CN111303053B - Cyclopenta [ d ] pyrimidine compound and pharmaceutically acceptable salt, solvate or prodrug thereof and application - Google Patents

Cyclopenta [ d ] pyrimidine compound and pharmaceutically acceptable salt, solvate or prodrug thereof and application Download PDF

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CN111303053B
CN111303053B CN202010179508.8A CN202010179508A CN111303053B CN 111303053 B CN111303053 B CN 111303053B CN 202010179508 A CN202010179508 A CN 202010179508A CN 111303053 B CN111303053 B CN 111303053B
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cyclopenta
dihydro
pyrimidin
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CN111303053A (en
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徐涛
卢玲
陈栋
秦玉婷
赵维峰
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Ocean University of China
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Abstract

The invention discloses a cyclopenta [ d ] group]Pyrimidine compounds, pharmaceutically acceptable salts, solvates or prodrugs thereof and applications thereof, wherein the compounds have the following structural formula:

Description

Cyclopenta [ d ] pyrimidine compound and pharmaceutically acceptable salt, solvate or prodrug thereof and application
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel cyclopenta [ d ] pyrimidine compound with antitumor activity, and pharmaceutically acceptable salt, solvate or prodrug thereof and application thereof.
Background
Renal cancer is a malignant tumor originating in the epithelial system of the urinary tubule of the renal parenchyma, and is known as renal cell carcinoma in academic terms, which is also called renal adenocarcinoma, and is referred to as renal cancer for short. The kidney cancer accounts for about 2-3% of adult malignant tumor and 80-90% of adult malignant tumor. The rising rate of renal cancer has ranked first among malignant tumors in recent years. Clinical treatment shows that kidney cancer is insensitive to radiotherapy and chemotherapy, and targeted antitumor drugs represented by VEGFR inhibitors sorafenib and sunitinib are first-line treatment drugs of late-stage kidney cancer. Although there are up to ten FDA-approved drugs for the treatment of renal cancer, these drugs have a very limited therapeutic effect on metastatic renal cancer and are susceptible to drug resistance. Therefore, finding and confirming a new target for the action of a specific drug for treating kidney cancer is a very urgent and significant task.
Hypoxia inducible factor 2a (HIF-2 a) is a transcription factor that affects the expression of a variety of genes. It is responsible for regulating the response of cells to an anaerobic environment and promoting the survival and proliferation of cells in an anaerobic environment. HIF-2a regulated genes affect a variety of physiological processes including metabolism, angiogenesis, cell proliferation, tumor metastasis, inflammation, and escape from anti-cancer immune responses. It is thought to be associated with the exacerbation of a variety of cancers, especially plays a very important role in Clear Cell Renal Cell Carcinoma (ccRCC). Therefore, the development of HIF-2a target inhibition drugs is of great significance.
There are currently few reports of HIF-2a inhibitors, with only one inhibitor PT2385 being in phase 1 clinical stage. Therefore, the development of new improved or more potent HIF-2a inhibitors is of great clinical significance for inhibiting the occurrence, metastasis and recurrence of tumors.
Disclosure of Invention
The invention aims to provide a cyclopenta [ d ] pyrimidine compound and a pharmaceutically acceptable salt, solvate or prodrug thereof and application thereof, and the cyclopenta [ d ] pyrimidine compound can be used as an HIF-2a inhibitor and can be used for treating or/and preventing HIF-2 alpha-related diseases or symptoms of mammals (including human beings).
In order to achieve the purpose, the technical scheme of the invention is as follows:
a cyclopenta [ d ] pyrimidine compound and a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound has a structure shown in formula (I):
Figure BDA0002411984510000021
wherein: r 1 Selected from aryl or heteroaryl;
R 2 selected from hydrogen or alkyl;
R 3 、R 4 selected from hydrogen, halogen or alkyl;
x is selected from oxygen, nitrogen and sulfur atoms.
In the above scheme, R is 1 Is phenyl, biphenyl, monocyclic heteroaryl, bicyclic heteroaryl or pyridyl.
In a further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halogen, cyano, C1-C4 alkyl, and C1-C4 alkoxy.
In the above scheme, R is 2 Is hydrogen or methyl.
In the above scheme, R 3 、R 4 Is hydrogen, fluorine or methyl.
Preferably, the compound is selected from the following compounds:
3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
2-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
4- (3,4- (methylenedioxy) phenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3,5-dichlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3,5-dimethoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3-fluoro-5-chlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3-fluoro-5-methoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3-fluoro-5-trifluoromethylphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- ((5-fluoropyridin-3-yl) oxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4-fluoro-3- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
4- (2,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (2,3-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) amino) benzonitrile;
4- (3,5-difluoroanilino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (2,3-difluorophenylthio) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3-fluoro-5-bromophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
3-fluoro-5- (((5R) -7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
(5R) -4- (3,5-difluorophenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
3-fluoro-5- ((7-hydroxy-6,6-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
4- (3,5-difluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
(R) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
(S) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
(R) -4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
(S) -4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
(S) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile;
(R) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile;
(S) -4- (3,5-difluorophenoxy) -6,6-difluoro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
(R) -4- (3,5-difluorophenoxy) -6,6-difluoro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol.
A pharmaceutical composition comprising a compound of any of the above and pharmaceutically acceptable salts, solvates or prodrugs thereof, and optionally one or more pharmaceutically acceptable excipients or carriers.
The application of the compound and the pharmaceutically acceptable salt, solvate or prodrug thereof in preparing medicaments for treating and/or preventing diseases or symptoms related to hypoxia inducible factor 2 alpha in mammals.
In a further embodiment, the disease or condition associated with hypoxia inducible factor 2 α is selected from the group consisting of cancer, inflammation, metabolic disease;
the cancer comprises skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, menstrual system tumor, brain tumor, and head and neck cancer; the inflammation comprises pneumonia, enteritis, nephritis, arthritis and trauma infection; the metabolic diseases comprise obesity, dyslipidemia and hyperlipidemia.
Through the technical scheme, the cyclopenta [ d ] pyrimidine compound and the pharmaceutically acceptable salt, solvate or prodrug thereof provided by the invention can effectively inhibit HIF-2a and HIF-1 beta from forming a dimer compound; has stronger in vitro binding capacity with HIF-2 alpha protein; can effectively inhibit expression of a downstream target gene VEGF of HIF-2 a.
The cyclopenta [ d ] pyrimidine compound shown in the formula (I) comprises isomers, racemes, enantiomers, diastereomers, enantiomer enrichments, deuterons, solvates and esters thereof; the compound of formula I and its isomer, racemate, enantiomer, diastereomer, enantiomer enrichment, deuteron, solvate and ester can also form solvate, such as hydrate, alcoholate and the like. The compounds may also be prodrugs or forms which release the active ingredient upon metabolic change in vivo. The selection and preparation of appropriate prodrug compounds is well within the skill of those in the art. Generally for the purposes of the present invention, the solvate forms of pharmaceutically acceptable solvents such as water, ethanol, etc. are equivalent to the non-solvate forms.
The compounds of formula (I) of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts may be prepared by reacting a compound of the invention with a suitable organic or inorganic acid.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on the vector, reference may be made to Remington, the science and practice of pharmacy,21stBd, lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
Drawings
FIG. 1 shows the results of HIF-2. Alpha. Transcriptional activity inhibition assays;
FIG. 2 is a diagram showing the inhibition of angiogenesis in zebra fish;
FIG. 3 is a statistical (. Mu.m) graph of the length of the blood vessels between the zebra fish internodes.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below.
