DK2834237T3 - Heterocyclylforbindelser som mek-inhitorer - Google Patents

Heterocyclylforbindelser som mek-inhitorer Download PDF

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DK2834237T3
DK2834237T3 DK13712929.2T DK13712929T DK2834237T3 DK 2834237 T3 DK2834237 T3 DK 2834237T3 DK 13712929 T DK13712929 T DK 13712929T DK 2834237 T3 DK2834237 T3 DK 2834237T3
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compound
amino
fluoro
substituted
alkyl
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Bhavesh Dave
Rakesh Kumar Banerjee
Samiron Phukan
Abhijit Datta Khoje
Rajkumar Hangarge
Jitendra Sambhaji Jadhav
Venkata P Palle
Rajender Kumar Kamboj
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Lupin Ltd
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Claims (17)

  1. 1. Forbindelse ifølge den generelle formel I, dens tautomere form, dens stereoisomer, dets farmaceutisk acceptable salt, dens kombinationer med egnet lægemiddel og dens farmaceutiske sammensætning,
    hvor: R1 er valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret alkynyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret cycloalkenyl, substitueret eller usubstitueret aryl, substitueret eller usubstitueret heteroaryl og substitueret eller usubstitueret heterocyclyl; R2 er valgt fra gruppen bestående af -(C(Rc)(Rd))m-C(=O)-N(R5)R7, -C(=O)N(R8)R9 og - O-(C(Rc)(Rd))m-C(=O)-N(R5)R7; R3 er valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl og substitueret eller usubstitueret cycloalkyl; R4 er valgt fra gruppen bestående af hydrogen, halogen, substitueret eller usubstitueret alkyl og substitueret eller usubstitueret cycloalkyl; R5 er substitueret eller usubstitueret aryl, hvor substituenterne er valgt blandt Ra og Rb; R5 og R7 er hver uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl; eller R5 og R7 sammen med nitrogenet, til hvilke de er bundet, danner en substitueret eller usubstitueret heterocyklus; R8 og R9 er hver uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl, eller R8 og R9 sammen med nitrogenet, til hvilke de er bundet, danner en substitueret eller usubstitueret heterocyklus; med betingelserne at både R8 og R9 ikke kan være hydrogen på samme tid; og når R8 og R9 ikke er en del af en heterocyklus dannet sammen med det nitrogen til hvilket de er bundet til, er mindst én af R8 og R9 substitueret eller usubstitueret cycloalkyl eller substitueret eller usubstitueret heterocyclyl; Ra og Rb er valgt fra gruppen bestående af hydrogen, halogen og haloalkyl; Rc og Rd er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, halogen, hydroxyl og substitueret eller usubstitueret alkyl; eller Rc og Rd sammen med carbonatomet, til hvilke de er bundet, danner en substitueret eller usubstitueret cycloalkyl; m er et heltal valgt fra gruppen bestående af 1, 2, 3 og 4; yderligere, hvor: når alkylgruppen eller alkenylgruppen er substitueret, er alkylgruppen eller alkenylgruppen substitueret med 1 til 4 substituenter uafhængigt af hinanden valgt fra gruppen bestående af oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO2R10a, -C(=O)OR10a, - OC(=O)R10a, -C(=O)N(H)R10, -OR10a, -C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, - N(alkyl)R10, -N(H)C(=O)N(H)R10, - N(H)C(=O)N(alkyl)R10, -NH-SO2-alkyl og -NH-SO2-cycloalkyl; når cycloalkylgruppen eller cycloalkenylgruppen er substitueret, er cycloalkylgruppen eller cycloalkenylgruppen substitueret med 1 til 3 substituenter uafhængigt af hinanden valgt fra gruppen bestående af oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO2R10a, -C(=O)R10a, -C(=O)OR10a, -OC(=O)R10a, - C(=O)N(H)R10, -C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, -N(alkyl)R10, -N(H)C(=O)N(H)R10, -N(H)C(=O)N(alkyl)R10, -NH-SO2-alkyl og -NH-SO2-cycloalkyl; når arylgruppen er substitueret, er arylgruppen substitueret med 1 til 3 substituenter uafhængigt af hinanden valgt fra gruppen bestående af halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyklus, -O-alkyl, -0-perhaloalkyl, - N(alkyl)alkyl, -N(H)alkyl, -NH2, -SO2-alkyl, -SO2-perhaloalkyl, N(alkyl)C(=O)alkyl, - N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, - SO2N(H)alkyl, -SO2NH2, -NH-SO2-alkyl og -NH-SO2-cycloalkyl; når heteroarylgruppen er substitueret, er heteroarylgruppen substitueret med 1 til 3 substituenter uafhængigt af hinanden valgt fra gruppen bestående af halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyklus, -0-alkyl, O-perhaloalkyl, -N(alkyl)alkyl, - N(H)alkyl, -NH2, -SO2-alkyl, -SO2-perhaloalkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, - C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -NH-SO2-alkyl og -NH-SO2-cycloalkyl; når heterocyclylgruppen er substitueret, er heterocyclylgruppen substitueret med 1 til 3 substituenter, når den heterocykliske gruppe er substitueret på en carbonring af 'heterocyklusen', substituenterne er uafhængigt af hinanden valgt fra gruppen bestående af halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, -OR10b, - C(=O)OR10a, -OC(=O)R10a, -C(=O)N(H)R10, C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, - N(alkyl)R10, -N(H)C(=O)N(H)R10, - N(H)C(=O)N(alkyl)R10; når den heterocykliske gruppe er substitueret på en nitrogenring af 'heterocyklusen', substituenterne er uafhængigt af hinanden valgt fra gruppen bestående af alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -SO2R10a, - C(=O)R10a, C(=O)OR10a, -C(=O)N(H)R10, -C(=O)N(alkyl)R10, -NH-SO2-alkyl og -NH-SO2-cycloalkyl; når den heterocykliske gruppe er substitueret på en svovlring af 'heterocyklusen', er svovlet substitueret med 1 eller 2 oxogrupper; R10 er valgt fra gruppen bestående af hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl og heterocyclyl; R10a er valgt fra gruppen bestående af alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl og heterocyclyl; og R10b er valgt fra gruppen bestående af hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl og heterocyclyl.
