10.51 (brs, 1H), 8.19 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.45-7.35 (m, 2H), 7.19-7.11 (m, 2H), 6.88 (s, 1H), 4.68 (s, 2H).
Example 2
Compound 2: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione
##STR00140##
[0162] By using the method in Example 1, the yellow solid compound 2 (104.6 mg, 32.42%) was prepared by using the 1-2 and corresponding aldehyde.
[0163] LC-MS m/z (ESI): 386.60 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 11.96 (s, 1H), 10.54-10.30 (m, 1H), 8.16 (d, J=1.9 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.32-7.27 (m, 2H), 7.10 (dd, J=8.5, 1.9 Hz, 1H), 6.85-6.83 (m, 1H), 4.64 (s, 2H).
Example 3
Compound 3: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(4-fluorobenzyl)imidazolidine-2,4-dione
##STR00141##
[0164] By using the method in Example 1, the yellow solid compound 3 (75.8 mg, 14.24%) was prepared by using 3-(4-fluorobenzyl)imidazolidine-2,4-dione and corresponding aldehyde.
[0165] LC-MS m/z (ESI): 369.70 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 11.99 (s, 1H), 10.50 (s, 1H), 8.19 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.6, 5.6 Hz, 2H), 7.24-7.10 (m, 3H), 6.87 (s, 1H), 4.67 (s, 2H).
Example 4
[0166] Compound 4: (Z)-4-((4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
##STR00142##
[0167] By using the method in Example 1, the white solid compound 4 (12.3 mg, 2.34%) was prepared by using the 1-3 and corresponding aldehyde.
[0168] LC-MS m/z (ESI): 376.70 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.01 (s, 1H), 10.56 (s, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.84 (dd, J=8.3, 1.6 Hz, 3H), 7.50 (d, J=8.2 Hz, 3H), 7.14 (dd, J=8.5, 1.8 Hz, 1H), 6.90 (s, 1H), 4.78 (s, 2H).
Example 5
Compound 5: (Z)-5-((6-bromo-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione
##STR00143##
[0169] By using the method in Example 1, the yellow solid compound 5 (15.6 mg, 6.73%) was prepared by using the I-2 and corresponding aldehyde.
[0170] LC-MS m/z (ESI): 430.50 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 12.00 (s, 1H), 10.45 (s, 1H), 8.18 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.3 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.28-7.23 (m, 1H), 6.87 (s, 1H), 4.68 (s, 2H).
Example 6
Compound 6: (Z)-5-((6-chloro-7-(fluoromethoxyl)-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00144##
[0171] By using the method in Example 1, the yellow solid compound 6 (32.5 mg, 34.43%) was prepared by using the I-1 and corresponding aldehyde.
[0172] .sup.1H NMR (400 MHz, DMSO-d6) 12.20 (s, 1H), 10.57 (s, 1H), 8.22 (s, 1H), 7.70 (m, 1H), 7.45-7.37 (m, 2H), 7.21 (d, J=8.5 Hz, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 5.90 (s, 1H), 5.77 (s, 1H), 4.68 (s, 2H).
Example 7
Compound 7: (Z)-5-((6,7-dichloro-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00145##
[0173] By using the method in Example 1, the yellow solid compound 7 (21.6 mg, 4.95%) was prepared by using the compound 1-1 and corresponding aldehyde.
[0174] LC-MS m/z (ESI): 420.05 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d6) 12.36 (s, 1H), 10.62 (s, 1H), 8.27 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.41 (ddd, J=13.5, 10.0, 6.9 Hz, 2H), 7.31 (d, J=8.5 Hz, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 4.68 (s, 2H).
Example 8
Compound 8: (Z)-5-((6-chloro-7-methoxyl-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00146##
[0175] By using the method in Example 1, the yellow solid compound 8 (40 mg, 16.56%) was prepared by using the intermediates I-5 and I-1.
[0176] LC-MS m/z (ESI): 417.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.19 (d, J=2.4 Hz, 1H), 10.53 (s, 1H), 8.17 (d, J=2.6 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.37 (ddt, J=10.0, 8.1, 5.3 Hz, 2H), 7.14-7.08 (m, 2H), 6.81 (s, 1H), 4.64 (s, 2H), 3.89 (s, 3H).
Example 9
Compound 9: (Z)-5-((6-chloro-7-(methylsulfonyl)-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00147##
[0177] By using the method in Example 1, the yellow solid compound 9 (12.7 mg, 33.28%) was prepared by using the intermediates I-9 and I-1.
[0178] LC-MS m/z (ESI): 433.9 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.06 (s, 1H), 10.63 (s, 1H), 8.25 (s, 1H), 7.86-7.83 (m, 1H), 7.44-7.29 (m, 3H), 7.26-7.16 (m, 1H), 6.86 (s, 1H), 4.68 (s, 2H), 2.43 (s, 3H).
Example 10
Compound 10: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione
##STR00148##
[0179] By using the method in Example 1, the yellow solid compound 10 (19.5 mg, 13.35%) was prepared by using the intermediates I-10 and I-1.
[0180] LC-MS m/z (ESI): 403.8 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.54 (s, 1H), 10.57 (s, 1H), 8.25 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.46-7.36 (m, 2H), 7.23-7.18 (m, 2H), 6.86 (s, 1H), 4.68 (s, 2H).
Example 11
Compound 11: (Z)-4-((4-((6-chloro-7-(fluoromethoxyl)-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile
##STR00149##
[0181] By using the method in Example 1, the yellow solid compound 11 (9.8 mg, 2.2%) was prepared by using the intermediates I-11 and I-4.
[0182] LC-MS m/z (ESI): 443.1 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.21 (s, 1H), 10.63 (s, 1H), 8.24 (s, 1H), 7.94-7.89 (m, 1H), 7.73-7.70 (m, 1H), 7.52-7.48 (m, 1H), 7.35-7.33 (m, 1H), 7.23-7.20 (m, 1H), 6.88 (s, 1H), 5.93 (s, 1H), 5.75 (s, 1H), 4.80 (s, 2H).
Example 12
Compound 12: (Z)-5-((6-chloro-7-(fluoromethoxyl)-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione
##STR00150##
[0183] By using the method in Example 1, the yellow solid compound 12 (8.9 mg, 5.18%) was prepared by using the intermediates I-11 and I-2.
[0184] LC-MS m/z (ESI): 431.8 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.20 (s, 1H), 10.58 (s, 1H), 8.22 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.35-7.22 (m, 2H), 7.17-7.27 (m, 1H), 6.86 (s, 1H), 5.93 (s, 1H), 5.75 (s, 1H), 4.68 (s, 2H).
Example 13
Compound 13: (Z)-4-((4-((6-chloro-7-(fluoromethoxyl)-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
##STR00151##
[0185] By using the method in Example 1, the yellow solid compound 13 (8.1 mg, 4.68%) was prepared by using the intermediates I-11 and I-3.
[0186] LC-MS m/z (ESI): 422.8 [MH]. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.21 (s, 1H), 10.62 (s, 1H), 8.23 (m, 1H), 7.85-7.82 (m, 2H), 7.72-7.69 (m, 1H), 7.51-7.48 (m, 2H), 7.22-7.20 (m, 1H), 6.87 (s, 1H), 5.93 (s, 1H), 5.75 (s, 1H), 4.78 (s, 2H).
Example 14
Compound 14: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile
##STR00152##
[0187] By using the method in Example 1, the yellow solid compound 14 (6.6 mg, 4.89%) was prepared by using the intermediates I-10 and I-4.
[0188] LC-MS m/z (ESI): 410.9 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.57 (s, 1H), 10.63 (s, 1H), 8.28 (s, 1H), 7.95-7.90 (m, 1H), 7.71-7.68 (m, 1H), 7.52-7.48 (m, 1H), 7.35-7.32 (m, 1H), 7.24-7.19 (m, 1H), 6.87 (s, 1H), 4.80 (s, 2H).
Example 15
Compound 15: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione
##STR00153##
[0189] By using the method in Example 1, the yellow solid compound 15 (9.4 mg, 7.51%) was prepared by using the intermediates I-10 and I-2.
[0190] LC-MS m/z (ESI): 401.70 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.53 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.43-7.33 (m, 4H), 7.22-7.19 (m, 1H), 6.85 (s, 1H), 4.68 (s, 2H).
Example 16
Compound 16: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
##STR00154##
[0191] By using the method in Example 1, the yellow solid compound 16 (25.9 mg, 12.16%) was prepared by using the intermediates I-10 and I-3.
[0192] LC-MS m/z (ESI): 392.8 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.54 (s, 1H), 10.60 (s, 1H), 8.26 (s, 1H), 7.83 (d, J=8.0 Hz 2H), 7.68 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.21 (t, J=6.8 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H).
Example 17
Compound 17: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(4-acetenylbenzyl)imidazolidine-2,4-dione
##STR00155##
[0193] By using the method in Example 1, the yellow solid compound 17 (23.1 mg, 22.88%) was prepared by using the intermediates I-10 and I-6.
[0194] LC-MS m/z (ESI): 391.9 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.56 (s, 1H), 10.59 (s, 1H), 8.26 (d, J=2.8 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.50-7.43 (m, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.20 (dd, J=8.5, 6.5 Hz, 1H), 6.85 (s, 1H), 4.70 (s, 2H), 4.18 (s, 1H).
Example 18
Compound 18: (Z)-3-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
##STR00156##
[0195] By using the method in Example 1, the yellow solid compound 18 (12.8 mg, 14.52%) was prepared by using the intermediates I-10 and I-7.
[0196] LC-MS m/z (ESI): 392.8 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.60-12.39 (m, 1H), 10.58 (s, 1H), 8.82-8.21 (m, 1H), 7.82-7.73 (m, 2H), 7.72-7.57 (m, 3H), 7.33-7.10 (m, 1H), 6.80 (s, 1H), 4.75 (s, 2H).
Example 19
Compound 19: (Z)-4-((4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
##STR00157##
[0197] By using the method in Example 1, the yellow solid compound 19 (47 mg, 23%) was prepared by using the intermediates I-3 and I-8.
[0198] LC-MS m/z (ESI): 388.8 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.00 (s, 1H), 10.55 (s, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.84-7.78 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.54-7.45 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 6.87 (d, J=0.6 Hz, 1H), 4.78 (s, 2H), 2.52 (s, 3H).
Example 20
Compound 20: (Z)-4-((4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile
##STR00158##
[0199] By using the method in Example 1, the yellow solid compound 20 (27 mg, 12%) was prepared by using the intermediate I-4 and corresponding aldehyde.
[0200] LC-MS m/z (ESI): 393.0 [M+H].sup.. .sup.1H NMR (400 MHz, DMSO-d6) 12.01-11.75 (m, 1H), 10.53 (m, 1H), 8.48 (m, 1H), 7.91 (t, J=7.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.67-7.45 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.15 (m, 1H), 6.84 (m, 1H), 4.79 (s, 2H).
Example 21
Compound 21: (Z)-4-((4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile
##STR00159##
[0201] By using the method in Example 1, the yellow solid compound 21 (42 mg, 18%) was prepared by using the intermediates I-4 and I-8.
[0202] LC-MS m/z (ESI): 407.1 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.02 (s, 1H), 10.57 (s, 1H), 8.22 (d, J=2.9 Hz, 1H), 7.91 (t, J=7.4 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.54-7.44 (m, 1H), 7.33 (dd, J=8.1, 1.6 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.88 (s, 1H), 4.80 (s, 2H), 2.52 (s, 3H).
Example 22
Compound 22: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00160##
[0203] The intermediate I-13 (150 mg, 0.35 mmol), HATU (199 mg, 0.52 mmol), and N,N-diisopropylethylamine (90 mg, 0.7 mmol) were added into a dimethylformamide (5 mL) solution. The mixture was stirred at 25 C. for 10 min, and then 2-aminopropane-1,3-diol (47 mg, 0.52 mmol) was added into the mixture. The mixture was continuously stirred at 25 C. for 2 h, concentrated in vacuum, and purified by preparative thin-layer chromatography to obtain a yellow solid compound 22 (160 mg, 90%).
[0204] LC-MS m/z (ESI): 502.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.98 (d, J=2.0 Hz, 1H), 10.53 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.46-7.39 (m, 4H), 7.13 (dd, J=8.5, 1.9 Hz, 1H), 6.83 (s, 1H), 5.77 (s, 1H), 4.63 (t, J=5.5 Hz, 1H), 4.49 (t, J=5.7 Hz, 1H), 3.85-3.77 (m, 1H), 3.47-3.35 (m, 4H).
Example 23
Compound 23: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)acetamide
##STR00161##
[0205] By using the method in Example 22, the yellow solid compound 23 (180 mg, 58.61%) was prepared by using the intermediate I-13 and N,N-diethenylethane-1,2-diamine.
[0206] LC-MS m/z (ESI): 527.9 [M+H].sup.+. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 12.08 (s, 1H), 10.68 (s, 1H), 8.26 (d, J=2.7 Hz, 2H), 7.87 (d, J=8.6 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.51 (s, 4H), 7.20 (dd, J=8.5, 1.9 Hz, 1H), 6.93 (s, 1H), 5.86 (s, 1H), 3.51 (m, 2H), 3.27-3.15 (m, 6H), 1.24 (t, J=7.1 Hz, 6H).
Example 24
Compound 24: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00162##
[0207] By using the method in Example 22, the yellow solid compound 24 (30 mg, 24.98%) was prepared by using the intermediate I-20 and 2-aminopropane-1,3-diol.
[0208] LC-MS m/z (ESI): 502.9 [MH].sup.. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 11.98 (s, 1H), 10.53 (s, 1H), 8.19 (s, 1H), 7.87-7.77 (m, 2H), 7.55-7.36 (m, 3H), 7.30-7.28 (m, 1H), 7.18-7.10 (m, 1H), 6.84 (s, 1H), 5.79 (s, 1H), 4.64-4.61 (m, 1H), 4.50-4.47 (m, 1H), 3.85-3.80 (m, 1H), 3.52-3.43 (m, 4H).
Example 25
Compound 25: (Z)-5-((6-chloro-7-methoxyl-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)ethyl)imidazolidine-2,4-dione
##STR00163##
[0209] By using the method in Example 1, the yellow solid compound 25 (7.3 mg, 0.76%) was prepared.
