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Mertk-specific pyrrolopyrimidine compounds

A compound and alkyl technology, applied in the field of MERTK-specific pyrrolopyrimidine compounds, can solve the problems of malignant transformation and unclear tumor

Inactive Publication Date: 2017-02-15
THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanism by which increased MerTK signaling in tumor cells contributes to tumor malignancy remains unclear

Method used

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  • Mertk-specific pyrrolopyrimidine compounds
  • Mertk-specific pyrrolopyrimidine compounds
  • Mertk-specific pyrrolopyrimidine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0727] Example 1. Synthesis of active compound

[0728] General process

[0729] Scheme 1 illustrates the general procedure used to prepare the compounds of the invention. According to methods known in the art, by using the required R 2 -LG 3 (LG 3 Is a leaving group) to alkylate the desired 7H-pyrrolo[2,3-d]pyrimidine to prepare structure 1-1. Those skilled in the art can comment on R 2 Part of the protection and deprotection is performed to produce the compound of formula I. See, for example, Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd edition, New York, John Wiley and Sons, Inc., 1991. For example, in the presence of phosphanes, such as (cyanomethylene)trimethylphosphine, in the presence of organic solvents, such as toluene and tetrahydrofuran, the desired alcohol, for example, cis-4-(tert- The 7H-pyrrolo[2,3-d]pyrimidine required for treatment with butyldimethylsilyloxy)cyclohexanol can prepare structure 1-1. In one embodiment, X'is nitrogen a...

Embodiment 2

[0742] Example 2. Trans-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(pent-2-ylamino)-7 H -Pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-ol

[0743] General Procedure A:

[0744]

[0745] The 5-bromo-7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-7 H -Pyrrolo[2,3- d ] Pyrimidine (200 mg, 0.45 mmol), 2-aminopentane (117.6 mg, 1.35 mmol) and diisopropylethylamine (174.5 mg, 1.35 mmol) in DMSO (8.0 mL) solution in a 35 ml heavy wall Heat in a pressure vessel at 100°C or overnight. The mixture was diluted with ethyl acetate (35 mL), washed with water (3x), dried (Na 2 SO 4 ) And concentrated to give 5-bromo-7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)- N -(Pent-2-yl)-7 H -Pyrrolo[2,3- d ]Pyrimidine-2-amine (MS m / z 496.30 [M+H] + ) (Used without further purification).

[0746] To 5-bromo-7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)- N -(Pent-2-yl)-7 H -Pyrrolo[2,3- d Add 4-(4-methylpiperazino)methylphenylboronic acid to a solution of pyrimidin-2-amine in...

Embodiment 3

[0756] Trans-4-(5-(4-((cyclopentylamino)methyl)phenyl)-2-(pent-2-ylamino)-7 H -Pyrrolo[2,3-d]pyrim (Pyridin-7-yl)cyclohexan-1-ol

[0757] General Procedure B:

[0758]

[0759] 4-(7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-(pent-2-ylamino)-7 H -Pyrrole And [2,3- d ]Pyrimidin-5-yl)benzaldehyde

[0760]

[0761] Make 5-bromo-7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)- N -(Pent-2-yl)-7 H -Pyrrolo[2,3- d ]Pyrimidine-2-amine (1.50 g, 3.03 mmol), (4-formylphenyl)boronic acid (681.8 mg, 4.54 mmol), Pd(PPh 3 ) 4 (175 mg, 0.15 mmol) and K 2 CO 3 The mixture of (628 mg, 4.54 mmol) in dioxane (50 mL) and water (10 mL) was thoroughly degassed and heated at 90° C. for 1 h under nitrogen. The reaction was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3x). The combined organic layer was dried (Na2SO4) and concentrated. The residue was purified by ISCO to provide the title compound (1.17 g, 74%) as a pale green solid. MS m / z 521.20...

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Abstract

The present invention includes pyrrolopyrimidine compounds that selectively inhibit Mer tyrosine kinase (MerTK) activity and / or Tyro3 tyrosine kinase activity, and use of these pyrrolopyrimidine compounds as anti-cancer agents, immunostimulatory and immunomodulatory agents, anti-platelet agents, anti-infective agents, and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.

Description

[0001] Cross reference of related applications [0002] This application requires U.S. Provisional Application No. 61 / 978,268 filed on April 11, 2014, U.S. Provisional Application No. 61 / 978,281 filed on April 11, 2014, and U.S. Provisional Application No. 61 / 978,290 filed on April 11, 2014 , U.S. Provisional Application No. 61 / 978,321 filed on April 11, 2014, U.S. Provisional Application No. 61 / 978,443 filed on April 11, 2014, U.S. Provisional Application No. 61 / 978,485, filed on April 11, 2014 U.S. Provisional Application No. 61 / 978,513 filed on April 11, 2014, U.S. Provisional Application No. 61 / 994,384 filed on May 16, 2014, and U.S. Provisional Application No. 62 / 088,159 filed on December 5, 2014. The full text of each of these applications is incorporated herein by reference for all purposes. [0003] Government interest [0004] The U.S. government has the right to the present invention with the support of the contract number HHSN261200800001E awarded by the National Cancer I...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519
CPCA61K31/506A61K31/5377A61K31/505A61K31/551A61K31/519A61K31/55A61K31/5513A61K45/06C07D487/04A61K31/529A61K31/635A61P31/00A61P31/04A61P31/12A61P35/00A61P37/02A61P37/04A61P43/00A61P7/02Y02A50/30C07D401/04C07D401/14C07D487/08
Inventor 王晓东张维河S.弗里D.基里夫
Owner THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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