It will be clear to those skilled in the art that the materials used and the methods of operation are well known in the art, unless otherwise specified, in the following text. Unless otherwise stated, wherein:
(1) Temperatures are expressed in degrees Celsius (. Degree. C.) and the operation is carried out at room temperature, which is generally 15-35℃, preferably 20-30℃, more preferably 20-25℃;
(2) Drying the organic solvent with anhydrous sodium sulfate, removing the solvent by vacuum evaporation with a rotary evaporator, and keeping the bath temperature not higher than 60 deg.C;
(3) The reaction process was followed by Thin Layer Chromatography (TLC);
(4) The final product has satisfactory hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR), and Mass Spectrometry (MS) data.
Example 1:
3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 1)
Figure BDA0002411984510000051
(1) 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (intermediate 1-a):
Figure BDA0002411984510000052
1,5,6,7-Tetrahydrocyclopenta [ d ] pyrimidin-4-one (6.8g, 50.0 mmol) was added to phosphorus oxychloride (60 mL), heated to 110 ℃ and stirred for 10h. TLC showed the reaction was complete, cooled to room temperature, the solvent was evaporated under reduced pressure, the residue was poured into water, the pH was adjusted to 7 with saturated sodium bicarbonate solution, ethyl acetate was added and extracted 2 times, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness to give 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (7.5 g, 98%) which was reacted directly in the next step. LCMS (ESI) m/z 155.1[ m +1].
(2) 1-oxo-4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (intermediate 1-B):
Figure BDA0002411984510000053
to a solution of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidine (5.0 g,32.5 mmol) in chloroform (80 mL) at 0 deg.C was added 77% m-chloroperoxybenzoic acid (10.1g, 58.5 mmol) in portions. Stir at room temperature overnight. TLC showed the reaction was complete, cooled to 0 deg.C and NaHCO was added 3 (25g, 196mmol) in water (100 mL) followed by addition of Na 2 CO 3 (14g, 128mmol) in water (100 mL), stirred for 0.5H, separated, the aqueous phase extracted with chloroform (100 mL), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated to dryness to give 1-oxo-4-chloro-6,7-dihydro-5H-cyclopenta [ d]Pyrimidine (5.5g, 100%) was reacted in the next step without purification.
(3) 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 1-C):
Figure BDA0002411984510000061
1-oxo-4-chloro-6,7-dihydro-5H-cyclopenta [ d]Pyrimidine (5.0 g,29.3 mmol) was added to acetic anhydride (40mL, 425mmol). Heating to 110 deg.C, stirring for 5H, TLC to show reaction completion, cooling to room temperature, evaporating solvent under reduced pressure, pouring residue into water, adjusting pH to 7 with saturated sodium bicarbonate solution, adding dichloromethane for extraction for 2 times, washing organic phase with saline, drying with anhydrous sodium sulfate, concentrating to dryness, purifying the obtained crude product by column chromatography (petroleum ether/ethyl acetate = 6:1) to obtain 4-chloro-6,7-dihydro-5H-cyclopenta [ d]Pyrimidin-7-ylethyl ester (2.7g, 43.3%). 1H NMR (400MHz, CDCl) 3 )δ8.91(s,1H),6.16(m,1H),3.10-3.16(m,1H),2.91–2.99(m,1H),2.66–2.75(m,1H),2.14(s,3H),2.06–2.12(m,1H).LCMS(ESI):m/z:213.1[M+1]。
(4) 4- (3-cyano-5-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ D ] pyrimidin-7-ylethyl ester (intermediate 1-D):
Figure BDA0002411984510000062
4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (0.50g, 2.4 mmol), 3-fluoro-5-hydroxybenzonitrile (0.39g, 2.8mmol), and potassium carbonate (0.50g, 3.6mmol) were added to DMF (15 mL). The temperature was raised to 85 ℃ and stirred overnight. TLC showed the reaction was complete, cooled to room temperature, poured into water, extracted 2 times with ethyl acetate, combined the organic phases, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness, purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give 4- (3-cyano-5-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (0.50g, 68%). 1H NMR (400MHz, CDCl3) delta 8.69 (s, 1H), 7.34 (s, 1H), 7.29 (dd, 1H), 7.26 (dd, 1H), 6.16 (m, 1H), 3.11-3.19 (m, 1H), 2.94-2.99 (m, 1H), 2.70-2.79 (m, 1H), 2.11-2.17 (m, 4H). LCMS (ESI): m/z:314.1[ M +1].
(5) 3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (compound 1):
4- (3-cyano-5-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (0.20g, 0.64mmol), lithium hydroxide monohydrate (67mg, 1.6 mmol) were added to a solution of tetrahydrofuran/water (2, 1, 10mL). Stir at room temperature overnight. TLC showed the reaction was complete, added 1M HCl solution to adjust pH to 5-6, extracted 2 times with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness, purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to give 3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (0.12g, 71%). 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.34 (s, 1H), 7.29 (dd, 1H), 7.23 (dd, 1H), 5.26 (m, 1H), 3.09-3.16 (m, 1H), 2.87-2.93 (m, 1H), 2.63-2.67 (m, 1H), 2.11-2.15 (m, 1H). LCMS (ESI): m/z:272.1[ M +1].
Example 2:
4- (3,5-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 2)
Figure BDA0002411984510000071
(1) 4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester:
Figure BDA0002411984510000072
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3,5-difluorophenol in 78.1% yield. 1H NMR (400MHz, CDCl3) delta 8.69 (s, 1H), 7.34 (s, 1H), 7.29 (dd, 1H), 7.26 (dd, 1H), 6.16 (m, 1H), 3.11-3.19 (m, 1H), 2.94-2.99 (m, 1H), 2.70-2.79 (m, 1H), 2.11-2.17 (m, 4H). LCMS (ESI): m/z:307.1[ M +1].
(2) 4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 2):
prepared in a similar manner to example 1 (5) from 4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.5% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 6.71-6.76 (m, 3H), 5.27 (m, 1H), 4.78 (s, 1H), 3.08-3.15 (m, 1H), 2.83-2.89 (m, 1H), 2.57-2.66 (m, 1H), 2.04-2.16 (m, 1H). LCMS (ESI): m/z:265.1[ M + [ 1].
Example 3
2-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 3)
Figure BDA0002411984510000081
(1) 4- (3-cyano-4-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 3-a):
Figure BDA0002411984510000082
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 2-fluoro-5-hydroxybenzonitrile in 76.5% yield. LCMS (ESI) m/z 314.1[ m +1].
(2) 2-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (compound 3):
prepared in a similar manner to example 1 (5) from 4- (3-cyano-4-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 81.5% yield. 1H NMR (400MHz, CDCl3) delta 8.62 (s, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 5.25 (m, 1H), 3.36 (s, 1H), 3.09-3.17 (m, 1H), 2.87-2.92 (m, 1H), 2.60-2.69 (m, 1H), 2.09-2.14 (m, 1H). LCMS (ESI): m/z:272.1[ m +1].
Example 4
4- (3,4- (methylenedioxy) phenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 4)
Figure BDA0002411984510000083
(1) 4- (3,4- (methylenedioxy) phenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 4-a):
Figure BDA0002411984510000084
prepared from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, sesamol in 71.2% yield using a method similar to example 1 (4). LCMS (ESI) is m/z 315.1[ m +1].