[0210] LC-MS m/z (ESI): 432.0 [M+H].sup.+. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 12.19 (s, 1H), 10.51 (s, 1H), 8.18 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.52-7.36 (m, 2H), 7.23 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.79 (s, 1H), 5.41-5.29 (m, 1H), 3.93 (s, 3H), 1.78 (d, J=7.2 Hz, 3H).
Example 26
Compound 26: 6-chloro-3-{[(4Z)-1-[1-(3,4-difluorophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidin-4-methylene]methyl}indol-1-carboxylate
##STR00164##
26-1: 2-bromo-1-(3,4-difluorophenyl)ethanone
[0211] At 0 C., bromine (2 g, 11.889 mmol) was slowly added into a solution of 1-(3,4-difluorophenyl)ethanone (2 g, 12.169 mmol) in dichloromethane (20 mL). After the reaction was finished, the mixture was poured into ice water. The obtained mixture was extracted with dichloromethane (40 mL) three times. Organic phases were combined, washed with saturated saline (20 mL), and dried with anhydrous sodium sulfate. After the organic phases were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with DCM/PE (1:20) to obtain the white solid 26-1 (1.68 g, 58%).
[0212] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.15-8.05 (m, 1H), 7.98-7.86 (m, 1H), 7.70-7.60 (m, 1H), 4.95 (s, 2H).
26-2: 1-(3,4-difluorophenyl)-2-hydroxyethanone
[0213] At room temperature, 2-bromo-1-(3,4-difluorophenyl)ethanone (2 g, 8.399 mmol), sodium formate (6.97 g, 97.365 mmol), and sodium hydrogen carbonate (800 mg, 9.047 mmol) were added into a mixed solution of acetonitrile (8 mL) and water (4 mL). The obtained mixture was heated to 65 C. under nitrogen protection and stirred for 18 h. After the reaction was completed, the mixture was cooled to room temperature. The obtained mixture was poured into water (5 mL). The mixture was extracted with ethyl acetate (20 mL) three times. Organic phases were combined, washed with saturated saline (10 mL) three times, and dried with anhydrous sodium sulfate. After the organic phases were filtered, a filtrate was concentrated in vacuum. A residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (2:1) to obtain the yellow solid 26-2 (610 mg, 39%).
[0214] .sup.1HNMR (300 MHz, DMSO-d6) 8.05-7.95 (m, 1H), 7.90-7.80 (m, 1H), 7.75-7.62 (m, 1H), 5.26-5.18 (m, 1H), 4.82-4.74 (m, 2H).
26-3: 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanone
[0215] At room temperature, 1-(3,4-difluorophenyl)-2-hydroxyethanone (2.1 g, 11.346 mmol) and triethylamine (1.48 g, 13.894 mmol) were added into a dichloromethane (20 mL) solution, and tert-butyl dimethyl chlorosilane (2.76 g, 17.396 mmol) was added into the solution when the solution was stirred. The obtained mixture was stirred at room temperature under nitrogen protection for 16 h. The mixture was poured into ice water, extracted with ethyl acetate (80 mL) three times, and combined organic phases were washed with saturated saline (50 mL) three times and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated in vacuum. A residue was purified by silica gel column chromatography and eluted with DCM/PE (1:2) to obtain the yellow oily 26-3 (2.48 g, 69%).
[0216] LC-MS m/z (ESI): 285.0 [MH].sup..
26-4: 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanol
[0217] Under nitrogen protection, 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanone (2.0 g, 6.299 mmol) was added into an ethanol (25 mL) solution, and at 0 C., sodium borohydride (800 mg, 20.090 mmol) was added in batches. After being stirred at room temperature for 0.5 h, the mixture was poured into ice water and extracted with ethyl acetate (10 mL) three times. Organic phases were combined, washed with saturated saline (5 mL) three times, and dried with anhydrous sodium sulfate. After the organic phases were filtered, a filtrate was concentrated in vacuum. A residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (1:20) to obtain the brown oily compound 26-4 (1.56 g, 86%).
[0218] .sup.1HNMR (400 MHz, DMSO-d6) 7.45-7.35 (m, 2H), 7.30-7.20 (m, 1H), 5.56-5.50 (m, 1H), 4.70-4.60 (m, 1H), 3.80-3.70 (m, 1H), 3.65-3.55 (m, 1H) 0.86 (s, 9H), 0.07 (s, 6H).
26-5: 3-{2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethyl}imidazolidine-2,4-dione
[0219] At 0 C., 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanol (1.56 g, 5.404 mmol) and triphenylphosphine (2.84 g, 10.286 mmol) were added into a THF (20 mL) solution, and under nitrogen protection, diethyl azodicarbonate (1.88 g, 10.255 mmol) was added into the mixture. The obtained mixture was heated to 40 C. and stirred for 16 h. After the system was cooled to room temperature, the obtained mixture was concentrated in vacuum. A residue was purified by reversed-phase chromatography to obtain the brown oily compound 26-5 (640 mg, 25%).
[0220] LC-MS m/z (ESI): 371.2 [M+H].sup.+.
26-6: (5Z) 3-{2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethyl}-5-[(6-chloro-1H-indol-3-yl)methylene]imidazolidine-2,4-dione
[0221] At room temperature, 3-{2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethyl}imidazolidine-2,4-dione (440 mg, 0.927 mmol) and 6-chloro-1H-indole-3-formaldehyde (236 mg, 1.25 mmol) were added into an ethanol (5 mL) solution, and piperidine (0.5 mL) was dropwise added into the system at room temperature. The obtained mixture was heated to 100 C. and stirred for 4 h. After being cooled to room temperature, the mixture was concentrated in vacuum. A residue was purified by reversed-phase chromatography to obtain the yellow solid compound solid 26-6 (325 mg, 37%).
[0222] LC-MS m/z (ESI): 532.3 [M+H].sup.+.
Compound 26: 6-chloro-3-{[(4Z)-1-[1-(3,4-difluorophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidin-4-methylene]methyl}indol-1-carboxylate
[0223] At room temperature, (Z)-3-(2-(tert-butyldimethylsilyloxy)-1-(3,4-difluorophenyl)ethyl)-5-((6-chloro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione (263 mg, 0.457 mmol) was added into a tetrahydrofuran (6 mL) solution, and tetramethylammonium fluoride (3.66 mL, 3.66 mmol, 1N) was dropwise added into the solution. The obtained mixture was stirred at room temperature for 1 h. The obtained mixture was concentrated in vacuum. A residue was purified by preparative high performance liquid chromatography to obtain the yellow solid compound solid 26 (2.4 mg, 29.66%).
[0224] LC-MS m/z (ESI): 416.1 [MH].sup.. .sup.1HNMR (300 MHz, DMSO-d6) 12.03-11.73 (m, 1H), 10.50 (s, 1H), 8.79-8.14 (m, 1H), 7.86-7.61 (m, 1H), 7.56-7.36 (m, 3H), 7.27 (dd, J=5.2, 3.0 Hz, 1H), 7.18-7.10 (m, 1H), 6.84 (s, 1H), 5.20 (dt, J=10.7, 5.7 Hz, 2H), 4.31 (td, J=10.3, 5.4 Hz, 1H), 3.94 (dt, J=11.2, 5.8 Hz, 1H).
Example 27
Compound 27: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00165##
27-1: 2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)-2-(2,5-dioxoimidazolidin-1-yl)acetamide
[0225] At room temperature, 2-aminopropane-1,3-diol (62 mg, 0.686 mmol) and HATU (261 mg, 0.686 mmol) were added into dimethylformamide (1 mL), and (4-cyano-3-fluorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (100 mg, 0.343 mmol) and diisopropylethylamine (74 mg, 0.686 mmol) were added in batches into the solution. The obtained mixture was heated to 40 C. under nitrogen protection and stirred for 12 h. The mixture was concentrated in vacuum, and a residue was purified by reversed-phase chromatography to obtain the yellow solid compound solid 27-1 (60 mg, 50%).
[0226] LC-MS m/z (ESI): 349.0 [MH].sup..
Compound 27: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
[0227] At room temperature, 2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)-2-(2,5-dioxoimidazolidin-1-yl) acetamide (20 mg, 0.051 mmol) was added into ethyl acetate (1 mL), piperidine (18.42 mg, 0.204 mmol) was added in batches into the mixed solution, and the obtained mixture was reflowed for 20 min. After the mixture was cooled to room temperature, 6-chloro-7-fluoro-1H-indole-3-formaldehyde (8 mg, 0.036 mmol) was added in batches. The obtained mixture was then reflowed for 12 h, and after being cooled to room temperature, the mixture was concentrated in vacuum. A residue was purified by preparative high performance liquid chromatography to obtain the yellow solid compound solid 27 (4.3 mg, 15.35%).
[0228] LC-MS m/z (ESI): 528.1 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.55 (d, J=3.0 Hz, 1H), 10.63 (s, 1H), 8.71-8.20 (m, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.96-7.80 (m, 1H), 7.76-7.55 (m, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.25-7.16 (m, 1H), 6.83 (s, 1H), 5.91 (s, 1H), 4.58 (dt, J=57.7, 5.7 Hz, 2H), 4.10-3.77 (m, 1H), 3.56-3.35 (m, 4H).
Example 28
Compound 28: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00166##
[0229] By using the method in Example 22, the yellow solid compound 28 (54.1 mg, 29%) was prepared by using the intermediate I-14 and 2-aminopropane-1,3-diol.
[0230] LC-MS m/z (ESI): 521.1 [M+H].sup.+. .sup.1HNMR (300 MHz, DMSO-d.sub.6) 12.52 (s, 1H), 10.57 (s, 1H), 8.24 (d, J=2.8 Hz, 1H), 7.69 (dd, J=17.6, 8.4 Hz, 2H), 7.42 (d, J=1.2 Hz, 5H), 7.20 (dd, J=8.6, 6.5 Hz, 1H), 6.81 (s, 1H), 5.77 (s, 1H), 4.60-4.30 (m, 1H), 3.86-3.75 (m, 1H), 3.48-3.33 (m, 5H).
Example 29
Compound 29: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00167##
[0231] By using the method in Example 22, the yellow solid compound 29 (34 mg, 21%) was prepared by using the intermediate I-16 and 2-aminopropane-1,3-diol.
[0232] LC-MS m/z (ESI): 510.1 [MH].sup.. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 12.59-12.37 (m, 1H), 10.62 (s, 1H), 8.25 (d, J=2.8 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.20 (dd, J=8.5, 6.4 Hz, 1H), 6.82 (s, 1H), 5.87 (s, 1H), 3.82 (q, J=6.5 Hz, 2H), 3.53-3.31 (m, 5H).
Example 30
Compound 30: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(1,3-dyhydroxl-2-(hydroxymethyl)-2-propyl)acetamide
##STR00168##
[0233] By using the method in Example 22, the yellow solid compound 30 (4.4 mg, 4.57%) was prepared by using the intermediate I-17 and 2-amino-2-(hydroxymethyl)propane-1,3-diol.
[0234] LC-MS m/z (ESI): 549.1 [M+H].sup.+. .sup.1HNMR (300 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 10.64 (s, 1H), 8.24 (s, 1H), 7.69-7.31 (m, 4H), 7.19-7.14 (m, 2H), 6.86 (s, 1H), 5.86 (s, 1H), 4.54 (br, 2H), 3.70-3.40 (m, 7H).
Example 31
Compound 31: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00169##
[0235] By using the method in Example 22, the yellow solid compound 31 (6.4 mg, 4.28%) was prepared by using the intermediate I-18 and 2-aminopropane-1,3-diol.
[0236] LC-MS m/z (ESI): 494.1 [M+H].sup.+. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 12.07 (d, J=2.8 Hz, 1H), 10.76 (s, 1H), 8.24 (d, J=2.5 Hz, 1H), 8.00 (s, 3H), 7.86 (dd, J=21.8, 8.3 Hz, 3H), 7.64 (d, J=8.0 Hz, 2H), 7.50 (d, J=1.9 Hz, 1H), 7.15 (dd, J=8.5, 1.9 Hz, 1H), 6.95 (s, 1H), 6.24 (s, 1H), 5.40 (s, 1H), 4.31 (q, J=6.9, 6.0 Hz, 2H), 3.62-3.53 (m, 1H), 3.51-3.45 (m, 1H).
Example 32
Compound 32: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
##STR00170##
[0237] By using the method in Example 22, the yellow solid compound 32 (58 mg, 21%) was prepared by using the intermediate I-19 and 2-aminopropane-1,3-diol.
[0238] LC-MS m/z (ESI): 508.0 [M+H].sup.+. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 12.01 (d, J=3.0 Hz, 1H), 10.57 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.87 (s, 1H), 4.18-3.65 (m, 3H), 3.53-3.31 (m, 4H), 2.51 (s, 3H).
Example 33
Compound 33: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-oxyethyl)-2-fluorobenzonitrile
##STR00171##
[0239] Under nitrogen protection at 78 C., Li MDS (4.8 mL, 4.8 mmol, 5 equiv, 1 N) was added into a solution of the compound 14 (400 mg, 0.958 mmol, 1 equiv, 98.9%) in tetrahydrofuran (24.5 mL), and the mixture was stirred at 78 C. for 1 h. Then formyl morpholine (1.4 g, 11.552 mmol, 12.05 equiv, 95%) was added, and the mixture was stirred at 80 C. for 4 h. A solution of HOAc (1 mL) in THF (3 mL) was added at 80 C. to terminate the reaction, the mixture was heated to 20 C., and water (100 mL) was added in the reaction. The obtained mixture was extracted with EtOAc (350 mL), and combined organic layers were washed with saline (100 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by reverse HPLC to obtain the yellow solid compound 33 (14.2 mg, 3.3%).
[0240] LC-MS m/z (ESI): 439.0 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 11.08 (s, 1H), 10.62 (s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.87-7.62 (m, 2H), 7.58-7.48 (m, 1H), 7.44-7.16 (m, 2H), 6.87 (s, 1H).
Example 34
Compound 34: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2,3-difluorobenzonitrile
##STR00172##
34-1: 4-(bromomethyl)-2,3-difluorobenzonitrile
[0241] At room temperature, AIBN (180 mg, 1.061 mmol, 1.0 equiv, 95%) was added in batches into a solution of 2,3-difluoro-4-methyl benzonitrile (2 g, 11.787 mmol, 1.0 equiv, 95%) and NBS (3 g, 16.738 mmol, 1.4 equiv, 95%) in CHCl.sub.3 (95 mL), and the obtained mixture was stirred under nitrogen protection at 80 C. for 8 h. The mixture was cooled to room temperature, and water was added to terminate the reaction. The obtained mixture was extracted with EtOAc (3200 mL), and combined organic layers were washed with saline (3200 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain the yellow oily 34-1 (1.7 g, 67.5%).
