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Fluorinated quinoline and quinoxaline derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors for treatment of cancer, autoimmune and inflammatory diseases

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

Pending Publication Date: 2022-06-21
JANSSEN BIOTECH INC
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  • 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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  • Fluorinated quinoline and quinoxaline derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors for treatment of cancer, autoimmune and inflammatory diseases
  • Fluorinated quinoline and quinoxaline derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors for treatment of cancer, autoimmune and inflammatory diseases
  • Fluorinated quinoline and quinoxaline derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors for treatment of cancer, autoimmune and inflammatory diseases

Examples

Experimental program
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preparation example

[0344] Exemplary compounds useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparations below and specific examples that follow.

[0345] plan 1

[0346]

[0347] According to Scheme 1, the 1,2,4-triazol-5(4H)-one compound of formula (IV), wherein PG is Bn, was prepared from ethyl 2-(benzyloxy)acetate in three steps. In the first step, 2-(benzyloxy)acetate is prepared by reacting ethyl 2-(benzyloxy)acetate with hydrazine hydrate in a suitable solvent such as EtOH etc. at a temperature ranging from 70°C to 85°C Acetylhydrazine. Hydrazides and isocyanates of formula (III) (wherein R c for C 1-6 alkyl) in a suitable solvent such as water etc. to give the corresponding semicarbazides. Subsequent cyclization of the semicarbazide with a suitable base such as NaOH in a suitable solvent such as water provides compounds of formula (IV) (wherein PG is Bn).

[0348] Scenario 2

[0349]

...

Embodiment 1

[0528] Example 1: 4-ethyl-1-(7-fluoro-4-isopropyl-2-(2-methoxyphenyl)quinolin-6-yl)-3-(hydroxymethyl) base)-1H-1,2,4-triazol-5(4H)-one.

[0529]

[0530] Step A. 3-((Benzyloxy)methyl)-4-ethyl-1-(7-fluoro-4-isopropyl-2-(2-methoxyphenyl)quinoline- 6-yl)-1H-1,2,4-triazol-5(4H)-one. in N 2 (2-Methoxyphenyl)boronic acid (39 mg, 256.7 μmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloride palladium(II) (Pd( dtbpf)Cl 2 ) (15 mg, 23.33 μmol) and K 2 CO 3 (97 mg, 701.9 μmol) added to 3-((benzyloxy)methyl)-1-(2-chloro-7-fluoro-4-isopropylquinolin-6-yl)-4-ethyl-1H -1,2,4-Triazol-5(4H)-one (Intermediate 2, 160 mg, 233.3 μmol) in dioxane / H 2 O mixture (v / v, 5 / 1, 6 mL) in solution. Put the mixture in N 2 was stirred at 85°C for 16 hours. Mix the mixture with H 2 Diluted with 0 (20 mL) and extracted with DCM (20 mL x 3). The organic layer was passed through Na 2 SO 4 Dry, filter and evaporate under reduced pressure. by flash column chromatography (SiO 2 , 0-80% e...

Embodiment 2

[0532] Example 2: 1-(2-(3-Chloro-5-methyl-1H-pyrazol-4-yl)-7-fluoro-4-isopropylquinolin-6-yl)-4-ethyl yl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

[0533]

[0534] Step A. 3-((Benzyloxy)methyl)-1-(2-(3-chloro-5-methyl-1H-pyrazol-4-yl)-7-fluoro-4-isopropyl Quinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. in N 2 Next, to 3-chloro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (middle body 3, 250 mg, 496 μmol), 3-((benzyloxy)methyl)-1-(2-chloro-7-fluoro-4-isopropylquinolin-6-yl)-4-ethyl-1H -1,2,4-Triazol-5(4H)-one (Intermediate 2, 235 mg, 413.33 μmol) and K 2 CO 3 (114 mg, 826.65 μmol) in dioxane / H 2 Add Pd(dppf)Cl to a solution in O(v / v, 5 / 1, 2 mL) 2 (33.8 mg, 41.33 μmol). The reaction mixture was stirred at 80°C overnight, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (10 mL), and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layer was pas...

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Abstract

Disclosed are compounds of formula (I): (I) wherein X is CH; the compounds of formula (I) of the present invention are dihydroorotate dehydrogenase (DHODH) inhibitors and are useful in the treatment of inflammatory disorders, autoimmune disorders and cancers such as, for example, lymphoma, leukemia, cancer and sarcoma. The present specification discloses synthesis and characterization of exemplary compounds and pharmacological data thereof (e.g., pages 60 to 136; embodiments 1 to 39; table 1 and Table 2). Exemplary compounds are, for example, 4-ethyl-1-(7-fluoro-4-isopropyl-2-(2-methoxyphenyl) quinolin-6-yl)-3-(hydroxymethyl)-1H-1, 2, 4-triazol-5 (4H)-one (embodiment 1): (AA).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of priority from US Provisional Application 62 / 929,163, filed November 1, 2019, which is incorporated herein by reference in its entirety and for all purposes. 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 for which there is an advantage in inhibiting DHODH. The present invention also relates to pharmaceutical compositions comprising one or more of such compounds, methods of making such compounds and compositions, and the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunity and inflammation Use of the method for diseases, syndromes and disorders. Background technique [0004] Acute myeloid leukemia (AML) is a clonal disease of the blood and bone marrow caused by ...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D403/04C07D401/14A61K31/4709A61K31/4196A61K31/517A61K31/4155A61K31/444A61K31/4439A61K31/351A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06
CPCC07D401/04C07D403/04A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06C07D401/14A61K31/4709A61K31/517C07D405/14C07D403/14
Inventor J·齐飒C·克奥哈内S·库杜克
Owner JANSSEN BIOTECH INC
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