(2) 4- (3,4- (methylenedioxy) phenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 4):
prepared in a similar manner to example 1 (5) from 4- (3,4- (methylenedioxy) phenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 86.7% yield. 1H NMR (400MHz, CDCl3). Delta.8.65 (s, 1H), 6.82 (d, 1H), 6.65 (s, 1H), 6.59 (d, 1H), 6.01 (s, 1H), 5.25 (m, 1H), 4.86 (s, 1H), 3.07-3.14 (m, 1H), 2.82-2.90 (m, 1H), 2.59-2.65 (m, 1H), 2.07-2.13 (m, 1H), LCMS (ESI): m/z:273.1[ LCM +1].
Example 5:
4- (3,5-Dichlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 5)
Figure BDA0002411984510000091
(1) 4- (3,5-dichlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 5-a):
Figure BDA0002411984510000092
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3,5-dichlorophenol, in 71.8% yield. LCMS (ESI) m/z 340.1[ m +1].
(2) 4- (3,5-dichlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 5):
prepared in a similar manner to example 1 (5) from 4- (3,5-dichlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 86.7% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.27 (dd, 1H), 7.12 (d, 2H), 5.26 (m, 1H), 4.64 (s, 1H), 3.07-3.14 (m, 1H), 2.82-2.91 (m, 1H), 2.58-2.67 (m, 1H), 2.07-2.14 (m, 1H). LCMS (ESI): m/z:298.1[ M +1].
Example 6:
4- (3,5-dimethoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 6)
Figure BDA0002411984510000101
(1) 4- (3,5-dimethoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 6-a):
Figure BDA0002411984510000102
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3,5-dimethoxyphenol in 79.8% yield. LCMS (ESI) m/z 331.1[ m +1].
(2) 4- (3,5-dimethoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 6):
prepared in a similar manner to example 1 (5) from 4- (3,5-dimethoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 81.9% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 6.37 (s, 1H), 6.30 (s, 2H), 5.27 (m, 1H), 4.78 (s, 1H), 3.78 (d, 6H), 3.07-3.14 (m, 1H), 2.84-2.90 (m, 1H), 2.60-2.65 (m, 1H), 2.07-2.12 (m, 1H). LCMS (ESI): m/z:289.1[ M +1].
Example 7:
4- (3-fluoro-5-chlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 7)
Figure BDA0002411984510000103
(1) 4- (3-fluoro-5-chlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 7-a):
Figure BDA0002411984510000104
prepared from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-chlorophenol in a 73.6% yield using a method similar to example 1 (4). LCMS (ESI) m/z:324.1[ m +1].
(2) 4- (3-fluoro-5-chlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 7):
prepared in a similar manner to example 1 (5) from 4- (3-fluoro-5-chlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.5% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.01 (m, 2H), 6.86 (m, 1H), 5.27 (m, 1H), 4.86 (s, 1H), 3.07-3.15 (m, 1H), 2.83-2.91 (m, 1H), 2.59-2.67 (m, 1H), 2.07-2.16 (m, 1H). LCMS (ESI): m/z:281.3[ M +1].
Example 8:
4- (3-fluoro-5-methoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 8)
Figure BDA0002411984510000111
(1) 4- (3-fluoro-5-methoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 8-a):
Figure BDA0002411984510000112
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-methoxyphenol in 75.8% yield. LCMS (ESI) m/z 319.1[ m +1].
(2) 4- (3-fluoro-5-methoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 8):
prepared in a similar manner to example 1 (5) from 4- (3-fluoro-5-methoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.5% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 6.50-6.55 (m, 3H), 5.26 (m, 1H), 4.92 (s, 1H), 3.79 (s, 3H), 3.07-3.14 (m, 1H), 2.82-2.90 (m, 1H), 2.57-2.64 (m, 1H), 2.06-2.16 (m, 1H). LCMS (ESI): m/z:277.1[ M +1].
Example 9:
4- (3-fluoro-5-trifluoromethylphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 9)
Figure BDA0002411984510000121
(1) 4- (3-fluoro-5-trifluoromethylphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 9-a):
Figure BDA0002411984510000122
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-trifluoromethylphenol in 76.9% yield. LCMS (ESI) is m/z:357.1[ m +1].
(2) 4- (3-fluoro-5-trifluoromethylphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 9):
prepared in a similar manner to example 1 (5) from 4- (3-fluoro-5-trifluoromethylphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.5% yield. 1H NMR (400MHz, CDCl3) delta 8.65 (s, 1H), 7.27 (m, 1H), 7.24 (m, 1H), 7.15 (dt, 1H), 5.27 (m, 1H), 4.83 (s, 1H), 3.10-3.17 (m, 1H), 2.85-2.93 (m, 1H), 2.60-2.69 (m, 1H), 2.08-2.18 (m, 1H). LCMS (ESI): m/z:315.1[ M +1].
Example 10:
4- ((5-Fluoropyridin-3-Yl) oxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-Yl) -7-ol (Compound 10)
Figure BDA0002411984510000123
(1) 4- ((5-Fluoropyridin-3-yl) oxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 10-a):
Figure BDA0002411984510000124
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-hydroxypyridine in 81.5% yield. LCMS (ESI) m/z 290.1[ m +1].
(2) 4- ((5-Fluoropyridin-3-yl) oxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 10):
prepared in a similar manner to example 1 (5) from 4- ((5-fluoropyridin-3-yl) oxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 76.4% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.34 (s, 1H), 7.29 (dd, 1H), 7.25 (dd, 1H), 5.26 (m, 1H), 5.68 (s, 1H), 3.09-3.16 (m, 1H), 2.87-2.93 (m, 1H), 2.63-2.67 (m, 1H), 2.11-2.15 (m, 1H). LCMS (ESI): m/z:248.1[ M +1].
Example 11
4-fluoro-3- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 11)
Figure BDA0002411984510000131
(1) 4- (3-cyano-2-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 11-a):
Figure BDA0002411984510000132
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 4-fluoro-3-hydroxybenzonitrile in 78.5% yield. LCMS (ESI) m/z 314.1[ m +1].
(2) 4-fluoro-3- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (compound 11):
prepared in a similar manner to example 1 (5) from 4- (3-cyano-2-fluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 81.5% yield. 1H NMR (400MHz, CDCl3) delta 8.60 (s, 1H), 7.57-7.63 (m, 2H), 7.29-7.34 (m, 1H), 7.25 (dd, 1H), 5.26 (m, 1H), 4.42 (s, 1H), 3.13-3.20 (m, 1H), 2.84-2.97 (m, 1H), 2.61-2.69 (m, 1H), 2.09-2.18 (m, 1H), LCMS (ESI): m/z:272.1[ M +1].
Example 12:
4- (2,4-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 12)
Figure BDA0002411984510000141
(1) 4- (2,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 12-a):
Figure BDA0002411984510000142
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 2,4-difluorophenol in 71.1% yield. LCMS (ESI) m/z 307.1[ m +1].
(2) 4- (2,4-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 12):
prepared in a similar manner to example 1 (5) from 4- (2,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.5% yield. 1H NMR (400MHz, CDCl3) delta 8.61 (s, 1H), 7.16-7.21 (m, 1H), 6.90-6.99 (m, 2H), 7.25 (dd, 1H), 5.27 (m, 1H), 4.95 (s, 1H), 3.12-3.19 (m, 1H), 2.87-2.95 (m, 1H), 2.59-2.67 (m, 1H), 2.08-2.17 (m, 1H), LCMS (ESI): m/z:265.1[ M +1].
Example 13:
4- (3,4-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 13)
Figure BDA0002411984510000143
(1) 4- (3,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 13-a):
Figure BDA0002411984510000144
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3,4-difluorophenol in 71.6% yield. LCMS (ESI) m/z 307.1[ m +1].
