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Substituted urea dihydroorotate dehydrogenase inhibitors

A technology of halogenated alkyl and alkyl, applied in the field of new compounds, can solve problems such as limited effectiveness

Pending Publication Date: 2022-04-05
JANSSEN BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Research efforts aimed at identifying additional inducers of differentiation have had limited success

Method used

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  • Substituted urea dihydroorotate dehydrogenase inhibitors
  • Substituted urea dihydroorotate dehydrogenase inhibitors
  • Substituted urea dihydroorotate dehydrogenase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0258] Exemplary compounds useful in the methods of the invention will now be described with reference to exemplary synthetic schemes for their general preparation below and the specific examples that follow.

[0259] plan 1

[0260]

[0261] Compounds of formula (III) can be prepared as shown in Scheme 1, wherein R 1 for H and R 2 and R 3 as defined in formula (III). At ambient temperature, in the presence of a suitable base such as Et 3 N, NaH, etc.), in a polar aprotic solvent (such as DCM, etc.), make (S)-(4-((2-chloro-6-fluorophenyl)carbamoyl)-2-fluoro Phenyl-5-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)carbamate (prepared as described in Intermediate 1 - Step F) was reacted with a secondary amine.

[0262] Scenario 2

[0263]

[0264] Compounds of formula (III) can be prepared as shown in Scheme 2, wherein R 1 and R 2 for H and R 3 as defined in formula (III). At elevated temperature (such as 100°C), in a base (such as Et 3 In the case of N, etc.), in a...

Embodiment 1

[0344] Example 1: (S)-N-(2-chloro-6-fluorophenyl)-4-(3,3-diethylureido)-5-fluoro-2-((1,1,1- Trifluoro Propan-2-yl)oxy)benzamide .

[0345]

[0346] To a mixture of N-ethylethylamine (6.82 mg, 93.23 μmol), TEA (15.72 mg, 155.39 μmol) in DCM (1 mL) was added N-[4-[(2-chloro-6-fluoro-phenyl )carbamoyl]-2-fluoro-5-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]phenyl]carbamate (40 mg, 77.70 μmol). The mixture was stirred at 25°C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method A) to afford the title compound as a white solid. MS (ESI): C 21 h 21 CIF 5 N 3 o 3 The mass calculated value is 493.1; m / z measured value is 494.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ=9.00-8.72(m,1H),7.88-7.66(m,2H),7.48(m,1H),5.52-5.32(m,1H),4.78(m,1H),4.65-4.41(m, 3H), 4.26(m, 1H), 3.93(m, 1H), 3.58(m, 1H), 3.09-2.90(m, 2H), 2.86-2.65(m, 2H).

Embodiment 2

[0347] Example 2: (S)-N-(4-((2-chloro-6-fluorophenyl)carbamoyl)-2-fluoro-5-((1,1,1-trifluoropropane-2- base) oxy) phenyl) piperidine-1-carboxamide .

[0348]

[0349] The title compound was prepared in a manner analogous to Example 1, however substituting piperidine for N-ethylethylamine. MS (ESI): C 22 h 21 CIF 5 N 3 o 3 The calculated value of the mass is 505.1; the measured value of m / z is 506.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ=8.37-8.27(m,1H),7.60(s,1H),7.53(s,1H),7.33(m,1H),4.79-4.70(m,2H),4.50(m,1H),3.93 (m, 2H), 3.78-3.57 (m, 1H), 3.41 (s, 3H), 3.22-3.16 (m, 1H), 3.12-2.65 (m, 4H).

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PUM

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Abstract

Disclosed are compounds, compositions, and methods for treating diseases, disorders, or medical conditions affected by DHODH modulation. Such compounds are represented by the following Formula I: wherein R1, R2, R3 and R6 are as defined herein.

Description

[0001] Cross References to Related Applications [0002] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 893,204, filed August 29, 2019, the disclosure of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to novel compounds that are inhibitors of dihydroorotate dehydrogenase (DHODH). These compounds are useful in the treatment of diseases, disorders or medical conditions in which inhibition of DHODH is advantageous. The invention also relates to pharmaceutical compositions comprising one or more of these compounds, methods of preparing such compounds and compositions, and the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmune and inflammatory Use of methods for diseases, syndromes and disorders. Background technique [0004] Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow caused by mutations in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C275/42C07D295/215C07D207/08C07D205/04C07D207/12C07D207/26C07D401/12C07D403/12C07D213/75C07D231/40A61K31/17A61K31/277A61K31/397A61K31/40A61K31/415A61K31/4453A61K31/4439A61K31/4155A61K31/44A61P35/00A61P35/02
CPCC07D205/04C07D207/08C07D295/215C07D207/12C07D401/12C07D231/40C07D213/75A61P29/00A61P35/00A61P37/00C07C275/42C07C275/40C07D403/12A61K31/17A61K31/4453A61K31/397A61K31/40A61K31/4015A61K31/4155A61K31/4439A61P35/02C07C2601/02C07D207/16
Inventor S·库杜克L·德拉特
Owner JANSSEN BIOTECH INC
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