[0242] LC-MS m/z (ESI): 299.8 [MH].sup..
34-2: 4-[(2,5-dioxoimidazolidin-1-yl)methyl]-2,3-difluorobenzonitrile
[0243] At room temperature, hydantoin (1.0 g, 9.398 mmol, 1.3 equiv, 95%) was added into a solution of 34-1 (1.7 g, 7.241 mmol, 1.0 equiv, 99%) and potassium carbonate (2.0 g, 13.748 mmol, 1.9 equiv, 95%) in DMF (15 mL), and the obtained mixture was stirred under nitrogen protection at room temperature for 12 h. Water was added to terminate the reaction, the obtained mixture was extracted with EtOAc (3100 mL), and combined organic layers were washed with saline (360 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure to obtain the white solid 34-2 (1.2 g, 67%).
[0244] LC-MS (MH).sup.=250.0
Compound 34: 4-{[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]methyl}-2,3-difluorobenzonitrile
[0245] By using the method in Example 1, the yellow solid compound 34 (31.7 mg, 14.6%) was prepared by using 34-2 and I-10.
[0246] LC-MS (MH).sup.=428.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.56 (s, 1H), 10.64 (s, 1H), 8.26 (s, 1H), 7.79-7.62 (m, 2H), 7.41-7.31 (m, 1H), 7.27-7.16 (m, 1H), 6.86 (s, 1H), 4.84 (s, 2H).
Example 35
Compound 35: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2,6-difluorobenzonitrile
##STR00173##
35-1: 2,6-difluoro-4-(hydroxymethyl)benzonitrile
[0247] At 0 C. and under nitrogen protection, sodium borohydride (257 mg, 6.458 mmol, 1.00 equiv) was added in batches into a solution of 2,6-difluoro-4-formyl benzonitrile (11.40 g, 6.458 mmol, 1.00 equiv) in methanol (25 mL), and the obtained mixture was stirred at 0 C. for 1 h. Water was added to terminate the reaction, the obtained mixture was extracted with EtOAc (3100 mL), and combined organic layers were washed with saline (350 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with CH.sub.2Cl.sub.2/EA (5:1) to obtain the yellow oily 35-1 (936 mg, 3.682 mmol, 84.7%).
[0248] LC-MS m/z (ESI): 168.0 [MH].sup.
35-2: 4-(bromomethyl)-2,6-difluorobenzonitrile
[0249] At 0 C. and under nitrogen protection, carbon tetrabromide (2.30 g, 6.917 mmol, 1.30 equiv) was added in batches into a solution of 35-1 (936 mg, 5.534 mmol, 1.00 equiv) and PPI (1.33 g, 6.032 mmol, 1.10 equiv) in THF (33.0 mL), and the obtained mixture was stirred at room temperature for 20 h. The mixture was filtered, a reaction solution was extracted with EtOAc (350 mL), and combined organic layers were washed with saline (330 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to obtain the yellow oily 35-2 (218 mg, 0.930 mmol, 16.8%).
[0250] LC-MS m/z (ESI): 247.9 [MH+18].sup.
35-3: Synthesis of 4-[(2,5-dioxoimidazolidin-1-yl)methyl]-2,6-difluorobenzonitrile
[0251] By using the method for 34-2, the white solid compound 35-3 (164 mg, 0.648 mmol, 75.9%) was prepared by using 35-2.
[0252] LC-MS m/z (ESI): 250.0 [MH].sup.
Compound 35: 4-{[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]methyl}-2,6-difluorobenzonitrile
[0253] By using the method in Example 1, the yellow solid compound 35 (5.1 mg, 0.011 mmol, 2.95%) was prepared by using 35-3 and I-10.
[0254] LC-MS m/z (ESI): 428.8[MH].sup.. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.62 (s, 1H), 8.27 (s, 1H), 7.73-7.63 (m, 1H), 7.55-7.35 (m, 2H), 7.27-7.17 (m, 1H), 6.87 (s, 1H), 4.80 (s, 2H).
Example 36
Compound 36: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2,5-difluorobenzonitrile
##STR00174##
36-1: Synthesis of 2,5-difluoro-4-(hydroxymethyl)benzonitrile
[0255] By using the method for 35-1, the white solid compound 36-1 (950 mg, 5.611 mmol, 96.6%) was prepared by using 2,5-difluoro-4-formyl benzonitrile.
[0256] LC-MS m/z (ESI): 168.0 [MH].sup.
36-2: 4-(bromomethyl)-2,5-difluorobenzonitrile
[0257] Under nitrogen protection, phosphorus tribromide (1.55 g, 5.804 mmol, 1.10 equiv) was dropwise added into a solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (920 mg, 5.276 mmol, 1.00 equiv) in DCM (5 mL) at 0 C., and the obtained mixture was stirred at room temperature for 20 h. The reaction solution was diluted with DCM (50 mL) and extracted with sodium hydrogen carbonate (370 mL), and organic phases were dried with anhydrous sodium sulfate. After the organic phases were filtered, a filtrate was concentrated at a reduced pressure to obtain the white solid 36-2 (545 mg, 1.966 mmol, 40.3%).
[0258] LC-MS m/z (ESI): 232.00 [M+H].sup.+
36-3: 4-[(2,5-dioxoimidazol-1-yl)methyl]-2,5-difluorobenzonitrile
[0259] By using the method for 34-2, the yellow solid compound 36-3 (183 mg, 0.626 mmol, 29.1%) was prepared by using 36-2.
[0260] LC-MS m/z (ESI): 250.0 [MH].sup.
Compound 36: 4-{[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]methyl}-2,5-difluorobenzonitrile
[0261] By using the method in Example 1, the yellow solid compound 36 (18.6 mg, 0.041 mmol, 13.6%) was prepared by using the 36-3 and corresponding aldehyde.
[0262] LC-MS m/z (ESI): 428.8 [MH]. .sup.1H NMR: (400 MHz, CDCl.sub.3) 12.55 (s, 1H), 10.61 (s, 1H), 8.27 (s, 1H), 8.07-7.97 (m, 1H), 7.78-7.68 (m, 1H), 7.65-7.45 (m, 1H), 7.28-7.18 (m, 1H), 6.86 (s, 1H), 4.79 (s, 2H).
Example 37
Compound 37: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)-2-fluorobenzonitrile
##STR00175##
[0263] STAB (38 mg, 0.174 mmol, 2.63 equiv) was added in batches into a stirred solution of 4-{1-[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-oxyethyl}-2-fluorobenzonitrile (30 mg, 0.066 mmol, 1 equiv) and AcOH (10 mg, 0.153 mmol, 2.32 equiv) in DCE (1 mL) at 0 C., and the obtained mixture was stirred at 40 C. for 1 h. The mixture was cooled to room temperature and concentrated in vacuum. A crude product was purified by preparative HPLC to obtain the yellow solid compound 37 (6.9 mg, 0.012 mmol, 18.8%).
[0264] LC-MS m/z (ESI): 440.9 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.54 (s, 1H), 10.61 (s, 1H), 8.31-8.21 (m, 1H), 7.98-7.88 (m, 1H), 7.73-7.63 (m, 1H), 7.65-7.55 (m, 1H), 7.50-7.40 (m, 1H), 7.27-7.17 (m, 1H), 6.84 (s, 1H), 5.35-5.25 (m, 2H), 4.33-4.23 (m, 1H), 4.09-3.99 (m, 1H).
Example 38
Compound 38: (Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00176##
38-1: 4-{1-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-hydroxyethyl}benzonitrile
[0265] By using the method in Example 33, the yellow solid 38-1 (220 mg, 0.327 mmol, 9.7%) was prepared by using the compound 4.
[0266] LC-MS m/z (ESI): 403.1 [MH].sup.
Compound 38: (Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl]-2-hydroxyethyl}benzonitrile
[0267] By using the method in Example 37, the yellow solid 38 (13.6 mg, 0.032 mmol, 40%) was prepared by using 38-1.
[0268] LC-MS m/z (ESI): 407.1 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.97 (s, 1H), 10.51 (brs, 1H), 8.19 (s, 1H), 7.88-7.68 (m, 3H), 7.66-7.56 (m, 2H), 7.55-7.45 (m, 1H), 7.21-7.09 (m, 1H), 6.85 (s, 1H), 5.33-5.17 (m, 2H), 4.37-4.27 (m, 1H), 4.07-3.97 (m, 1H).
Example 39
Compound 39: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00177##
39-1: 2-[(4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-(3,4-difluorophenyl)acetaldehyde
[0269] By using the method in Example 33, the yellow solid 39-1 (80 mg, 0.219 mmol, 12.7%) was prepared by using (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione.
[0270] LC-MS m/z (ESI): 430.0 [M+H].sup.+
Compound 39: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0271] By using the method in Example 37, the yellow solid 39 (8.5 mg, 0.019 mmol, 9.5%) was prepared by using 39-1.
[0272] LC-MS m/z (ESI): 430.0 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.99 (s, 1H), 10.51 (s, 1H), 8.21 (s, 1H), 7.69-7.59 (m, 1H), 7.58-7.35 (m, 2H), 7.33-7.10 (m, 2H), 6.83 (s, 1H), 5.26-5.15 (m, 2H), 4.37-4.27 (m, 1H), 4.00-3.90 (m, 1H). 2.45 (s, 3H).
Example 40
Compound 40: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrophosphate
##STR00178##
40-1: tert-butyl 3-{[(4Z)-3-(tert-butoxycarbonyl)-1-[1-(4-cyanophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidin-4-ylene]methyl}-6-chloroindole-1-carboxylate
[0273] DIEA (104 mg, 0.763 mmol, 2.12 equiv) was added into a stirred solution of 4-{1-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-hydroxyethyl}benzonitrile (155 mg, 0.360 mmol, 1 equiv), DMAP (9 mg, 0.068 mmol, 0.19 equiv), and Boc.sub.2O (243 mg, 1.058 mmol, 2.94 equiv) in DMF (3 mL), and the obtained mixture was stirred in a nitrogen atmosphere at 40 C. for 2 h. The mixture was cooled to room temperature and concentrated in vacuum. A residue was purified by fast reversed-phase chromatography to obtain the yellow solid 40-1 (20 mg, 0.033 mmol, 9.13%).
[0274] LC-MS m/z (ESI): 505.1 [MH100].sup.
40-2: 2-[(4Z)-3-(tert-butoxycarbonyl)-4-{[1-(tert-butoxycarbonyl)-6-chloroindol-3-yl]methylene}-2,5-dioxoimidazolidin-1-yl]-2-(4-cyanophenyl)ethoxyl phosphonic acid
[0275] Phosphorus oxychloride (125 mg, 0.772 mmol, 0.16 mL, 18.83 equiv) was added into a stirred solution of tert-butyl 3-{[(4Z)-3-(tert-butoxycarbonyl)-1-[1-(4-cyanophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidin-4-ylene]methyl}-6-chloroindol-1-carboxylate (25 mg, 0.041 mmol, 1 equiv) and TEA (150 mg, 1.403 mmol, 0.20 MI, 34.23 equiv) in THF (1 mL) at 0 C., and the obtained mixture was stirred at room temperature for 18 h. Then, water (0.5 mL) was added into a reaction solution at 0 C., and the obtained mixture was stirred at room temperature for 2 h. The obtained mixture was concentrated in vacuum to obtain the yellow solid 40-2 (40 mg, crude product). The crude product was directly used for a next step without further purification.
[0276] LC-MS m/z (ESI): 685.1 [MH].sup.
Compound 40: 2-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-(4-cyanophenyl)ethoxyl phosphonic acid
[0277] A 1,4-dioxane (1 mL, 4.000 mmol, 4 N) in HCl was added into 2-[(4Z)-3-(tert-butoxycarbonyl)-4-{[1-(tert-butoxycarbonyl)-6-chloroindol-3-yl]methylene}-2,5-dioxoimidazol-1-yl]-2-(4-cyanophenyl)ethoxyl phosphonic acid (40 mg, crude product), and the obtained mixture was stirred at room temperature for 12 h. The obtained mixture was concentrated in vacuum. The crude product was purified by reversed-phase HPLC to obtain the white solid compound 40 (2.2 mg, 0.004 mmol, 29.11%).
[0278] LC-MS m/z (ESI): 484.9 [MH].sup..
[0279] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.20 (s, 1H), 7.85-7.75 (m, 3H), 7.71-7.57 (m, 2H), 7.54-7.44 (m, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 5.47-5.37 (m, 1H), 4.46-4.36 (m, 2H).
Example 41
Compound 41: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00179##
41-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)acetic acid
[0280] Pyridine (341 mg, 4.100 mmol, 4.0 equiv, 95%) was added in batches into a solution of methyl 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (300 mg, 1.020 mmol, 1.0 equiv, 99%) and 6-chloro-7-fluoro-1H-indole-3-formaldehyde (409 mg, 2.050 mmol, 2.0 equiv, 99%) in ethanol (5 mL) at room temperature, and the obtained mixture was stirred under nitrogen protection at 60 C. for 4 h. A residue was purified by fast reversed-phase chromatography to obtain the yellow solid compound 41-1 (120 mg, 23%).
[0281] LC-MS (MH).sup.=455.0.
Compound 41: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazol-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide
[0282] Cholamine (27 mg, 0.420 mmol, 9.80 equiv) was dropwise added into a stirred solution of [(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyano-3-fluorophenyl)acetic acid (20 mg, 0.043 mmol, 1 equiv), HATU (30 mg, 0.075 mmol, 1.75 equiv), and DIEA (27 mg, 0.198 mmol, 4.63 equiv) in DMF (0.5 mL), and the obtained mixture was stirred under nitrogen protection at 40 C. for 12 h. The mixture was cooled to room temperature and purified by Prep-HPLC to obtain the yellow solid compound 41 (1.6 mg, 0.003 mmol, 7.55%).
[0283] LC-MS m/z (ESI): 500.1 [M+H].sup.+.
[0284] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.56 (s, 1H), 10.64 (s, 1H), 8.29-8.18 (m, 2H), 7.97-7.89 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.59 (d, J=10.6 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.28-7.17 (m, 1H), 6.84 (s, 1H), 5.89 (s, 1H), 4.67-4.60 (m, 1H), 3.46-3.39 (m, 2H), 3.26-3.19 (m, 1H), 3.18-3.09 (m, 1H).