(2) 4- (3,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 13):
prepared in a similar manner to example 1 (5) from 4- (3,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.8% yield. 1H NMR (400MHz, CDCl3) delta 8.63 (s, 1H), 7.20 (m, 1H), 7.01-7.06 (m, 1H), 6.88-6.93 (m, 1H), 5.26 (m, 1H), 4.09 (s, 1H), 3.08-3.15 (m, 1H), 2.83-2.91 (m, 1H), 2.58-2.67 (m, 1H), 2.03-2.13 (m, 1H), LCMS (ESI): m/z: 265.1M +1].
Example 14:
4- (2,3-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 14)
Figure BDA0002411984510000151
(1) 4- (2,3-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 14-a):
Figure BDA0002411984510000152
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 2,3-difluorophenol in 75.7% yield. LCMS (ESI) m/z 307.1[ m +1].
(2) 4- (2,3-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 14):
prepared in a similar manner to example 1 (5) from 4- (2,3-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 80.2% yield. 1H NMR (400MHz, CDCl3) delta 8.63 (s, 1H), 7.20 (m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 5.26 (m, 1H), 4.61 (s, 1H), 3.08-3.16 (m, 1H), 2.83-2.92 (m, 1H), 2.59-2.67 (m, 1H), 2.07-2.16 (m, 1H). LCMS (ESI): m/z:265.1[ M +1].
Example 15:
3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) amino) benzonitrile (compound 15)
Figure BDA0002411984510000161
(1) 4- (3-cyano-5-fluorophenylamino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 15-a):
Figure BDA0002411984510000162
4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (0.50g, 2.4 mmol), 3-fluoro-5-cyanoaniline (0.35g, 2.6 mmol) were added to isopropanol (15 mL), 2 drops of concentrated HCl were added, and the mixture was heated to 85 ℃ and refluxed overnight. TLC showed the reaction was complete, cooled to room temperature, evaporated to dryness and purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to give 4- (3-cyano-5-fluorophenylamino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (0.56g, 76%). 1H NMR (400MHz, CDCl3) delta 8.69 (s, 1H), 7.34 (s, 1H), 7.29 (dd, 1H), 7.26 (dd, 1H), 6.16 (m, 1H), 3.11-3.19 (m, 1H), 2.94-2.99 (m, 1H), 2.70-2.79 (m, 1H), 2.11-2.17 (m, 4H). LCMS (ESI): m/z:313.1[ M +1].
(2) 3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) amino) benzonitrile (compound 15):
4- (3-cyano-5-fluorophenylamino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (0.20g, 0.64mmol) lithium hydroxide monohydrate (67mg, 1.6mmol) was added to a tetrahydrofuran/water (2. Stir at room temperature overnight. TLC showed the reaction was complete, added 1M HCl solution to adjust pH to 5-6, extracted 2 times with ethyl acetate, combined the organic phases, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness, purified by column chromatography (petroleum ether/ethyl acetate = 1:1) to give 3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) amino) benzonitrile (0.12g, 71%). 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.34 (s, 1H), 7.29 (dd, 1H), 7.25 (dd, 1H), 5.26 (m, 1H), 5.68 (s, 1H), 3.09-3.16 (m, 1H), 2.87-2.93 (m, 1H), 2.63-2.67 (m, 1H), 2.11-2.15 (m, 1H). LCMS (ESI): m/z:271.1 and LCM +1].
Example 16:
4- (3,5-difluoroanilino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 16)
Figure BDA0002411984510000171
(1) 4- (3,5-difluoroanilino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-yl ethyl ester (intermediate 16-A):
Figure BDA0002411984510000172
prepared in a similar manner to example 15 (1) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3,5-difluoroaniline, in 65.7% yield. LCMS (ESI) m/z 306.1[ m +1].
(2) 4- (3,5-difluoroaniline) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 16):
prepared in a similar manner to example 15 (2) from 4- (3,5-difluoroanilino) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 80.5% yield. 1H NMR (400MHz, CDCl3) delta 8.57 (s, 1H), 7.50 (dd, 2H), 6.56 (dd, 1H), 5.00 (m, 1H), 4.56 (s, 1H), 2.93-3.00 (m, 1H), 2.70-2.78 (m, 1H), 2.47-2.53 (m, 1H), 1.92-1.99 (m, 1H). LCMS (ESI): m/z:264.1[ M +1].
Example 17:
4- (2,3-difluorophenylthio) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 17)
Figure BDA0002411984510000173
(1) 4- (2,3-difluorophenylthio) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 17-a):
Figure BDA0002411984510000174
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 2,3-difluorothiophenol, in 71.8% yield. LCMS (ESI) m/z 323.1[ m +1].
(2) 4- (2,3-difluorophenylthio) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 17):
prepared in a similar manner to example 1 (5) from 4- (2,3-difluorophenylthio) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 77.2% yield. 1H NMR (400MHz, CDCl3) delta 8.75 (s, 1H), 7.12 (dd, 2H), 6.89 (dd, 1H), 5.20 (m, 1H), 4.46 (s, 1H), 2.92-2.99 (m, 1H), 2.69-2.77 (m, 1H), 2.55-2.63 (m, 1H), 2.05-2.09 (m, 1H). LCMS (ESI): m/z:281.1[ M +1].
Example 18:
4- (3-fluoro-5-bromophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 18)
Figure BDA0002411984510000181
(1) 4- (3-fluoro-5-bromophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 18-a):
Figure BDA0002411984510000182
prepared in a similar manner to example 1 (4) from 4-chloro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-bromophenol in 73.6% yield. LCMS (ESI) m/z 368.1[ m +1].
(2) 4- (3-fluoro-5-bromophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 18):
prepared in a similar manner to example 1 (5) from 4- (3-fluoro-5-bromophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester in 82.5% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.18 (m, 2H), 6.89 (dd, 1H), 5.27 (m, 1H), 4.86 (s, 1H), 3.07-3.15 (m, 1H), 2.80-2.89 (m, 1H), 2.59-2.67 (m, 1H), 2.04-2.16 (m, 1H). LCMS (ESI): m/z:326.1[ M +1].
Example 19:
3-fluoro-5- (((5R) -7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 19)
Figure BDA0002411984510000191
(1) (2R) -2-methyl-5- (prop-2-ylidene) cyclopentanecarboxylic acid ethyl ester (intermediate 19-A):
Figure BDA0002411984510000192
to a 500mL round bottom flask was added (R) - (+) -pulegone (7.61g, 50mmol), anhydrous NaHCO3 (1.25g, 15mmol) and anhydrous ether (50 mL). The reaction mixture was cooled with an ice bath under nitrogen. Liquid bromine (2.6 mL, 50mmol) was added dropwise. The mixture was filtered and carefully added to NaOEt (21%, 42mL, 110mmol) in an ice bath. The mixture was stirred at room temperature overnight, then 100mL of 5% HC1 and 30mL of diethyl ether were added. The aqueous phase was extracted with ether (2 × 30 mL), the combined organic phases were washed with water, dried and concentrated. Semicarbazide hydrochloride (3.75g, 34mmol), naOAc (37.5g, 46mmol), ethanol (40 mL), and water (40 mL) were added to the solution, and the mixture was heated under reflux for 3 hours, followed by stirring at room temperature overnight. The mixture was treated with 100mL of water and 30mL of diethyl ether. The aqueous phase was extracted with ether (2 × 30 mL). The combined organic phases were washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by distillation under the reduced pressure (at 0.8mm Hg73-76 ℃ C.) to give ethyl (2R) -2-methyl-5- (propan-2-ylidene) cyclopentacarboxylate (6.5g, 66%). 1H NMR (400MHz, CDCl) 3 )δ3.58–3.28(m,2H),2.87–2.77(m,1H),2.59–2.45(m,1H),2.41–2.22(m,3H),2.13(d,J＝5.1Hz,6H),1.78–1.72(m,1H),1.45(d,J＝7.0Hz,3H),1.36(d,J＝7.1Hz,3H).LCMS(ESI):m/z:197.1[M+1]。
(2) (2R) -2-methyl-5-oxocyclopentanecarboxylic acid ethyl ester (intermediate 19-B):
Figure BDA0002411984510000193
ethyl (2R) -2-methyl-5- (propan-2-ylidene) cyclopentanecarboxylate (5.0 g,25.5 mmol) was added to ethyl acetate (100 mL), cooled to-68 ℃ and ozonized oxygen was passed through for 5 hours. TLC check, reaction complete, reaction mixture at room temperature with nitrogen purge until color disappeared. Ethyl acetate was removed under reduced pressure and the residue was dissolved in 30mL of acetic acid and cooled with ice water, and zinc powder (10 g) was added. The solution was stirred for 30 minutes and then filtered. The filtrate was neutralized with 2N NaOH (250 mL) and saturated NaHC03 solution, and the aqueous phase was extracted with diethyl ether (3X 50 mL). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to give ethyl (2R) -2-methyl-5-oxocyclopentate carboxylate (3.8g, 88%). 1H NMR (400MHz, CDC)l 3 )δ4.24–4.12(m,2H),2.72(d,J＝11.3Hz,1H),2.62–2.50(m,1H),2.42–2.24(m,2H),2.21–2.10(m,1H),1.39–1.50(m,1H),1.25(td,J＝7.1,1.3Hz,3H),1.17–1.12(m,3H).LCMS(ESI):m/z:171.1[M+1]。
(3) (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-ol (intermediate 19-C):
Figure BDA0002411984510000201
ethyl (2R) -2-methyl-5-oxocyclopentecarboxylate (3.0g, 17.6mmol), thiourea (1.5g, 19.7mmol), KOH (1.3g, 23.2mmol) were added to ethanol (60 mL). The mixture was heated to reflux for 10 hours. Cool and remove the solvent under reduced pressure, and the residue is adjusted to pH 1 with 3N HCl at 0 ℃ and then extracted with DCM (3 × 50 mL). The solvent was removed and purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to give (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-ol (1.9 g, 59%). LCMS (ESI) m/z 183.1[ m +1].
(4) (R) -5-methyl-6,7-dihydro-5H-cyclopenta [ D ] pyrimidin-4-ol (intermediate 19-D):
Figure BDA0002411984510000202
in the presence of (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [ d ]]Raney nickel (3.0 g) and aqueous ammonia (5 ml) were added to a suspension of pyrimidin-4-ol (1.6 g,8.8 mmol) and water (20 ml). The mixture was heated to reflux for 10h. Filtering while hot, concentrating the filtrate to obtain (R) -5-methyl-6,7-dihydro-5H-cyclopenta [ d]Pyrimidin-4-ol (1.3g, 99%). 1H NMR (400MHz, CDCl) 3 )δ8.06(s,1H),3.30(s,1H),3.04–2.73(m,2H),2.29(dd,J＝14.1,7.6Hz,1H),1.75–1.55(m,1H),1.28(s,3H).LCMS(ESI):m/z:151.1[M+1]。
(5) (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (intermediate 19-E):
Figure BDA0002411984510000203
prepared from (R) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-ol in 80.5% yield using a similar method to example 1 (1). LCMS (ESI) m/z 169.5[ m +1].
(6) (R) -1-oxo-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (intermediate 19-F):
Figure BDA0002411984510000211
prepared from (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine using a method similar to example 1 (2).
(7) (5R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 19-G):
Figure BDA0002411984510000212
prepared from (R) -1-oxo-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine in 61.6% yield using a method similar to example 1 (3). 1H NMR (400MHz, chloroform-d) Δ 8.90 (s, 1H), 6.31-5.99 (m, 1H), 3.58-3.28 (m, 1H), 2.87-2.76 (m, 1H), 2.47-2.18 (m, 2H), 2.12 (s, 3H), 1.48-1.33 (m, 3H). LCMS (ESI): m/z:227.5[ M +1].
(8) (5R) -4- (3-cyano-5-fluorophenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 19-H):
Figure BDA0002411984510000213
prepared from (5R) -4-chloro-5 methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-hydroxybenzonitrile in a yield of 81.2% by a similar method to example 1 (4). LCMS (ESI) is m/z:328.1[ m +1].
(9) 3-fluoro-5- (((5R) -7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (compound 19):
using a method similar to that of example 1 (5)The method is carried out by reacting (5R) -4- (3-cyano-5-fluorophenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d]Pyrimidin-7-ylethyl ester preparation in 80.7% yield. 1H NMR (400MHz, CDCl) 3 )δ8.65(s,1H),7.33(s,1H),7.28(d,J＝7.7Hz,1H),7.22(d,J＝9.3Hz,1H),5.39–5.12(m,1H),3.33–2.77(m,1H),2.38–2.17(m,2H),1.52–1.36(m,3H).LCMS(ESI):m/z:286.1[M+1]。
Example 20:
(5R) -4- (3,5-Difluorophenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 20)
Figure BDA0002411984510000221
(1) (5R) -4- (2,3-Difluoroxyphenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 20-A):
Figure BDA0002411984510000222
prepared from (5R) -4-chloro-5 methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester 3,5-difluorophenol in a 77.8% yield using a method similar to example 1 (4). LCMS (ESI) is m/z:321.1[ m +1].
(2) (5R) -4- (3,5-Difluorophenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 20):
using a method similar to example 1 (5), a mixture of (5R) -4- (2,3-difluorophenoxy) -5-methyl-6,7-dihydro-5H-cyclopenta [ d ] and N-tert-butyl acetate was prepared]Pyrimidin-7-ylethyl ester preparation in 76.2% yield. 1H NMR (400MHz, CDCl) 3 )δ8.66(s,1H),6.75(m,3H),5.37–5.11(m,1H),3.35–2.79(m,1H),2.40–2.16(m,2H),1.51–1.34(m,3H).LCMS(ESI):m/z:279.1[M+1]。
Example 21:
3-fluoro-5- ((7-hydroxy-6,6-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (compound 21)
Figure BDA0002411984510000223
(1) 3,3 dimethyl dimethyladipate (intermediate 21-A):
Figure BDA0002411984510000224
to a solution of 4,4-dimethylcyclohexanone (5.0 g, 40mmol) in glacial acetic acid (100 ml) was added a solution of CrO3 (12.0 g, 120mmol) in glacial acetic acid (50 ml) and water (50 ml). The mixture was stirred at 60 ℃ overnight. Cooled to room temperature and adjusted to pH 14 with 40% aq. NaOH. The mixture was washed with diethyl ether (2x 200ml) and the aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid. The solution was extracted with ether (3x 200ml) and the organic phases were combined, washed with brine, dried over anhydrous sodium sulphate and concentrated. The residue was dissolved in methanol (100 ml), thionyl chloride (4 ml) was added and the solution was warmed to 60 ℃ and stirred for 6 hours, cooled to room temperature and concentrated under reduced pressure to give the crude product which was purified by column chromatography (petroleum ether/ethyl acetate 10) to give 3,3-dimethyl adipate as a colourless oil (7.1 g, 88.6% yield).