Example 42
Compound 42: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)ethyl dihydrophosphate
##STR00180##
[0285] Dichlorophosphonic anhydride (35 mg, 0.14 mmol, 3.91 eq) was dropwise added into a stirred solution of (5Z)-5-[(6-chloro-1H-indol-3-yl)methylene]-3-[1-(3,4-difluorophenyl)-2-hydroxyethyl]imidazolidine-2,4-dione (15 mg, 0.036 mmol, 1 eq) in ACN (1 mL) at 0 C., and the obtained mixture was then stirred at 0 C. for 3 h. The mixture was alkalized with sodium hydrogen carbonate (1 M) at 0 C. till the pH=8-9, and the mixture was stirred at 0 C. for 30 min. Then, the mixture was acidized with HCl (12 M) till pH=1, and the mixture was stirred at 0 C. for 1.5 h. The obtained mixture was extracted with EtOAc (325 mL), and combined organic layers were washed with saline (125 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. The product was purified by Prep-HPLC to obtain the yellow solid compound 42 (4.4 mg, 23.0%).
[0286] LC-MS m/z (ESI): 496.0 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.09 (s, 1H), 8.20 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.60-7.20 (m, 4H), 7.19-7.05 (m, 1H), 6.84 (s, 1H), 5.42-5.28 (m, 1H), 4.60-4.30 (m, 2H).
Example 43
Compound 43: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)ethyl dihydrophosphate
##STR00181##
[0287] By using the method in Example 42, the yellow solid compound 43 (10.9 mg, 17.4%) was prepared by using the compound 39.
[0288] LC-MS m/z (ESI): 510.1 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.09 (s, 1H), 8.21 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.57-7.32 (m, 2H), 7.30-7.21 (m, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 5.40-5.29 (m, 1H), 4.56-4.25 (m, 2H), 2.54 (s, 3H).
Example 44
Compound 44: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)dihydroethyl phosphate
##STR00182##
44-1:2,5-dioxopyrrolidin-1-yl(z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetate
[0289] Under nitrogen protection at 0 C., DCC (30 mg, 0.138 mmol) was added into a stirred solution of [(4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin 1-yl](3,4-difluorophenyl)acetic acid (60 mg, 0.128 mmol, 1 equiv) and N-hydroxysuccinimide (16 mg, 0.132 mmol, 1.03 equiv, 95%) in DCM (2 mL), and the obtained mixture was stirred at room temperature for 12 h. The reaction was terminated with ice water. The obtained mixture was extracted with DCM (310 mL). Combined organic layers were washed with saline (35 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure to obtain the yellow solid 44-1 (100 mg, 99.12%). The crude product was directly used for a next step without further purification.
[0290] LC-MS m/z (ESI): 541.0 [MH].sup..
Compound 44: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)dihydroethyl phosphate
[0291] Under nitrogen protection at 0 C., TEA (33 mg, 0.308 mmol, 2.37 equiv) was added into a stirred solution of 2,5-pyrrolidin-1-yl-2-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-(3,4-difluorophenyl)acetate (100 mg, 0.130 mmol, 1 equiv) and O-phosphorylethanolamine (33 mg, 0.221 mmol, 1.70 equiv) in DMF (3 mL) and water (2 mL), and the obtained mixture was stirred at room temperature for 16 h. The obtained mixture was concentrated in vacuum. The crude product was purified by Prep-HPLC to obtain the yellow solid compound 44 (17.3 mg, 19.85%).
[0292] LC-MS m/z (ESI): 569.1 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.02 (s, 1H), 8.52-8.46 (m, 1H), 8.21 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.55-7.21 (m, 3H), 7.14 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 5.75 (s, 1H), 3.75-3.69 (m, 2H), 3.27-3.08 (m, 2H), 2.51 (s, 3H).
Example 45
Compound 45: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00183##
45-1: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetaldehyde
[0293] By using the method for the compound 33, the yellow solid compound 45-1 (205 mg, 38.2%) was prepared by using the compound 2.
[0294] LC-MS m/z (ESI): 411.9 [MH].sup..
Compound 45: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0295] By using the method for the compound 37, the yellow solid compound 45 (8.9 mg, 40.3%) was prepared by using the compound 45-1.
[0296] LC-MS m/z (ESI): 413.9 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.96 (s, 1H), 10.47 (s, 1H), 8.18 (s, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.54-7.40 (m, 5H), 7.13 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.24-5.13 (m, 2H), 4.42-4.28 (m, 1H), 4.01-3.87 (m, 1H).
Example 46
Compound 46: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)ethyl dihydrophosphate
##STR00184##
[0297] By using the method for the compound 42, the yellow solid compound 46 (13.3 mg, 31.6%) was prepared by using the compound 45.
[0298] LC-MS m/z (ESI): 496.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.13 (s, 1H), 8.21 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.51-7.37 (m, 5H), 7.13 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.40-5.30 (m, 1H), 4.56-4.47 (m, 1H), 4.39-4.27 (m, 1H).
Example 47
Compound 47: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)ethyl dihydrophosphate
##STR00185##
47-1: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)-2-fluorobenzonitrile
[0299] By using the method for the compound 37, the yellow solid compound 47-1 (19 mg, 39.4%) was prepared by using the compound 33.
[0300] LC-MS m/z (ESI): 441.0[MH].sup.
Compound 47: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)ethyl dihydrophosphate
[0301] By using the method for the compound 42, the yellow solid compound 44 (2.8 mg, 17.8%) was prepared by using the compound 47-1.
[0302] LC-MS m/z (ESI): 521.0[MH].sup.. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 12.57 (s, 1H), 10.67 (s, 1H), 8.26 (s, 1H), 7.98-7.90 (m, 1H), 7.69-7.55 (m, 2H), 7.53-7.40 (m, 1H), 7.25-7.17 (m, 1H), 6.84 (s, 1H), 5.57-5.45 (m, 1H), 4.65-4.46 (m, 2H), 3.40-3.30 (s, 2H).
Example 48
Compound 48: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00186##
48-1: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetic acid
[0303] By using the method for the 1-19, the yellow solid compound 48-1 (16 g, 52%) was prepared by using I-14-3 and I-8.
[0304] LC-MS m/z (ESI): 442.1.0[MH].sup..
Compound 48: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide
[0305] By using the method for the compound 41, the yellow solid 48 (10 g, 57%) was prepared by using 48-1.
[0306] LC-MS m/z (ESI): 485.1 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d6) 12.00 (s, 1H), 10.52 (s, 1H), 8.20 (s, 1H), 8.07-8.02 (m, 1H), 7.64-7.62 (m, 1H), 7.48-7.40 (m, 4H), 7.20-7.13 (m, 1H), 6.82 (s, 1H), 5.76-5.73 (m, 1H), 4.63-4.55 (m, 1H), 3.44-3.30 (m, 3H), 3.25-3.12 (m, 3H).
Example 49
Compound 49: (R,Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00187##
[0307] The compound 38 was separated by chiral SFC according to the following condition to obtain the compound 49: column: CHIRALPAK ID-3 4.650 mm 3 um; mobile phase: Hex (0.1% DEA): EtOH=50:50, 20 min; detector, UV 254 nm.
[0308] LC-MS m/z (ESI): 404.8 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.98 (s, 1H), 10.53 (s, 1H), 8.20 (s, 1H), 7.88-7.79 (m, 3H), 7.64-7.58 (m, 2H), 7.52-7.47 (m, 1H), 7.20-7.11 (m, 1H), 6.85 (s, 1H), 5.32-5.23 (m, 2H), 4.38-4.28 (m, 1H), 4.07-3.97 (m, 1H).
Example 50
Compound 50: (S,Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00188##
[0309] The compound 38 was separated by chiral SFC according to the following condition to obtain the compound 50: column: CHIRALPAK ID-3 4.650 mm 3 um; mobile phase: Hex (0.1% DEA): EtOH=50:50, 20 min; detector, UV 254 nm.
[0310] LC-MS m/z (ESI): 404.8 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.99 (s, 1H), 10.53 (s, 1H), 8.20 (s, 1H), 7.89-7.79 (m, 3H), 7.63-7.59 (m, 2H), 7.50-7.46 (m, 1H), 7.22-7.11 (m, 1H), 6.86 (s, 1H), 5.32-5.24 (m, 2H), 4.39-4.28 (m, 1H), 4.07-3.98 (m, 1H).
Example 51
Compound 51: (R,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrophosphate
##STR00189##
[0311] By using the method for the compound 42, the yellow solid compound 51 (17.3 mg, 53.0%) was prepared by using the compound 49.
[0312] LC-MS m/z (ESI): 484.9 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.20 (s, 1H), 8.21 (s, 1H), 7.85-7.75 (m, 3H), 7.72-7.57 (m, 2H), 7.54-7.46 (m, 1H), 7.17-7.08 (m, 1H), 6.84 (s, 1H), 5.49-5.38 (m, 1H), 4.59-4.33 (m, 2H).
Example 52
Compound 52: (S,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrophosphate
##STR00190##
[0313] By using the method for the compound 42, the yellow solid compound 52 (17.9 mg, 59.1%) was prepared by using the compound 50.
[0314] LC-MS m/z (ESI): 487.0 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.19 (s, 1H), 8.21 (s, 1H), 7.85-7.75 (m, 3H), 7.72-7.57 (m, 2H), 7.54-7.46 (m, 1H), 7.17-7.07 (m, 1H), 6.84 (s, 1H), 5.49-5.38 (m, 1H), 4.52-4.34 (m, 2H).
Example 53
Compound 53: (S,Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00191##
[0315] The compound 26 was separated by chiral HPLC according to the following condition to obtain the compound 53: CHIRALPAK IG, 225 cm; mobile phase, Hex (0.5% 2M NH3-MeOH) in MeOH, 50% isocratic in 15 min; detector, UV 254 nm.
[0316] LC-MS m/z (ESI): 415.8 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.96 (s, 1H), 10.49 (s, 1H), 8.19 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.57-7.47 (m, 2H), 7.47-7.37 (m, 1H), 7.33-7.23 (m, 1H), 7.19-7.09 (m, 1H), 6.83 (s, 1H), 5.25-5.15 (m, 2H), 4.36-4.26 (m, 1H), 3.99-3.89 (m, 1H).
Example 54
Compound 54: (R,Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00192##
[0317] The compound 26 was separated by chiral HPLC according to the following condition to obtain the compound 54: CHIRALPAK IG, 225 cm; mobile phase, Hex (0.5% 2M NH3-MeOH) in MeOH, 50% isocratic in 15 min; detector, UV 254 nm.
[0318] LC-MS m/z (ESI): 415.8 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d6) 11.96 (s, 1H), 10.49 (s, 1H), 8.19 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.57-7.37 (m, 3H), 7.33-7.23 (m, 1H), 7.19-7.09 (m, 1H), 6.83 (s, 1H), 5.25-5.15 (m, 2H), 4.36-4.26 (m, 1H), 3.99-3.89 (m, 1H).
Example 55
Compound 55: (Z)-(6-chloro-3-((1-(3,4-difluorobenzyl)-2,5-dioxoimidazolidin-4-ylene)methyl)-1H-indol-1-yl)phosphonic acid
##STR00193##
[0319] NaH (68 mg, 2.84 mmol, 2.20 eq) was added into a solution of the compound 1 (500 mg, 1.29 mmol, 1.00 eq) in THF (10 mL) and DCM (20 mL), and the mixture was stirred under argon protection at room temperature for 15 min. Phosphorus oxychloride (988 mg, 6.44 mmol, 5.00 eq) was dropwise added into the mixture at 0 C., and the mixture was stirred under argon protection at 0 C. for 3 h. The obtained mixture was concentrated at a reduced pressure, and a residue was dissolved in acetonitrile (10 mL). The mixture was alkalized with cold saturated sodium hydrogen carbonate till pH=8, and the obtained mixture was stirred at 0 C. for 30 min. The mixture was acidized with concentrated hydrochloric acid till pH=1, and the obtained mixture was stirred at 0 C. for 30 min and extracted with EtOAc (330 mL). Combined organic layers were dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A crude product was purified by Prep-HPLC to obtain the yellow solid compound 55 (20.1 mg, 3.10%).
[0320] LC-MS m/z (ESI): 466.0[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.36 (s, 1H), 8.01 (s, 1H), 7.75-7.55 (m, 1H), 7.54-7.29 (m, 2H), 7.28-7.00 (m, 2H), 6.72 (s, 1H), 4.70 (s, 2H).
Example 56
Compound 56: (Z)-(6-chloro-3-((1-(1-(4-cyano-3-fluorophenyl)-2-((2-hydroxyethyl)amino)-2-oxyethyl)-2,5-dioxoimidazolidin-4-ylene)methyl)-7-fluoro-1H-indol-1-yl)phosphonic acid
##STR00194##
[0321] By using the method for the compound 42, the yellow solid compound 56 (6.1 mg, 15.6%) was prepared by using the compound 41.
[0322] LC-MS m/z (ESI): 578.2 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.19 (s, 1H), 7.85-7.75 (m, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.49 (d, J=10.4 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.20-7.09 (m, 1H), 6.76 (s, 1H), 4.50 (s, 1H), 3.70-3.61 (m, 2H), 3.36-3.17 (m, 2H).
Example 57
Compound 57: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(3-hydroxyl bicyclo[1.1.1]pentan-1-yl)acetamide
##STR00195##
[0323] By using the method for the compound 41, the yellow solid compound 57 (12.4 mg, 34.5%) was prepared by using I-17.
[0324] LC-MS m/z (ESI): 527.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 11.99 (s, 1H), 10.51 (s, 1H), 8.68 (s, 1H), 8.20-8.19 (m, 1H), 7.67-7.64 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 7.22-7.13 (m, 2H), 6.82 (s, 1H), 6.18 (s, 1H), 5.68 (s, 1H), 2.54 (s, 3H), 2.02 (s, 6H).
Example 58
Compound 58: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(2-hydroxyethyl)acetamide
##STR00196##
[0325] By using the method for the compound 41, the yellow solid compound 58 (11.2 mg, 29.9%) was prepared by using the 1-16.
[0326] LC-MS m/z (ESI): 480.0 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.54 (s, 1H), 10.61 (s, 1H), 8.30-8.14 (m, 2H), 7.83 (d, J=7.9 Hz, 2H), 7.72-7.52 (m, 3H), 7.32-7.15 (m, 1H), 6.82 (s, 1H), 5.84 (s, 1H), 4.66-4.56 (m, 1H), 3.53-3.15 (m, 4H).