(2) 4,4-dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (intermediate 21-B):
Figure BDA0002411984510000231
3,3-dimethyl adipate (6.0g, 29.7mmol) was added to methanol (200 ml) and toluene (20 ml), sodium metal (1.4g, 60mmol) was added, the mixture was heated under reflux overnight, cooled, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate 10) to give 4,4-dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester as colorless oil (4.3 g, 85.6% yield). LCMS (ESI) m/z 171.1[ m +1].
(3) 2-mercapto-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-ol (intermediate 21-C):
Figure BDA0002411984510000232
prepared in a similar manner to example 19 (3) from 4,4-dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester in 58.9% yield. LCMS (ESI) m/z:197.1[ m +1].
(4) 5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ D ] pyrimidin-4-ol (intermediate 21-D):
Figure BDA0002411984510000233
prepared from 2-mercapto-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-ol in a 96.5% yield using a method similar to example 19 (3). LCMS (ESI) m/z 165.1[ m +1].
(5) 4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (intermediate 21-E):
Figure BDA0002411984510000234
prepared in a similar manner to example 1 (1) from 5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-ol in 81.6% yield. LCMS (ESI) m/z 183.5[ m +1].
(6) 1-oxo-4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine (intermediate 21-F):
Figure BDA0002411984510000241
prepared from 4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidine using a method similar to example 1 (2).
(7) 4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 21-G):
Figure BDA0002411984510000242
using a method similar to example 1 (3), a reaction mixture was prepared from 1-oxo-4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d]Pyrimidine was prepared in 53.4% yield. 1H NMR (400MHz, CDCl) 3 )δ8.84(s,1H),5.91(s,1H),2.89–2.72(m,2H),1.24(s,3H),1.04(s,3H).LCMS(ESI):m/z:241.5[M+1]。
(8) 4- (3-cyano-5-fluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 21-H):
Figure BDA0002411984510000243
prepared in a similar manner to example 1 (4) from 4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester, 3-fluoro-5-hydroxybenzonitrile in 77.6% yield. LCMS (ESI) m/z 342.1[ m +1].
(9) 3-fluoro-5- ((7-hydroxy-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (compound 21):
using a method similar to example 1 (5), a solution of 4- (3-cyano-5-fluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] was prepared]Pyrimidin-7-ylethyl ester was prepared in 87.5% yield. 1H NMR (400MHz, CDCl) 3 )δ8.63(s,1H),7.33(s,1H),7.28(s,1H),7.21(s,1H),4.74(s,1H),2.84(d,J＝16.2Hz,1H),2.71(d,J＝16.3Hz,1H),1.32(s,3H),1.11(s,3H).LCMS(ESI):m/z:300.1[M+1]。
Example 22:
4- (3,5-Difluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 22)
Figure BDA0002411984510000251
(1) 4- (2,3-difluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester (intermediate 22-a):
Figure BDA0002411984510000252
prepared in a similar manner to example 1 (4) from 4-chloro-5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-ylethyl ester 3,5-difluorophenol in 76.9% yield. LCMS (ESI) m/z 335.1[ M +1].
(2) 4- (3,5-Difluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 22):
using a method similar to example 1 (5), a mixture of 4- (2,3-difluorophenoxy) -5,5-dimethyl-6,7-dihydro-5H-cyclopenta [ d ] and its derivatives]Pyrimidin-7-ylethyl ester preparation in 80.8% yield. 1H NMR (400MHz, CDCl) 3 )δ8.64(s,1H),6.75-6.70(m,3H),4.73(s,1H),2.82(d,J＝16.2Hz,1H),2.68(d,J＝16.2Hz,1H),1.31(s,3H),1.10(s,3H).LCMS(ESI):m/z:293.1[M+1]。
Example 23:
(R) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 23)
Figure BDA0002411984510000253
(1) 3-fluoro-5- ((7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (intermediate 23-a):
Figure BDA0002411984510000261
Dess-Martin oxidant (156mg, 0.40mmol) was added to the solution of 3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (100mg, 0.40mmol) in dichloromethane (50 mL) at room temperature. Stirring 1h, TLC showed the reaction was complete. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and dilute aqueous sodium thiosulphate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 3-fluoro-5- ((7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (81 mg, 81% yield). LCMS (ESI) m/z 270.1[ m +1].
(2) (R) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 23):
RuCl (p-isopropyltoluene) [ (S, S) -Ts-DPEN ] (2mg, 0.003mmol) was added to a nitrogen flushed solution of 3-fluoro-5- ((7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (10mg, 0.03mmol), formic acid (7mg, 0.15mmol), and triethylamine (0.015mL, 0.10mmol) in dichloromethane (5 mL) at 0 ℃. The reaction vial was sealed and placed in a 4 ℃ freezer overnight. TLC showed the reaction was complete and the reaction mixture was spin dried and the residue was purified by column chromatography (dichloromethane: methanol =20: 1) to give (R) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (5 mg, 50%). 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 7.35 (s, 1H), 7.29 (dd, 1H), 7.23 (dd, 1H), 5.26 (m, 1H), 3.08-3.16 (m, 1H), 2.88-2.93 (m, 1H), 2.64-2.68 (m, 1H), 2.11-2.15 (m, 1H). LCMS (ESI): m/z:272.1[ M +1].
Example 24:
(S) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (Compound 24)
Figure BDA0002411984510000262
RuCl (p-isopropyltoluene) [ (R, R) -Ts-DPEN ] (2mg, 0.003mmol) was added to a nitrogen flushed solution of 3-fluoro-5- ((7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (10mg, 0.03mmol), formic acid (7mg, 0.15mmol), and triethylamine (0.015mL, 0.10mmol) in dichloromethane (5 mL) at 0 ℃. The reaction flask was sealed and placed in a refrigerator at 4 ℃ overnight. TLC showed the reaction was complete and the reaction mixture was spin dried and the residue was purified by column chromatography (dichloromethane: methanol =20: 1) to give (S) -3- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (6 mg, 60%). 1H NMR (400MHz, CDCl3) delta 8.67 (s, 1H), 7.35 (s, 1H), 7.29 (dd, 1H), 7.23 (dd, 1H), 5.26 (m, 1H), 3.09-3.16 (m, 1H), 2.88-2.93 (m, 1H), 2.63-2.68 (m, 1H), 2.10-2.15 (m, 1H). LCMS (ESI): m/z:272.1[ M +1].
Example 25:
(R) -4- (3,5-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 25)
Figure BDA0002411984510000271
(1) 4- (3,5-difluorophenoxy) -5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one (intermediate 25-a):
Figure BDA0002411984510000272
prepared in a similar manner to example 23 (1) from 4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol in 68.8% yield. LCMS (ESI) is m/z:263.1[ m +1].
(2) (R) -4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 25):
prepared in a similar manner to example 23 (2) from 4- (3,5-difluorophenoxy) -6,6-difluoro-5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one in 78% yield. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H), 6.70-6.76 (m, 3H), 5.27 (m, 1H), 4.78 (s, 1H), 3.08-3.14 (m, 1H), 2.82-2.89 (m, 1H), 2.57-2.66 (m, 1H), 2.04-2.16 (m, 1H). LCMS (ESI): m/z:265.1[ M + [ 1].
Example 26:
(S) -4- (3,5-Difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 26)
Figure BDA0002411984510000281
Prepared in a similar manner to example 24 from 4- (3,5-difluorophenoxy) -6,6-difluoro-5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one in 81% yield. 1H NMR (400MHz, CDCl3) delta 8.65 (s, 1H), 6.70-6.76 (m, 3H), 5.27 (m, 1H), 4.78 (s, 1H), 3.08-3.14 (m, 1H), 2.82-2.88 (m, 1H), 2.58-2.66 (m, 1H), 2.04-2.16 (m, 1H). LCMS (ESI): m/z:265.1[ M + [ 1].
Example 27:
(S) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (compound 27)
Figure BDA0002411984510000282
(1) 3- ((6,6-difluoro-7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (intermediate 27-a):
Figure BDA0002411984510000283
the 3-fluoro-5- ((7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile (80mg, 0.30mmol), 3-methoxypropylamine (160mg, 1.80mmol), pivalic acid (6mg, 0.06mmol) were placed in a mixed solution of toluene (20 mL) and cyclohexane (10 mL) and heated at reflux with a connected Dean-Stark trap for 10H. Cool to room temperature, evaporate the reaction mixture to dryness and dissolve the residue in acetonitrile (10 mL). 1-chloromethyl-4-fluoro-1,4-diammonium bicyclo [2.2.2] octane bis (tetrafluoroborate) (682mg, 0.85mmol) and anhydrous sodium sulfate (86mg, 0.60mmol) were added. Heating to 70 ℃, and continuing stirring for reaction for 2h. TLC showed the reaction was complete, cooled to room temperature, and the reaction mixture was treated with 1M HCl (3 mL,3.0 mmol) and stirred at room temperature for 1h. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness, and the crude product was purified by column chromatography (dichloromethane: methanol = 30) to give 3- ((6,6-difluoro-7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (20 mg, 23% yield). LCMS (ESI) m/z 306.1[ m +1].
(2) (S) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (compound 27):
RuCl (p-isopropyltoluene) [ (R, R) -Ts-DPEN ] (2mg, 0.003mmol) was added to a nitrogen flushed solution of 3- ((6,6-difluoro-7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (10mg, 0.03mmol), formic acid (7mg, 0.15mmol), and triethylamine (0.015mL, 0.10mmol) in dichloromethane (5 mL) at 0 ℃. The reaction vial was sealed and placed in a 4 ℃ freezer overnight. TLC showed the reaction was complete and the reaction mixture was spin dried and the residue was purified by column chromatography (dichloromethane: methanol =20: 1) to give (S) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (6 mg, 60%). 1H NMR (400MHz, CDCl3) delta 8.69 (s, 1H), 7.36 (s, 1H), 7.31 (dd, 1H), 7.25 (dd, 1H), 5.50 (m, 1H), 3.29-3.46 (m, 2H),. LCMS (ESI): m/z:308.1[ M + ] 1].
Example 28:
(R) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (Compound 28)
Figure BDA0002411984510000291
RuCl (p-isopropyltoluene) [ (S, S) -Ts-DPEN ] (2mg, 0.003mmol) was added to a nitrogen purged solution of 3- ((6,6-difluoro-7-oxo-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (10mg, 0.03mmol), formic acid (7mg, 0.15mmol), and triethylamine (0.015mL, 0.10mmol) in dichloromethane (5 mL) at 0 ℃. The reaction vial was sealed and placed in a 4 ℃ freezer overnight. TLC showed the reaction was complete and the reaction mixture was spin dried and the residue was purified by column chromatography (dichloromethane: methanol =20: 1) to give (R) -3- ((6,6-difluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) -5-fluorobenzonitrile (5 mg, 50%). 1H NMR (400MHz, CDCl3) delta 8.69 (s, 1H), 7.37 (s, 1H), 7.31 (dd, 1H), 7.24 (dd, 1H), 5.51 (m, 1H), 3.28-3.44 (m, 2H),. LCMS (ESI): m/z:308.1[ M +1].
Example 29:
(S) -4- (3,5-Difluoroxyphenoxy) -6,6-difluoro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 29)
Figure BDA0002411984510000301
(1) 4- (3,5-difluorophenoxy) -6,6-difluoro-5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one (intermediate 29-a):
Figure BDA0002411984510000302
prepared in a similar manner to example 27 (1) from 4- (3,5-difluorophenoxy) -5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one in 25% yield. LCMS (ESI) m/z 299.1[ m +1].
(2) (S) -4- (3,5-Difluorophenoxy) -6,6-difluoro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (Compound 29):
prepared in a similar manner to example 27 (2) from 4- (3,5-difluorophenoxy) -6,6-difluoro-5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one in 61% yield. 1H NMR (400MHz, CDCl3) delta 8.69 (s, 1H), 6.73-6.79 (m, 3H), 5.52 (m, 1H), 3.38-3.51 (m, 2H). LCMS (ESI): m/z:301.1[ LCM ] +1].
Example 30:
(R) -4- (3,5-Difluoroxyphenoxy) -6,6-difluoro-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol (compound 30)
Figure BDA0002411984510000303
Prepared in a similar manner to example 28 from 4- (3,5-difluorophenoxy) -6,6-difluoro-5,6-dihydro-7H-cyclopenta [ d ] pyrimidin-7-one in 65% yield. 1H NMR (400MHz, CDCl3) delta 8.68 (s, 1H), 6.72-6.79 (m, 3H), 5.51 (m, 1H), 3.36-3.48 (m, 2H). LCMS (ESI): m/z:301.1[ m/Z ] +1].
Biological experiments
1.VEGF ELISA assay
786-0 cells in logarithmic growth phase were seeded in 96-well plates (Fisher Scientific) at 7500 cells per well (180. Mu.L/well), and after 4h of culture, 20. Mu.L of different concentrations of compound stock was added to each well to give final concentrations as follows (μ M): 0.01, 0.05, 0.25, 1.25, 6.25, 30. After about 20h, the medium was removed by aspiration and 180 μ L of growth medium was provided to each well. Add 20 μ L of freshly prepared stock 6 × test compound to each well. Hypoxic (1% oxygen +5% carbon dioxide +94% nitrogen) culture for 24h, the cell culture medium was removed. Then, follow the manufacturer's recommended method, adopt from R&VEGF concentrations were determined by ELISA kits purchased from D Systems. The reaction was stopped by adding 50. Mu.L of Celltiter Glo reagent to each wellAnd slightly shaking the enzyme label plate to ensure that the termination reaction is fully performed. The cell-seeded plates were subjected to CellTiter-Glo luminescent cell viability assay (Promega) and the light absorbance of each well was immediately measured at a wavelength of 450nm using a microplate reader. EC was calculated by analyzing data using a dose-response-inhibition (four parameter) equation by GraphPadPrism 50 The results are shown in Table 1.
TABLE 1 EC for selected compounds in VEGF ELISA assay 50
Figure BDA0002411984510000311
Figure BDA0002411984510000321
Note: positive control drug: PT-2385.
As shown in the experimental results in Table 1: compounds 1, 2, 5, 8, 10, 12, 23, 25, 26 all had significant activity in inhibiting VEGF expression, with compounds 2, 23, and 25 having better activity than the positive control PT-2385.