Example 59
Compound 59: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00197##
[0327] By using the method for the compound 41, the yellow solid compound 59 (6.2 mg, 17.0%) was prepared by using the I-14.
[0328] LC-MS m/z (ESI): 491.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.54 (s, 1H), 10.59 (s, 1H), 8.25 (s, 1H), 8.09-8.00 (m, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.52-7.38 (m, 4H), 7.25-7.17 (m, 1H), 6.82 (s, 1H), 5.74 (s, 1H), 4.65-4.58 (m, 1H), 3.46-3.39 (m, 2H), 3.28-3.10 (m, 2H).
Example 60
Compound 60: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(2-hydroxyethyl)acetamide
##STR00198##
[0329] By using the method for the compound 41, the yellow solid compound 60 (12 mg, 42.1%) was prepared by using I-19.
[0330] LC-MS m/z (ESI): 476.1 [MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.99 (s, 1H), 10.54 (s, 1H), 8.24-8.13 (m, 2H), 7.87-7.78 (m, 2H), 7.68-7.55 (m, 3H), 7.15 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.84 (s, 1H), 4.65-4.55 (m, 1H), 3.49-3.36 (m, 2H), 3.27-3.08 (m, 2H), 2.50 (s, 3H).
Example 61
Compound 61: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(2-hydroxyethyl)acetamide
##STR00199##
[0331] By using the method for the compound 41, the yellow solid compound 61 (14.1 mg, 29.9%) was prepared by using I-18.
[0332] LC-MS m/z (ESI): 464.1 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.97 (s, 1H), 10.54 (s, 1H), 8.23-8.13 (m, 2H), 7.87-7.77 (m, 3H), 7.65-7.55 (m, 2H), 7.53-7.43 (m, 1H), 7.19-7.09 (m, 1H), 6.85 (s, 1H), 5.84 (s, 1H), 4.70-4.56 (m, 1H), 3.48-3.37 (m, 2H), 3.29-3.08 (m, 2H).
Example 62
Compound 62: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00200##
[0333] By using the method for the compound 41, the yellow solid compound 62 (12.1 mg, 38.5%) was prepared by using I-13.
[0334] LC-MS m/z (ESI): 473.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 11.95 (s, 1H), 10.50 (s, 1H), 8.18 (s, 1H), 8.05-8.03 (m, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.48-7.39 (m, 5H), 7.13 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.73 (s, 1H), 4.61-4.57 (m, 1H), 3.44-3.39 (m, 2H), 3.25-3.13 (m, 2H).
Example 63
Compound 63: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00201##
[0335] By using the method for the compound 41, the yellow solid compound 63 (11 mg, 14.5%) was prepared by using the 1-20.
[0336] LC-MS m/z (ESI): 475.0 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.97 (s, 1H), 10.52 (s, 1H), 8.19 (s, 1H), 8.11-8.00 (m, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.58-7.34 (m, 3H), 7.32-7.21 (m, 1H), 7.14 (d, J=8.6, 1H), 6.85 (s, 1H), 5.75 (s, 1H), 3.48-3.35 (m, 2H), 3.31-3.05 (m, 2H).
Example 64
Compound 64: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-((4-hydroxylbicyclo[2.2.2]octan-1-yl)methyl)acetamide
##STR00202##
[0337] By using the method for the compound 41, the yellow solid compound 64 (19.1 mg, 47.0%) was prepared by using I-17.
[0338] LC-MS m/z (ESI): 581.0 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d6) 12.00 (s, 1H), 10.53 (s, 1H), 8.28 (s, 1H), 7.97-7.94 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.51-7.26 (m, 2H), 7.30-7.22 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 5.74 (s, 1H), 4.22-4.12 (m, 1H), 2.89-2.78 (m, 2H), 2.51 (s, 3H), 1.43-1.42 (m, 12H).
Example 65
Compound 65: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)-3-hydroxypropyl dihydrophosphate
##STR00203##
65-1: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide
[0339] By using the method for the compound 41, the yellow solid compound 65-1 (23.4 mg, 41%) was prepared by using the I-17.
[0340] LC-MS m/z (ESI): 519.05 [M+H].sup.+.
Compound 65: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)-3-hydroxypropyl dihydrophosphate
[0341] Under argon protection at 0 C., dichlorophosphate anhydride (243 mg, 0.96 mmol, 5.00 eq) was added into a stirred solution of the compound 65-1 (100 mg, 0.19 mmol, 1.00 eq) in ACN (5 mL) and THF (2.5 mL), and the obtained mixture was stirred at 0 C. for 3 h. Ice water (3 mL) was added to terminate the reaction, and the mixture was neutralized with saturated sodium hydrogen carbonate till pH=8. The obtained mixture was stirred under argon protection at 0 C. for 30 min. The mixture was acidized with concentrated hydrochloric acid till pH=1. The obtained mixture was stirred under argon protection at 0 C. for 1.5 h. The obtained mixture was extracted with EtOAc (330 mL), and combined organic layers were washed with saline (30 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. The crude product was purified by Prep-HPLC to obtain the yellow solid compound 65 (4.9 mg, 4.16%).
[0342] LC-MS m/z (ESI): 597.1[MH].sup.. .sup.1HNMR (300 MHz, DMSO-d.sub.6) 8.20 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.57-7.32 (m, 2H), 7.31-7.11 (m, 2H), 6.82 (s, 1H), 5.78 (s, 1H), 3.88-3.83 (m, 1H), 3.82-3.65 (m, 2H), 3.46-3.30 (m, 2H), 2.57 (s, 3H).
Example 66
Compound 66: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(4-hydroxyl bicyclo[2.2.2]octan-1-yl)acetamide
##STR00204##
[0343] By using the method for the compound 41, the yellow solid compound 66 (2.2 mg, 49.5%) was prepared by using the I-17.
[0344] LC-MS m/z (ESI): 566.9 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d6) 11.97 (s, 1H), 10.04 (s, 1H), 8.18 (s, 1H), 7.64-7.61 (m, 2H), 7.48-7.35 (m, 2H), 7.18-7.12 (m, 2H), 6.77 (s, 1H), 5.64 (s, 1H), 4.27 (s, 1H), 2.45 (s, 3H), 1.92-1.87 (m, 6H), 1.59-1.53 (m, 6H).
Example 67
Compound 67: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00205##
67-1: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)acetic acid
[0345] Under nitrogen protection at 78 C., LiHMDS (1 mL, 1.000 mmol, 5.4 equiv) was added into a stirred solution of the compound 21 (80 mg, 0.186 mmol, 1.0 equiv) in THF (3 mL), and the obtained mixture was stirred at 78 C. for 1 h. Then, the mixture was stirred in a CO.sub.2 atmosphere to react for 15 min. Then, the obtained mixture was stirred under nitrogen protection at 65 C. for 30 min. The reaction was terminated at 65 C. with a solution of HOAc (2 mL) in THF (1 mL). Then, the reaction mixture was poured into 50 mL of cold water. The obtained mixture was extracted with EtOAc (330 mL). Combined organic layers were washed with saline (215 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by fast reversed-phase chromatography to obtain the yellow solid compound 67-1 (23 mg, 27.3%).
Compound 67: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide
[0346] By using the method for the compound 41, the yellow solid compound 67 (3.7 mg, 13.0%) was prepared by using 67-1.
[0347] LC-MS m/z (ESI): 496.1 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.01 (s, 1H), 10.59 (s, 1H), 8.29-8.19 (m, 2H), 7.98-7.87 (m, 1H), 7.67-7.57 (m, 2H), 7.53-7.40 (m, 1H), 7.20-7.05 (m, 1H), 6.85 (s, 1H), 5.88 (s, 1H), 3.48-3.40 (m, 2H), 3.30-3.06 (m, 2H), 2.50 (s, 3H).
Example 68
Compound 68: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-((3-hydroxyl bicyclo[1.1.1]pentan-1-yl)methyl)acetamide
##STR00206##
[0348] By using the method for the compound 41, the yellow solid compound 68 (5.1 mg, 24.44%) was prepared by using the I-17.
[0349] LC-MS m/z (ESI): 541.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 11.99 (s, 1H), 10.53 (s, 1H), 8.20 (s, 1H), 8.15-8.05 (m, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.55-7.37 (m, 2H), 7.40-7.30 (m, 1H), 7.26 (s, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 5.73 (s, 1H), 3.35-3.30 (m, 2H), 2.51 (s, 3H), 1.65 (s, 6H).
Example 69
Compound 69: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00207##
69-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetaldehyde
[0350] By using the method for the compound 33, the white solid compound 69-1 (80 mg, 53.3%) was prepared by using the compound 15.
[0351] LC-MS m/z (ESI): 430.0 [MH].sup.
Compound 69: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0352] By using the method for the compound 37, the yellow solid compound 69 (12.3 mg, 20.4%) was prepared by using 69-1.
[0353] LC-MS m/z (ESI): 434.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.53 (s, 1H), 10.55 (s, 1H), 8.25 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.49-7.39 (m, 4H), 7.26-7.16 (m, 1H), 6.81 (s, 1H), 5.25-5.15 (m, 2H), 4.40-4.31 (m, 1H), 3.98-3.92 (m, 1H).
Example 70
Compound 70: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00208##
70-1: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione
[0354] By using the method in Example 1, the yellow solid compound 70-1 (800 mg, 62%) was prepared by using the intermediates I-2 and I-8.
70-2: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetaldehyde
[0355] By using the method for the compound 33, the white solid compound 70-2 (140 mg, 21.2%) was prepared by using the compound 70-1.
Compound 70: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0356] By using the method for the compound 37, the yellow solid compound 70 (20 mg, 30.5%) was prepared by using the compound 70-2.
[0357] LC-MS m/z (ESI): 428.0 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.99 (s, 1H), 10.50 (s, 1H), 8.20 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.46-7.41 (m, 4H), 7.15 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 5.26-5.14 (m, 2H), 4.41-4.30 (m, 1H), 4.00-3.90 (m, 1H), 2.52 (s, 3H).
Example 71
Compound 71: (Z)-(6-chloro-3-((1-(4-cyano-3-fluorobenzyl)-2,5-dioxoimidazolidin-4-ylene)methyl)-7-fluoro-1H-indol-1-yl)phosphonic acid
##STR00209##
[0358] Under argon protection at 0 C., a solution of phosphorus oxychloride (186 mg, 1.21 mmol, 5.00 eq) in THF (1 mL) was added into a stirred solution of the compound 14 (100 mg, 0.24 mmol, 1.00 eq) in THF (1 mL). A THF solution (1 mL) of TEA (278 mg, 2.74 mmol, 11.32 eq) was dropwise added into the mixture at 0 C., and the obtained mixture was then stirred at 0 C. for 2 h. The mixture was alkalized with saturated sodium hydrogen carbonate till pH=8, and the obtained mixture was stirred at 0 C. for 30 min. The mixture was acidized with concentrated hydrochloric acid till pH=1. The obtained mixture was diluted with water (20 mL) and extracted with EtOAc (350 mL). Combined organic layers were washed with saline (50 mL) and dried with anhydrous sodium sulfate. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. The crude product was purified by Prep-HPLC to obtain the yellow solid compound 71 (13.1 mg, 0.018 mmol 7.4%).
[0359] LC-MS m/z (ESI): 491.0[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.15 (s, 1H), 7.91-7.79 (m, 1H), 7.47-7.36 (m, 1H), 7.32-7.19 (m, 2H), 7.07-6.97 (m, 1H), 6.27 (s, 1H), 4.70 (s, 2H).
Example 72
Compound 72: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(2-hydroxyethyl)acetamide
##STR00210##
72-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetic acid
[0360] By using the method for the compound 67-1, the yellow solid compound 72-1 (23 mg, 47%) was prepared by using the compound 10.
[0361] LC-MS m/z (ESI): 448.01 [MH]. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
Compound 72: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(2-hydroxyethyl)acetamide
[0362] By using the method for the compound 41, the yellow solid compound 72 (10.6 mg, 45.6%) was prepared by using the compound 72-1.
[0363] LC-MS m/z (ESI): 493.15 [M+H].sup.+ 0.1H NMR (400 MHz, DMSO-d.sub.6) 12.54 (d, J=2.8 Hz, 1H), 10.60 (s, 1H), 8.25 (d, J=2.8 Hz, 1H), 8.08 (t, J=5.7 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.54-7.48 (m, 1H), 7.46-7.38 (m, 1H), 7.29-7.18 (m, 2H), 6.83 (s, 1H), 5.76 (s, 1H), 4.61 (s, 1H), 3.43-3.40 (m, 2H), 3.26-3.12 (m, 2H).
Example 73
Compound 73: (Z)-3-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)bicyclo[1.1.1]pentan-1-yl dihydrophosphate
##STR00211##
[0364] By using the method for the compound 42, the yellow solid compound 73 (6.1 mg, 16.69%) was prepared by using the compound 57.
[0365] LC-MS m/z (ESI): 607.01 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 12.04 (s, 1H), 8.72 (s, 1H), 8.12 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.48-7.34 (m, 2H), 7.26-7.18 (s, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 5.69 (s, 1H), 3.60-3.50 (m, 5H), 2.49 (s, 3H), 2.27-2.16 (m, 6H).
Example 74
Compound 74: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)propane-1,3-diylbis(dihydrophosphate)
##STR00212##
74-1: (Z)-tetra-tert-butyl (2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)propane-1,3-diyl)bis(phosphate)
[0366] In an argon atmosphere, a MeCN (9.5 mL) of 1H-1,2,3,4-tetrazole (259 mg, 3.70 mmol, 8.00 eq) and [bis(tert-butoxyl)phosphono]diethylamine (464 mg, 1.86 mmol, 4.02 eq) were added into a solution of 65-1 (240 mg, 0.46 mmol, 1.00 eq) in THF (24 mL), and the obtained mixture was stirred under argon protection at room temperature for 12 h. A solution of metachloroperbenzoic acid (563 mg, 2.78 mmol, 6.00 eq, 85%) in DCM (24 mL) was added into the mixture at 0 C., and the obtained mixture was then stirred at 4 C. for 1.5 h. The obtained mixture was diluted with DCM (50 mL) and continuously washed 10% Na.sub.2S.sub.2O.sub.5, sodium hydrogen carbonate, and saline respectively. Organic phases were concentrated. A residue was purified by fast reversed-phase chromatography to obtain the light brown syrupy compound 74-1 (120 mg, 26.5%).
[0367] LC-MS m/z (ESI): 901.3[MH].sup..
Compound 74: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)propane-1,3-diylbis(dihydrophosphate)
[0368] TFA (5 mL, 1283 eq) was dropwise added into a solution of 74-1 (50 mg, 0.05 mmol, 1.00 eq) in DCM (10 mL) at 0 C., and a reaction mixture was stirred at room temperature for 1 h. The obtained mixture was concentrated in vacuum. A crude product was purified by Prep-HPLC to obtain the yellow solid compound 74 (3.8 mg, 11.2%).
[0369] LC-MS m/z (ESI): 677.0[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.99 (s, 1H), 8.19 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.48-7.34 (m, 3H), 7.29-7.20 (m, 1H), 7.17-7.12 (m, 1H), 6.81 (s, 1H), 4.80 (s, 1H), 4.02-3.94 (m, 1H), 3.93-3.85 (m, 2H), 3.84-3.66 (m, 2H), 2.52 (s, 3H).
Example 75
Compound 75: (Z)-4-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)bicyclo[2.2.2]octan-1-yl dihydrophosphate
##STR00213##
[0370] By using the method for the compound 42, the yellow solid compound 75 (15.2 mg, 33.7%) was prepared by using the compound 66.
[0371] LC-MS m/z (ESI): 647.05 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.04 (s, 1H), 8.12 (s, 1H), 7.67-7.61 (m, 2H), 7.46-7.35 (m, 2H), 7.19-7.12 (m, 2H), 6.78 (s, 1H), 5.64 (s, 1H), 2.49 (s, 3H), 1.91 (s, 12H).
Example 76
Compound 76: (Z)-4-((2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)methyl)bicyclo[2.2.2]octan-1-yl dihydrophosphate
##STR00214##
[0372] By using the method for the compound 42, the yellow solid compound 76 (24.7 mg, 37.6%) was prepared by using the compound 64.
[0373] LC-MS m/z (ESI): 663.01 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.93 (s, 1H), 8.13-8.11 (m, 1H), 7.53-7.45 (m, 1H), 7.57-7.59 (d, J=8.5 Hz, 1H), 7.42-7.29 (m, 2H), 7.22-7.14 (m, 1H), 7.07-7.05 (d, J=8.5 Hz, 1H), 6.75 (s, 1H), 5.67 (s, 1H), 2.82-2.60 (m, 2H), 2.44 (s, 3H), 1.79-1.69 (m, 6H), 1.41-1.31 (m, 6H).
Example 77
Compound 77: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00215##
77-1: 3-(4-chloro-3-fluorobenzyl)imidazolidine-2,4-dione
[0374] By using the method for the compound 1-1, the offwhite solid compound 77-1 (10 g, 88.4%) was prepared by using hydantoin and 4-(bromomethyl)-1-chloro-2-fluorobenzene.
[0375] LC-MS m/z (ESI): 241.0[MH].sup..
77-2: (Z)-3-(4-chloro-3-fluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0376] By using the method for the compound 1, the yellow solid compound 77-2 (2.0 g, 91.5%) was prepared by using the compounds 77-1 and I-10.
[0377] LC-MS m/z (ESI): 420.0[MH].sup..
77-3: (Z)-2-(4-chloro-3-fluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde
[0378] By using the method for the compound 33, the yellow solid compound 77-3 (50 mg, 8.3%) was prepared by using the compound 77-2.
[0379] LC-MS m/z (ESI): 450.0[M+H].sup.+.
Compound 77: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0380] By using the method for the compound 37, the yellow solid compound 77 (22.4 mg, 53.1%) was prepared by using the compound 77-3.
[0381] LC-MS m/z (ESI): 451.9[M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.53 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.72-7.64 (m, 1H), 7.63-7.55 (m, 1H), 7.49 (d, J=10.6, 1H), 7.32-7.16 (m, 2H), 6.82 (s, 1H), 5.30-5.15 (m, 2H), 4.40-4.20 (m, 1H), 4.10-3.90 (m, 1H).
Example 78
Compound 78: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00216##
78-1: (Z)-5-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-3-(4-chloro-3-fluorobenzyl)imidazolidine-2,4-dione
[0382] By using the method for the compound 1, the yellow solid compound 78-1 (1.9 g, 97.6%) was prepared by using the compound 77-1 and 7-bromo-6-chloro-1H-indole-3-formaldehyde.
[0383] LC-MS m/z (ESI): 481.9[M+H].sup.+.
78-2: (Z)-2-(4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chloro-3-fluorophenyl)acetaldehyde
[0384] By using the method for the compound 33, the yellow solid compound 78-2 (110 mg, 13.5%) was prepared by using the compound 78-1.
[0385] LC-MS m/z (ESI): 509.9[M+H].sup.+.
78-3: (Z)-5-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0386] By using the method for the compound 37, the yellow solid compound 78-3 (66 mg, 57.5%) was prepared by using the compound 78-2.
[0387] LC-MS m/z (ESI): 510.0[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d6) 12.18 (s, 1H), 10.64 (s, 1H), 8.26 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.60-7.58 (m, 1H), 7.48 (d, J=10.6, 1H), 7.34-7.20 (m, 2H), 6.81 (s, 1H), 5.30-5.10 (m, 2H), 4.40-4.20 (m, 1H), 4.05-3.90 (m, 1H).
Compound 78: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0388] Trimethyl-1,3,5,2,4,6-trioxatripyridone (350 uL, 1.23 mmol, 19.64 eq) and potassium carbonate (51 mg, 0.5 mg) were added into a stirred mixture of the compound 78-3 (32 mg, 0.062 mmol, 1.00 eq) and dioxane (3 mL) of and H2O (0.3 mL) of Pd(dppf)Cl.sub.2 (8 mg, 0.01 mmol, 0.18 eq), and the obtained mixture was stirred under argon protection at 120 C. for 12 h. The mixture was cooled to room temperature and diluted with EtOAc (50 mL). The obtained mixture was washed with saline (530 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. A filtrate was concentrated at a reduced pressure. A crude product was purified by Prep-HPLC to obtain the yellow solid compound 78 (3.1 mg, 9.9%).
[0389] LC-MS m/z (ESI): 448.2[M+H].sup.+ 0.1H NMR (300 MHz, DMSO-d.sub.6) 12.00 (s, 1H), 10.53 (s, 1H), 8.21 (s, 1H), 7.72-7.40 (m, 3H), 7.27 (d, J=8.3, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.84 (s, 1H), 5.30-5.16 (m, 2H), 4.48-4.23 (m, 1H), 4.10-3.90 (m, 1H), 2.45 (s, 3H).
Example 79
Compound 79: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00217##
79-1: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(4-chloro-3-fluorobenzyl)imidazolidine-2,4-dione
[0390] By using the method for the compound 1, the yellow solid compound 79-1 (2.1 g, 90.3%) was prepared by using the compound 77-1 and 6-chloro-1H-indole-3-formaldehyde.
[0391] LC-MS m/z (ESI): 402.0[MH].sup..
79-2: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chloro-3-fluorophenyl)acetaldehyde
[0392] By using the method for the compound 33, the yellow solid compound 79-2 (210 mg, 36.1%) was prepared by using the compound 79-1.
[0393] LC-MS m/z (ESI): 432.0[M+H].sup.+.
79: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0394] By using the method for the compound 37, the yellow solid compound 79 (40.2 g, 39.2%) was prepared by using the compound 79-2.
[0395] LC-MS m/z (ESI): 431.8[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.97 (s, 1H), 10.50 (s, 1H), 8.19 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.65-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.27 (d, J=8.3, 1H), 7.14 (d, J=8.5, 1H), 6.85 (s, 1H), 5.30-5.15 (m, 2H), 4.40-4.18 (m, 1H), 4.10-3.90 (m, 1H).
Example 84
Compound 84: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00218##
84-1: 3-(4-fluorobenzyl)imidazolidine-2,4-dione
[0396] By using the method for the compound I-1, the white solid compound 84-1 (4.12 g, 77.9%) was prepared by using the hydantoin and 4-(bromomethyl)-1,2-difluorbenzene.
[0397] LC-MS m/z (ESI): 207.0 [MH].sup..
84-2: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(4-fluorobenzyl)imidazolidine-2,4-dione
[0398] By using the method for the compound 1, the yellow solid compound 84-2 (1.1 g, 79.7%) was prepared by using the compounds 84-1 and I-10.
[0399] LC-MS m/z (ESI): 386.0 [MH].sup..
84-3: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-fluorophenyl)acetaldehyde
[0400] By using the method for the compound 33, the yellow solid compound 84-3 (340 mg, 61.45%) was prepared by using the compound 84-2.
[0401] LC-MS m/z (ESI): 414.0[MH].sup..
Compound 84: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0402] By using the method for the compound 37, the yellow solid compound 84 (28.0 mg, 28.2%) was prepared by using the compound 84-3.
[0403] LC-MS m/z (ESI): 418.1[M+H].sup.+ 0.1H NMR (400 MHz, DMSO-d.sub.6) 12.52 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.71-7.61 (m, 1H), 7.60-7.35 (m, 2H), 7.34-7.10 (m, 3H), 6.81 (s, 1H), 5.25-5.15 (m, 2H), 4.50-4.30 (m, 1H), 3.97-3.88 (m, 1H).
Example 85
Compound 85: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00219##
85-1: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-oxyethyl)benzonitrile
[0404] By using the method for the compound 33, the brown solid compound 85-1 (120 mg, 23.0%) was prepared by using the compound 16.
[0405] LC-MS m/z (ESI): 423.1[M+H].sup.+.
Compound 85: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
[0406] By using the method for the compound 37, the yellow solid compound 85 (38.1 mg, 31.1%) was prepared by using the compound 85-1.
[0407] LC-MS m/z (ESI): 423.1[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.53 (s, 1H), 10.59 (s, 1H), 8.26 (s, 1H), 7.89-7.79 (m, 2H), 7.71-7.61 (m, 3H), 7.24-7.19 (m, 1H), 6.83 (s, 1H), 5.31-5.24 (m, 2H), 4.37-4.29 (m, 1H), 4.06-3.99 (m, 1H).
Example 86
Compound 86: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
##STR00220##
86-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetaldehyde
[0408] By using the method for the compound 33, the brown solid compound 86-1 (240 mg, 33.5%) was prepared by using the compound 10.
[0409] LC-MS m/z (ESI): 434.0[M+H].sup.+.
Compound 86: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione
[0410] By using the method for the compound 37, the yellow solid compound 86 (90 mg, 46.4%) was prepared by using the compound 86-1.
[0411] LC-MS m/z (ESI): 434.1[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.52 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.57-7.38 (m, 2H), 7.30-7.17 (m, 2H), 6.82 (s, 1H), 5.25-5.16 (m, 2H), 4.40-4.25 (m, 1H), 4.00-3.90 (m, 1H).
Example 88
Compound 88: (Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00221##
88-1: 7-bromo-6-chloro-1H-indole-3-formaldehyde
[0412] By using the method for the compound 1-10, the light brown solid compound 88-1 (4.45 g, 68.9%) was prepared by using 7-bromo-6-chloro-1H-indole.
[0413] LC-MS m/z (ESI): 257.9[M+H].sup.+.
88-2: (Z)-4-((4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile
[0414] By using the method for the compound 1, the yellow solid compound 88-2 (5.0 g, 96.9%) was prepared by using the compound 88-1.
[0415] LC-MS m/z (ESI): 454.9[M+H].sup.+.
88-3: (Z)-4-(1-(4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-oxyethyl)benzonitrile
[0416] By using the method for the compound 33, the brown solid compound 88-3 (320 mg, 14.9%) was prepared by using the compound 88-2.
[0417] LC-MS m/z (ESI): 482.9[M+H].sup.+.
88-4: (Z)-4-(1-(4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
[0418] By using the method for the compound 37, the yellow solid compound 88-4 (120 mg, 46.7%) was prepared by using the compound 88-3.
[0419] LC-MS m/z (ESI): 485.0 [M+H].sup.+.
Compound 88: (Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
[0420] Pd(dppf)Cl.sub.2 (18.1 mg, 0.025 mmol, 0.10 eq) and K.sub.2CO.sub.3 (204 mg, 1.48 mmol, 6.00 eq) were added into a stirred mixture of the compound 88-4 (120 mg, 0.25 mmol, 1.00 eq) and trimethyl-1,3,5,2,4,6-trioxaterphenyl (186 mg, 1.48 mmol, 6.00 eq) in 1,4-dioxane (12 mL) and water (0.3 mL), and the obtained mixture was stirred under argon protection at 120 C. for 6 h. The mixture was cooled to room temperature and the reaction was terminated at room temperature with water. The obtained mixture was extracted with EtOAc (330 mL). Combined organic layers were washed with saline (330 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. A filtrate was concentrated at a reduced pressure. A crude product was purified by Prep-HPLC to obtain the yellow solid compound 88 (19.3 mg, 18.2%).
[0421] LC-MS m/z (ESI): 421.1[M+H].sup.+ 0.1H NMR (400 MHz, DMSO-d.sub.6) 12.00 (s, 1H), 10.55 (s, 1H), 8.21 (s, 1H), 7.85-7.83 (m, 2H), 7.65-7.60 (m, 3H), 7.15 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.30-5.26 (m, 1H), 4.35-4.30 (m, 1H), 4.04-3.99 (m, 1H), 2.50 (s, 3H).
Example 92
Compound 92: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrophosphate
##STR00222##
[0422] By using the method for the compound 42, the yellow solid compound 92 (44.7 mg, 24.6%) was prepared by using the compound 88.
[0423] LC-MS m/z (ESI): 499.1[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.04 (s, 1H), 8.23 (s, 1H), 7.85-7.75 (m, 2H), 7.69-7.56 (m, 3H), 7.13 (d, J=8.5 Hz, 1H), 6.83 (s, 1H), 5.55-5.39 (m, 1H), 4.54-4.36 (m, 2H), 2.52 (s, 3H).
Example 93
Compound 93: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)ethyl dihydrophosphate
##STR00223##
[0424] By using the method for the compound 42, the yellow solid compound 93 (232.5 mg, 45.0%) was prepared by using the compound 69.