2. Testing compound interactions with HIF-2 alpha protein using the SPRi System
1) Principle of experiment
The biomolecule interaction system is a Surface Plasma Resonance Imaging (SPRi) system based on microarray technology, thousands of sampling points on a chip are shot by adopting two-dimensional CCD technology, the interaction among various biomolecules is analyzed in real time, and no mark is needed. Therefore, the specificity of molecular combination is known, the kinetic data of molecular combination is accurately calculated, and the combination process of biological molecules is known. The method is widely used for the determination of various biological systems, including the interaction among various small molecular compounds, polypeptides, proteins, oligonucleotides and saccharides. Kinetic data such as binding curves, binding, dissociation, equilibrium dissociation constants, etc. can be obtained by data Analysis and fitting with PLEXERA SPR Date Analysis Module (DAM) Analysis software.
2) Experimental methods
The compound is placed on the surface of a biochip Graft-to-PCL by means of SpotBot3 microarray control software in an Arrayit, spotBot3 needle point platform, and the compound is crosslinked on the surface of the biochip by ultraviolet light for 15 min. Diluting the initial concentration of protein at 0.1-1 μ M with PBS buffer solution according to a certain proportion, and injecting prepared compounds with different concentrations for detection. The data obtained were analyzed and fitted according to the PLEXERA SPR Date Analysis Module (DAM) Analysis software to obtain binding kinetics constants, the results of which are shown in Table 2.
Buffer (buffer): 1 XPBS
A regeneration liquid: gly-Hcl (PH = 2)
The sample introduction flow rate is 1 mul/s, and the sample introduction time is 180s; the dissociation flow rate is 1 mul/s, and the sample injection time is 200s;
the regeneration flow rate is 2 mul/s, and the regeneration time is 200s.
3) Results of the experiment
The binding constant (ka), dissociation constant (KD), and equilibrium dissociation constant (KD) for example compounds to HIF-2 α protein are shown in table 2.
TABLE 2 binding kinetics constants of Compounds to HIF-2. Alpha. Protein
Figure BDA0002411984510000322
Figure BDA0002411984510000331
As shown in the experimental results in Table 2: determining that the test compound can bind to HIF-2 alpha protein, wherein Compounds 1 and 2 have a greater binding capacity to HIF-2 alpha than the positive control PT2385.
3. Luciferase reporter gene assay (Luciferase assay) for detecting inhibition of HIF-2 alpha transcriptional activity by compounds
HEK293T17 cells were plated in 24-well plates and cultured to 50% -60% confluence. 100 mul of DMEM is put into a 1.5ml EP tube, a pcs2-HIF2 alpha-myc plasmid, a pcs2-flag plasmid (contrast), an HRE-miniP-luciferase plasmid (reflecting HIF-alpha transcriptional activity) and a Renilla luciferase reporter plasmid (internal reference) with proper volumes are added, polyetherimide (PEI) with the volume (mul) being 2-4 times of the mass (mug) of the plasmid is added, and the mixture is evenly mixed and centrifuged and is placed in a constant temperature incubator at 37 ℃ for standing for 15 minutes. And when the standing is about to end, taking out the cells, absorbing the culture medium, adding a proper amount of D-hanks for cleaning twice, supplementing the previous plasmid mixed solution to the required volume by using DMEM, transfecting, and adding into a 24-pore plate. After culturing at 37 ℃ for 6 hours, the cells were removed, and an equal volume of 20% FBS-containing medium was added thereto, while adding compounds 3, 6,7 and 9, respectively, to a final concentration of 20. Mu.M, and the culture was continued for 24 hours. After the culture was completed, the cells were removed and the experiment was carried out using lucifurase kit purchased from Premega, following the method suggested by the manufacturer: the culture medium is sucked dry, D-hanks are washed for 1-2 times, an appropriate amount of PLB lysate is added into each hole, shaking is carried out for 15 minutes at room temperature, the cell lysate is transferred into a 1.5ml EP tube, and centrifugation is carried out for 3 minutes at 12000 rpm. And (3) adding 50 mu l of LAR solution into each hole of a light-tight 96-hole plate, adding 50 mu l of cell lysate, uniformly mixing, putting the mixture into an enzyme-linked immunosorbent assay for reading, taking out the 96-hole plate, adding 50 mu l of SG solution into each hole, uniformly mixing, and putting the mixture into the enzyme-linked immunosorbent assay for reading. And summarizing the three detection data, and performing statistical analysis to obtain a result. The experimental results are shown in fig. 1, and the compound 9 in fig. 1 is the positive control PT2385.
As can be seen from fig. 1, overexpression of HIF-2 α resulted in a significant increase in fluorescence values, and a significant decrease in fluorescence values was observed after treatment with compounds 3, 6, and 7, demonstrating that compounds 3, 6, and 7 were able to inhibit HIF-2 α transcriptional activity (. P <0.05,. P <0.01,. P < 0.0001).
4. Zebra fish in vivo experiment for detecting whether compound can inhibit angiogenesis activity
Sexually mature and healthy transgenic Tg (flk 1:: eGFP) hybrid fish and WT (wild type) fish are mated, embryos are collected and placed in a fresh PTU-containing embryo culture solution to be incubated at a constant temperature of 28.5 ℃; setting a proper concentration gradient, adding the compound mother solution into an embryo culture solution, diluting a low-concentration solution by a high-concentration solution to obtain a low-concentration solution, and selecting sorafenib with the working concentration of 5mmol/L as a positive control. When the embryos developed to 4hpf, healthy embryos of the same development period were selected, placed in 24-well plates, 10 per well, and the residual embryo culture solution was carefully blotted with a disposable pipette. The plate was incubated with 500. Mu.l of compound (10. Mu.M) in embryo culture medium in an embryo incubator for 48h. The embryos are placed in a 96-well plate, individuals with vascular fluorescence are selected, the membrane is peeled off, an appropriate amount of tricaine solution is used for anesthesia, the embryos are placed in 2% (w/v) methylcellulose gel for arrangement, 52hpf (hpf, hours post-fertilization) is observed under an inverted fluorescence microscope, and pictures are taken. Image Pro Plus6 was used to measure internode vessel length (μm) per fish, statistics were summarized. The angiogenesis and blood vessel length statistics of the transgenic zebra fish are shown in fig. 2 and fig. 3.
As shown in FIGS. 2 and 3, significant incomplete development of blood vessels was observed in the 48-hour treatment with the addition of compounds 6 and 7. The results of statistics of internode blood vessel length of different groups of zebra fishes show that the internode blood vessel length of the zebra fishes treated by the compounds No. 6 and No. 7 is obviously reduced, and the function of inhibiting angiogenesis is presumably exerted by inhibiting the activity of HIF-2 alpha.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (4)

1. Cyclopenta [ d ] pyrimidine compounds and pharmaceutically acceptable salts thereof, characterized by being selected from the following compounds:
3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
2-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
4- (3,5-dichlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3,5-dimethoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3-fluoro-5-chlorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (3-fluoro-5-methoxyphenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- ((5-fluoropyridin-3-yl) oxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
4- (2,4-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
(R) -3-fluoro-5- ((7-hydroxy-6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) oxy) benzonitrile;
(R) -4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol;
(S) -4- (3,5-difluorophenoxy) -6,7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) -7-ol.
2. A pharmaceutical composition comprising a compound of claim 1 and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
3. The use of a compound according to claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with hypoxia inducible factor 2 α in a mammal.
4. The use according to claim 3, wherein the disease or condition associated with hypoxia inducible factor 2 α is selected from the group consisting of cancer, inflammation, metabolic disease;
the cancer comprises skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, menstrual system tumor, brain tumor, and head and neck cancer; the inflammation comprises pneumonia, enteritis, nephritis, arthritis and trauma infection; the metabolic diseases comprise obesity, dyslipidemia and hyperlipidemia.
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