[0425] LC-MS m/z (ESI): 511.9[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.63 (s, 1H), 8.26 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.52-7.38 (m, 4H), 7.30-7.15 (m, 1H), 6.84 (s, 1H), 5.50-5.32 (m, 1H), 4.90-4.67 (m, 1H), 4.55-4.36 (m, 1H).
Example 94
Compound 94: (S,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)dihydroethyl phosphate
##STR00224##
[0426] By using the method for the compound 42, the yellow solid compound 94 (16.4 mg, 0.032 mmol) was prepared by using the compound 53.
[0427] LC-MS m/z (ESI): 498.1 [M+H].sup.+ 0.1H NMR (400 MHz, DMSO-d.sub.6) 12.04 (s, 1H), 8.19 (s, 1H), 7.83-7.77 (d, J=8.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.54-7.45 (m, 1H), 7.29-7.25 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 5.40-5.31 (m, 1H), 4.52-4.47 (m, 2H).
Example 95
Compound 95: (R,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)dihydroethyl phosphate
##STR00225##
[0428] By using the method for the compound 42, the yellow solid compound 95 (21.2 mg, 0.042 mmol) was prepared by using the compound 54.
[0429] LC-MS m/z (ESI): 498.1 [M+H].sup.+ 0.1H NMR (400 MHz, DMSO-d.sub.6) 12.04 (s, 1H), 8.19 (s, 1H), 7.83-7.77 (d, J=8.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.54-7.45 (m, 1H), 7.29-7.25 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 5.40-5.31 (m, 1H), 4.52-4.47 (m, 2H).
Example 96
Compound 96: (R,Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00226##
[0430] The compound 88 (60 mg, 0.14 mmol, 1.0 equiv) was separated by a chiral column: CHIRALPAKIG-34.6*50 mm 3 um; Mobile Phase A: MtBE (0.1% DEA): EtOH=93: 7; Flow rate: 1.0 mL/min mL/min; Gradient: isocratic; Injection Volume: 1.0 L mL to finally obtain the yellow solid compound 96 (17.0 mg, 29.1%).
[0431] LC-MS m/z (ESI): 419.1[MH]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.00 (s, 1H), 10.55 (s, 1H), 8.24-8.19 (m, 1H), 7.88-7.81 (m, 2H), 7.67-7.58 (m, 3H), 7.19-7.12 (m, 1H), 6.84 (s, 1H), 5.32-5.22 (m, 2H), 4.39-4.28 (m, 1H), 4.07-3.97 (m, 1H), 2.52 (s, 3H).
Example 97
Compound 97: (S,Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile
##STR00227##
[0432] The compound 88 (60 mg, 0.14 mmol, 1.0 equiv) was separated by a chiral column: CHIRALPAKIG-34.6*50 mm 3 um; Mobile Phase A: MtBE (0.1% DEA): EtOH=93: 7; Flow rate: 1.0 mL/min mL/min; Gradient: isocratic; Injection Volume: 1.0 L mL to finally obtain the yellow solid compound 97 (23.3 mg, 39.8%).
[0433] LC-MS m/z (ESI): 419.1[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.00 (s, 1H), 10.55 (s, 1H), 8.24-8.19 (m, 1H), 7.88-7.81 (m, 2H), 7.67-7.58 (m, 3H), 7.19-7.12 (m, 1H), 6.84 (s, 1H), 5.32-5.22 (m, 2H), 4.39-4.28 (m, 1H), 4.07-3.97 (m, 1H), 2.52 (s, 3H).
Example 98: Compound 98: (Z)-3-(4-chloro-2-fluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00228##
98-1: 3-(4-chloro-2-fluorobenzyl)imidazolidine-2,4-dione
[0434] By using the method for the compound I-1, the offwhite solid compound 98-1 (2.2 g, 66.1%) was prepared by using 1-(bromomethyl)-4-chloro-2-fluorobenzene and hydantoin.
[0435] LC-MS m/z (ESI): 241.0[MH].sup..
Compound 98: (Z)-3-(4-chloro-2-fluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0436] By using the method for the compound 1, the light yellow solid compound 98 (36.3 mg, 16.2%) was prepared by using 98-1 and I-10.
[0437] LC-MS m/z (ESI): 420.1[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.60 (s, 1H), 8.26 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.36-7.34 (m, 1H), 7.30-7.27 (m, 1H), 7.25-7.20 (m, 1H), 6.85 (s, 1H), 4.72 (s, 2H).
Example 99: Compound 99: (Z)-3-(1-(4-chloro-2-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00229##
99-1: (Z)-2-(4-chloro-2-fluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde
[0438] By using the method for the compound 33, the brown solid compound 99-1 (120 mg, 33.1%) was prepared by using the compound 98.
[0439] LC-MS m/z (ESI): 450.0[M+H].sup.+.
Compound 99: (Z)-3-(1-(4-chloro-2-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0440] By using the method for the compound 37, the yellow solid compound 99 (32.5 mg, 30.8%) was prepared by using the compound 99-1.
[0441] LC-MS m/z (ESI): 450.1[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.53 (s, 1H), 10.55 (s, 1H), 8.24 (s, 1H), 7.67-7.62 (m, 2H), 7.46-7.44 (m, 1H), 7.34-7.32 (m, 1H), 7.23-7.21 (m, 1H), 6.80 (s, 1H), 5.45-5.41 (m, 1H), 5.30-5.27 (m, 1H), 4.40-4.20 (m, 1H), 3.99-3.81 (m, 1H).
Example 100: Compound 100: (Z)-3-(4-chloro-2,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00230##
100-1: 3-(4-chloro-2,5-difluorobenzyl)imidazolidine-2,4-dione
[0442] By using the method for the compound 1-1, the light yellow solid compound 100-1 (1.8 g, 78.5%) was prepared by using hydantoin and 1-(bromomethyl)-4-chloro-2,5-difluorobenzene.
[0443] LC-MS m/z (ESI): 259.0[MH].sup..
Compound 100: (Z)-3-(4-chloro-2,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0444] By using the method for the compound 1, the light yellow solid compound 100 (45.6 mg, 19.5%) was prepared by using the compounds 100-1 and I-10.
[0445] LC-MS m/z (ESI): 438.0[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.60 (s, 1H), 8.26 (s, 1H), 7.69-7.66 (m, 2H), 7.50-7.42 (m, 1H), 7.28-7.17 (m, 1H), 6.85 (s, 1H), 4.72 (s, 2H).
Example 101: Compound 101: (Z)-3-(1-(4-chloro-2,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00231##
101-1: (Z)-2-(4-chloro-2,5-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde
[0446] By using the method for the compound 33, the brown solid compound 101-1 (200 mg, 56.0%) was prepared by using the compound 100.
[0447] LC-MS m/z (ESI): 466.0[MH].sup..
Compound 101: (Z)-3-(1-(4-chloro-2,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0448] By using the method for the compound 37, the yellow solid compound 101 (24.3 mg, 14.2%) was prepared by using the compound 101-1.
[0449] LC-MS m/z (ESI): 468.1[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.56 (s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 3H), 7.23-7.18 (m, 1H), 6.81 (s, 1H), 5.44-5.39 (m, 1H), 5.34-5.20 (m, 1H), 4.28-4.19 (m, 1H), 3.96-3.85 (m, 1H).
Example 102: Compound 102: (Z)-3-(4-chloro-2,6-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00232##
102-1: 3-(4-chloro-2,6-difluorobenzyl)imidazolidine-2,4-dione
[0450] By using the method for the compound I-1, the white solid compound 102-1 (1.3 g, 56.9%) was prepared by using hydantoin and 2-(bromomethyl)-5-1,3-difluorobenzene.
[0451] LC-MS m/z (ESI): 259.0[MH].sup..
Compound 102: (Z)-3-(4-chloro-2,6-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0452] By using the method for the compound 1, the light yellow solid compound 102 (41.4 mg, 18.3%) was prepared by using the compounds 102-1 and I-10.
[0453] LC-MS m/z (ESI): 438.0[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.52 (s, 1H), 10.50 (s, 1H), 8.23 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.42-7.32 (m, 2H), 7.22-7.18 (m, 1H), 6.80 (s, 1H), 4.76 (s, 2H).
Example 103: Compound 103: (Z)-3-(1-(4-chloro-2,6-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00233##
103-1: (Z)-2-(4-chloro-2,6 difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde
[0454] By using the method for the compound 33, the brown solid compound 103-1 (160 mg, 36.8%) was prepared by using the compound 102.
[0455] LC-MS m/z (ESI): 468.2[M+H].sup.+.
Compound 103: (Z)-3-(1-(4-chloro-2,6-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0456] By using the method for the compound 37, the light yellow solid compound 103 (23.3 mg, 12.48%) was prepared by using the compound 103-1.
[0457] LC-MS m/z (ESI): 468.1[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.51 (s, 1H), 10.48 (s, 1H), 8.22 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.42-7.29 (m, 2H), 7.23-7.10 (m, 1H), 6.77 (s, 1H), 5.50-5.30 (m, 1H), 5.28-5.10 (m, 1H), 4.50-4.15 (m, 1H), 4.10-3.90 (m, 1H)
Example 104: Compound 104: (Z)-3-(4-chloro-2,3-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00234##
104-1: 3-(4-chloro-2,3-difluorobenzyl)imidazolidine-2,4-dione
[0458] By using the method for the compound I-1, the white solid compound 104-1 (0.9 g, 3.3 mmol, 79.0%) was prepared by using hydantoin and 1-(bromomethyl)-4-chloro-2,3-difluorobenzene.
[0459] LC-MS m/z (ESI): 259.0[MH].sup..
Compound 104: (Z)-3-(4-chloro-2,3-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0460] By using the method for the compound 1, the yellow solid compound 104 (41.6 mg, 16.2%) was prepared by using the compounds 104-1 and I-10.
[0461] LC-MS m/z (ESI): 438.0[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.59 (s, 1H), 8.25 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.52-7.38 (m, 1H), 7.28-7.16 (m, 2H), 6.86 (s, 1H), 4.77 (s, 2H)
Example 105: Compound 105: (Z)-3-(1-(4-chloro-2,3-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00235##
105-1: (Z)-2-(4-chloro-2,3-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde
[0462] By using the method for the compound 33, the brown solid compound 105-1 (257 mg, 55.3%) was prepared by using the compound 104.
[0463] LC-MS m/z (ESI): 468.0[M+H].sup.+.
Compound 105: (Z)-3-(1-(4-chloro-2,3-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0464] By using the method for the compound 37, the light yellow solid compound 105 (20.5 mg, 22.8%) was prepared by using the compound 105-1.
[0465] LC-MS m/z (ESI): 468.1[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.54 (s, 1H), 10.58 (s, 1H), 8.24 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.55-7.36 (m, 2H), 7.34-7.11 (m, 1H), 6.81 (s, 1H), 5.61-5.40 (m, 1H), 5.39-5.20 (m, 1H), 4.50-4.20 (m, 1H), 4.05-3.85 (m, 1H).
Example 106: Compound 106: (Z)-3-(4-chloro-3,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00236##
106-1: 3-(4-chloro-3,5-difluorobenzyl)imidazolidine-2,4-dione
[0466] By using the method for the compound I-1, the white solid compound 106-1 (1.82 g, 83.2%) was prepared by using the hydantoin and 5-(bromomethyl)-2-chloro-1,3-difluorbenzene.
[0467] LC-MS m/z (ESI): 259.0[MH].sup..
Compound 106: (Z)-3-(4-chloro-3,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0468] By using the method for the compound 1, the gray solid compound 106 (38.0 mg, 16.5%) was prepared by using the compounds 106-1 and I-10.
[0469] LC-MS m/z (ESI): 438.0[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.55 (s, 1H), 10.59 (s, 1H), 8.27 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.40-7.29 (m, 2H), 7.28-7.10 (m, 1H), 6.86 (s, 1H), 4.72 (s, 2H).
Example 107: Compound 107: (Z)-3-(1-(4-chloro-3,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
##STR00237##
107-1: (Z)-2-(4-chloro-3,5-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde
[0470] By using the method for the compound 33, the brown solid compound 107-1 (180 mg, 34.02%) was prepared by using the compound 106.
[0471] LC-MS m/z (ESI): 466.0[MH].sup..
Compound 107: (Z)-3-(1-(4-chloro-3,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione
[0472] By using the method for the compound 37, the yellow solid compound 107 (31.1 mg, 24.7%) was prepared by using the compound 107-1.
[0473] LC-MS m/z (ESI): 468.1[MH].sup.. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.90-10.50 (br, 1H), 8.26 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.30-7.16 (m, 1H), 6.82 (s, 1H), 5.45-5.17 (m, 2H), 4.4-4.12 (m, 1H), 4.10-3.85 (m, 1H)
Example 108: Compound 108: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-3-hydroxypropyl)imidazolidine-2,4-dione
##STR00238##
108-1: tert-butyl (3-(4-chlorophenyl)propoxyl)dimethylsilane
[0474] At room temperature and in a nitrogen atmosphere, TEA (8.9 g, 87.95 mmol, 3.00 eq) was added in batches into a stirred solution of 3-(4-chlorophenyl)-1-propanol (5 g, 29.30 mmol, 1.00 eq) and DMAP (0.36 g, 2.95 mmol, 0.10 eq) in DCM (50 mL), and the obtained mixture was stirred in the nitrogen atmosphere at room temperature for 16 h. The obtained mixture was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to obtain the colorless liquid compound 108-1 (6.6 g, 78.5%).
108-2: (3-bromo-3-(4-chlorophenyl)propoxyl)(tert-butyl)dimethylsilane
[0475] At room temperature, a benzoylphenyl carbon peroxide (168 mg, 0.70 mmol, 0.03 eq) was added into a stirred mixture of the 108-1 (6.6 g, 23.17 mmol, 1.00 eq) and NBS (4.12 g, 23.15 mmol, 1.00 eq) in CCl.sub.4 (120 mL), and the obtained mixture was stirred for 3 h. The mixture was cooled to room temperature. The obtained mixture was filtered. A filter cake was washed with CCl.sub.4 (220 mL). A filtrate was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with PE/EA (15:1) to obtain the light brown liquid compound 108-2 (2.7 g, 25.8%).
108-3: 3-(3-((tert-butyldimethylsilyl)oxyl)-1-(4-chlorophenyl)propyl)imidazolidine-2,4-dione
[0476] At room temperature, the 108-2 (2.7 g, 7.42 mmol, 1.00 eq) was added into a mixture of hydantoin (2.23 g, 22.28 mmol, 3.00 eq) and K.sub.2CO.sub.3 (1.54 g, 11.13 mmol, 1.50 eq) in DMF (54 mL). In a nitrogen atmosphere, the obtained mixture was stirred at 60 C. for 16 h. The mixture was cooled to room temperature. A cold saturated ammonium chloride aqueous solution (200 mL) was added to terminate the reaction. The obtained mixture was extracted with ethyl acetate (3150 mL). Combined organic layers were washed with saline (2100 mL) and dried with anhydrous Na.sub.2SO.sub.4. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by fast reversed-phase chromatography to obtain the light yellow syrupy compound 108-3 (1.5 g, 47.0%).
[0477] LC-MS m/z (ESI): 383.1[M+H].sup.+.
Compound 108: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-3-hydroxypropyl)imidazolidine-2,4-dione
[0478] At room temperature, HOAc (122 mg, 2.03 mmol, 5.00 eq) was dropwise added into a stirred solution of 108-3 (186 mg, 0.49 mmol, 1.20 eq) and 6-chloro-7-fluoro-1H-indole-3-formaldehyde (80 mg, 0.41 mmol, 1.00 eq) in ethanol (10 mL). In an argon atmosphere, the obtained mixture was stirred at 100 C. for 16 min and cooled to room temperature. The obtained mixture was concentrated at a reduced pressure. A residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to obtain a brown syrupy crude product. The residue was dissolved in methanol (2 mL). A methanol solution (0.51 mL, 2.04 mmol, 5.04 eq) was dropwise added into the mixture at room temperature. The obtained mixture was then stirred at room temperature for 2 h, and the obtained mixture was concentrated in vacuum. The crude product (50 mg) was purified by HPLC to obtain the yellow solid compound 108 (12.5 mg, 6.11%).
[0479] LC-MS m/z (ESI): 446.0[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (s, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.51-7.40 (m, 4H), 7.30-7.16 (m, 1H), 6.79 (s, 1H), 5.50-5.22 (m, J=9.4, 6.4 Hz, 1H), 4.64 (s, 1H), 3.46-3.42 (m, 2H), 2.71-2.56 (m, 1H), 2.34-2.22 (m, 1H).
Example 109: compound 109: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-4-hydroxybutyl)imidazolidine-2,4-dione
##STR00239##
109-1: tert-butyl(Z)-4-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-4-(4-chlorophenyl)butyrate
[0480] At 78 C. and in an argon atmosphere, n-BuLi (4.2 mL, 10.50 mmol, 10.11 eq) was dropwise added into a stirred solution of the compound 15 (420 mg, 1.04 mmol, 1.00 eq) and tert-butyl 2-acrylate (2.66 g, 20.78 mmol, 20.00 eq) in THF (140 mL). In the argon atmosphere, the obtained mixture was stirred at 78 C. for 1 h. At 82 C., the reaction was quenched with a solution of THF in acetic acid. The mixture was heated to 30 C. and the obtained mixture was poured into 300 mL of water. The obtained mixture was extracted with ethyl acetate (1300 mL). Combined organic layers was washed with saline (2150 mL) and dried with anhydrous Na.sub.2SO.sub.4. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by fast reversed-phase chromatography to obtain the light yellow solid compound 109-1 (305 mg, 53.2%).
[0481] LC-MS m/z (ESI): 530.2[MH].sup..
109-2: (Z)-4-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-4-(4-chlorophenyl)butyric acid
[0482] At room temperature, TFA (3 mL) was dropwise added into a stirred solution of 109-1 (300 mg, 0.56 mmol, 1.00 eq) in DCM (20 mL), and the obtained mixture was stirred at room temperature for 2 h. The obtained mixture was concentrated in vacuum. A residue was purified by fast reversed-phase chromatography to obtain the yellow solid compound 109-2 (135 mg, 49.8%).
[0483] LC-MS m/z (ESI): 476.1[M+H].sup.+.
Example 109: Compound 109: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-4-hydroxybutyl)imidazolidine-2,4-dione
[0484] At room temperature and in a nitrogen atmosphere, TiCl.sub.4 (8.4 mg, 0.04 mmol, 0.20 eq) was dropwise added into a mixture of 109-2 (105 mg, 0.22 mmol, 1.00 eq) and ammonia borane (13.7 mg, 0.44 mmol, 2.01 eq) in ether (2.8 mL), and the obtained mixture was stirred in the nitrogen atmosphere at room temperature for 2 h. A saturated ammonium chloride (20 mL) solution was added at room temperature to terminate the reaction. The obtained mixture was extracted with ethyl acetate (450 mL). Combined organic layers were washed with saline (250 mL) and dried with anhydrous Na.sub.2SO.sub.4. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A crude product was purified by HPLC to obtain the yellow solid compound 109 (50.6 mg, 48.9%).
[0485] LC-MS m/z (ESI): 460.0[MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.04 br, 1H), 10.63 (br, 1H), 8.24 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.55-7.35 (m, 4H), 7.30-7.10 (m, 1H), 6.81 (s, 1H), 5.22-5.10 (m, 1H), 4.55-4.31 (m, 1H), 3.5-3.41 (m, 2H), 2.49-2.37 (m, 1H), 2.30-2.10 (m, 1H), 1.51-1.30 (m, 2H)
Compound 110: (Z)-3-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-3-(4-chlorophenyl)propyl dihydrophosphate
##STR00240##
[0486] At 0 C. and in a nitrogen atmosphere, phosphoryl chloride (513 mg, 3.35 mmol, 10.00 eq) was added into a stirred solution of the compound 108 (150 mg, 0.34 mmol, 1.00 eq) in THF (9 mL). In the nitrogen atmosphere, the obtained mixture was stirred at room temperature for 7 h. The reaction was quenched with a saturated NaHCO.sub.3 solution at room temperature, and the obtained mixture was stirred for 30 min. The mixture was acidized with HCl (aqueous solution) till pH=2 and extracted with EtOAc (350 mL). Combined organic layers were washed with saline (250 mL) and dried with anhydrous Na.sub.2SO.sub.4. After the organic layers were filtered, a filtrate was concentrated at a reduced pressure. A residue was purified by fast reversed-phase chromatography to obtain the yellow solid compound 110 (39.2 mg, 21.9%).
[0487] LC-MS m/z (ESI): 528.0[M+H].sup.+ 0.1H NMR (300 MHz, DMSO-d.sub.6)) 8.24 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.51-7.35 (m, 4H), 7.25-7.11 (m, 1H), 6.79 (s, 1H), 5.45-5.21 (m, 1H), 3.70-3.60 (m, 2H), 2.70-2.51 (m, 1H), 2.45-2.40 (m, 1H).
Test Example 1: Activity Determination for Compounds
Test of Candidate Compounds on Growth Inhibition of Cells Determined by CellTiter Glo
[0488] Candidate compounds were dissolved in DMSO, with an initial concentration of 50 mM, and were diluted to a 384-well storage plate at a triple gradient. The compounds in the storage plate were pumped into a 96-well cell culture plate (Corning 3610) with an Echo 520 instrument, with a volume of 100 nL/well, and were diluted at a triple gradient in duplicate. Blood cancer cells RS4; 11 were inoculated into the 96-well cell culture plate through Multidrop 3000 cells per well, with a volume of 100 L. The final compound concentration ranged from 50 M to 0.01 M at 9 concentration gradients and the DMSO final concentration was 0.1%. The cells and compounds were co-incubated in a cell incubator at 37 C. for 72 h, a CellTiter-Glo Luminescent Cell Viability Assay reagent was added 100 L/well, the cells and compound were uniformly mixed and incubated at room temperature for 10 min, and Envision reading was performed. A sample treated with 50 M of a positive compound was taken as a positive control and a sample treated with 100 nL of DMSO was taken as a negative control. A calculation formula was as follows: (sample reading-positive control reading)/(negative control reading-positive control reading)*100%, and IC.sub.50 was calculated by a four-parameter formula. The cell viability IC.sub.50 intervals of the compounds were as follows: A1 M, 1B10 M, C>10 M.
HTRF Test: Test of Respectively Detecting Inhibition of Candidate Compounds on MDM2-p53 and MDMX-p53 Protein Binding
[0489] Candidate compounds were dissolved in DMSO, with an initial concentration of 50 mM, and were diluted to a 384-well storage plate at a triple gradient. The compounds in the storage plate were pumped into a 384-well cell culture plate (PE 6008280) with an Echo 520 instrument, with a volume of 100 nL/well, and were diluted at a triple gradient in duplicate. Proteins and/or polypeptides were respectively diluted with HTRT buffer solutions (1PBS pH 7.4, 0.1% BSA and 1 mM DTT) as follows: An MDM2-p53 reaction system was purified 10 nM GST-MDM2 (2-138 aa) and 5 nM HIS-p53 (2-312 aa) proteins; an MDMX reaction system was 5 nM GST-MDMX (2-134 aa) proteins and 100 nM WI HIS-p53 peptide fragments (Rui Biotech). Proteins in a negative control group in the MDM2-p53 binding inhibition test were 10 nM GST proteins and 5 nM HIS-p53 (2-312 aa) proteins, proteins in a negative control group in the MDMX-p53 binding inhibition test were 10 nM GST proteins and 100 nM WT HIS-p53 peptide fragments, and positive control groups in the above two binding tests were DMSO treated groups. 10 L of the above proteins and/or polypeptide reaction system were respectively added into the 384-well plate with the added compounds through multidrop. The final compound concentration ranged from 250 IIM to 0.05 nM, they were diluted at a triple gradient, with 15 concentrations in duplicate. The DMSO final concentration was 1%, and they were incubated at room temperature for 1 h. Anti 6HIS-Tb cryptate Gold (Cisbio 61HI2TLF) and Anti GST-XL665 (Cisbio 61GSTXLF) diluted at 400 times were added into the above buffer solution, and they were uniformly mixed. The antibody mixed solution was added into the 384-well plate through multidrop 10 L/well, and was incubated at room temperature for 1 h. Data was read by Envision. The wavelength of laser-excited light was 340 nM, readings with the wavelengths of emitted light of 665 nM and 615 nM were respectively read, and a 665/615 ratio was calculated. A known MDM2-p53 binding inhibitor Siremadlin (NVP-HDM201; MCE HY-18658) was the positive control group. 100 nL of DMSO treated group was the negative control group. A calculation formula was as follows: (sample reading-positive control reading)/(negative control reading-positive control reading)*100%, and IC.sub.50 was calculated by a four-parameter formula. The protein binding IC.sub.50 intervals of the compounds were as follows: A10 nM; 10<B100 nM; C>100 nM.
TABLE-US-00002 HTRF test CellTiter Glo test MDM2 MDMX RS4; 11 Examples IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (M) 1 B B B 2 B B A 3 B B A 4 B B A 5 B B B 6 B B / 7 B B / 8 B B B 9 B B C 10 B B B 11 A B B 12 B B C 13 A B C 14 A A A 15 B B A 16 A A A 17 B B A 18 B B A 19 A A A 20 B B A 21 B A A 22 A B / 23 B B / 24 B B B 25 B B / 26 A A A 27 A A A 28 A A A 29 A A B 30 A A A 31 B B B 32 A A B 33 B B B 34 A B A 35 B B A 36 A B A 37 B B A 38 A B A 39 B B B 40 B C / 41 A A A 43 B B / 44 A A / 45 B B A 48 A A A 49 A B A 50 B C A 53 A A B 54 B B A 56 B B B 57 A A A 58 A A A 59 A B A 60 A A A 61 A B B 62 A B A 64 A A A 66 A A A 67 A A A 68 A A A 69 B B A 70 B B A 72 A A A 74 C B / 77 B B A 78 B B A 79 B B A 84 A A A 85 A A A 86 B B A 88 A A A 92 B B / 94 A A / 95 B B / 96 A A A 97 B B A 98 B C A 99 B B A 100 A B A 101 B C B 102 B B A 103 A C B 104 B B A 105 B B A 106 B B A 107 B B A 108 / / A 109 / / A
Test Example 2: Solubility Test
1) Preparation of a Stock Solution
[0490] A test substance and a control drug progesterone were prepared with DMSO into a 10 mM stock solution
2) Steps of Determining Solubility
[0491] 30 L 10 mM stock solution prepared from the test substance and the control drug progesterone was taken and added into bottles in corresponding positions of 96-well sample plate in a specified order. Then, 970 L of phosphate buffer with pH 7.4 was added into corresponding bottles of the sample plate. The experiments were two parallel experiments. A stirring rod was added into each bottle, and each bottle was covered with a polytetrafluoroethylene/silicon organic resin bottle plug. Then, a sample tray was placed in Eppendorf Thermomixer Comfort and vibrated at a rotating speed of 1100/min at 25 C. for 2 h. 2 h later, the bottle plug was removed, the stirring rod was taken away with a large magnet, and then samples were transferred to a filter plate from the sample plate. A vacuum pump generated a negative pressure to filter the samples. 5 L of a filtrate was transferred to a new sample plate. Then, 5 L of DMSO and 490 L of acetonitrile/water (1:1 in v/v) were added. The dilution ratio might be adjusted according to the magnitude of the solubility of the test substance or the intensity of a liquid response signal thereof.
3) Preparation of a Standard Product Solution
[0492] 15 L of the stock solution was transferred from 10 mM DMSO stock solution to an empty plate, and 485 L of DMSO was added to prepare a 300 M standard product solution. 5 L of the standard product solution was transferred from a plate of the 300 M standard product solution to another empty plate, and then 5 L of a phosphate buffer with pH 7.4 and 490 L of acetonitrile/water (1:1 in v/v) were added to obtain a standard product solution with the concentration of 3 M. The concentration of the standard product solution might be adjusted according to the intensity of the liquid response signal thereof.
4) Sample Analysis Step
[0493] A sample injection plate was placed in a sample injection tray of an automatic sample injection, and samples were evaluated through liquid analysis.
5) Data Analysis
[0494] All calculations were performed through Microsoft Excel.
[0495] Analysis and quantification of the filter of the samples were completed by qualitatively and quantitatively analyzing the peak of a standard product with known concentration through liquid chromatography-mass spectrometry. A calculation formula for solubility values of the control drug and test substance was as follows:
[0496] DF refers to the dilution ratio.
TABLE-US-00003 40
[0497] The embodiments of the technical solutions of the disclosure are exemplarily described above. It should be understood that the protection scope of the disclosure is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by persons skilled in the art within the spirit and principle of this application should fall within the scope of claims of this application.