  2. 2. Forbindelse ifølge krav 1, hvor R1 er valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl.
  3. 3. Forbindelse ifølge krav 1 eller 2, hvor R3 og R4 er uafhængigt af hinanden substitueret eller usubstitueret alkyl, og/eller, hvor Ra og Rb er uafhængigt af hinanden hydrogen eller halogen, og/eller hvor Rc og Rd er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, halogen og hydroxyl; eller Rc og Rd sammen med carbonatomet, til hvilke de er bundet, danner en substitueret eller usubstitueret cycloalkyl ring.
  4. 4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor m er 1 eller 2.
  5. 5. Forbindelse ifølge et hvilket som helst af kravene 1-4, hvor R5 og R7 er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl; eller R5 og R7 sammen med nitrogenatomet, til hvilke de er bundet, danner en substitueret eller usubstitueret heterocyklus.
  6. 6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R8 og R9 er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl; eller R8 og R9 sammen med nitrogenet, til hvilke de er bundet, danner en substitueret eller usubstitueret heterocyklus; med betingelsenen at både R8 og R9 ikke er hydrogen på samme tid, og når R8 og R9 ikke er en del af en heterocyklus dannet sammen med det nitrogen de er bundet til, er mindst én af R8 og R9 substitueret eller usubstitueret cycloalkyl eller substitueret eller usubstitueret heterocyclyl.
  7. 7. Forbindelse ifølge et hvilket som helst af kravene 1-6, hvor: R1 er valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret alkenyl og substitueret eller usubstitueret heterocyclyl; R3 og R4 er uafhængigt af hinanden substitueret eller usubstitueret alkyl; Ra og Rb er uafhængigt af hinanden hydrogen eller halogen; Rc og Rd er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret al kyl, halogen og hydroxyl, eller Rc og Rd sammen med carbonatomet, til hvilke de er bundet, danner en substitueret eller usubstitueret cycloalkylring; m er 1 eller 2; R5 og R7 er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl; eller R5 og R7 sammen med nitrogenatomet, til hvilke de er bundet, danner en substitueret eller usubstitueret heterocyklus; R8 og R9 er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, substitueret eller usubstitueret cycloalkyl og substitueret eller usubstitueret heterocyclyl, eller R8 og R9 sammen med nitrogenet, til hvilke de er bundet, danner en substitueret eller usubstitueret heterocyklus; med betingelserne at både R8 og R9 ikke er hydrogen på samme tid, og når R8 og R9 ikke er en del af en heterocyklus dannet sammen med det nitrogen til hvilket de er bundet, er mindst én af R8 og R9 substitueret eller usubstitueret cycloalkyl eller substitueret eller usubstitueret heterocyclyl.
  8. 8. Forbindelse ifølge et hvilket som helst af kravene 1-7, hvor: R1 er valgt fra gruppen bestående af hydrogen, methyl, ethyl, isopropyl, allyl, difluoromethyl, cyclopropyl, 3-oxetanyl, -CH2COOC2H5, -CH2CH(OH)CH2(OH) og^FUOH; R3 og R4 er methyl; Ra og Rb er uafhængigt af hinanden hydrogen, fluor eller iod; Rc og Rd er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, methyl, fluor og hydroxyl, eller Rc og Rd sammen med carbonatomet, til hvilket de er bundet, danner en substitueret eller usubstitueret cyclopropyl; m er 1 eller 2; R5 og R7 er uafhængigt af hinanden valgt fra gruppen bestående af methyl, cyclopropyl og 3-oxetan; eller R5 og R7 sammen med nitrogenatomet, til hvilket de er bundet, danner enzetidinyl eller 3-hydroxyazetidinyl; R8 og R9 er uafhængigt af hinanden valgt fra gruppen bestående af hydrogen, cyclopropyl, cyclopropyl substitueret med -C(=O)NH2 eller -CH2OH, 3-oxetanyl, tetrahydrofuran-3-yl og tetrahydro-2H-pyranyl, eller R8 og R9 er sammen med nitrogenet som de er bundet til danner 1,1-dioxidothiazolidinyl, 1,1-dioxidothiomorpholinyl, morpholinyl, azetidinyl, 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 3-hydroxypyrrolidinyl eller 4-hydroxypiperidinyl; med betingelserne, at både R8 og R9 ikke er hydrogen på samme tid, og når R8 og R9 ikke er en del af en heterocyklus dannet sammen med det nitrogen som de er bundet til, er mindst én af R8 og R9 substitueret eller usubstitueret cycloalkyl eller substitueret eller usubstitueret heterocyclyl.
  9. 9. Forbindelser ifølge et hvilket som helst af kravene 1 til 8, hvor forbindelsen er valgt fra gruppen bestående af 3-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)propanamid(Forbindelse-l); N-cyclopropyl-3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 2); 1- (3-(azetidine-l-carbonyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse-3); N-cyclopropyl-2-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3.4.6.7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)acetamid (Forbindelse 4); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)-N-methylacetamid (Forbindelse 5); N-cyclopropyl-2-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3.4.6.7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 6); 5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-l-(3-(morpholin-4-carbonyl)phenyl) pyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 7); 1- (3-(l,l-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 8); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-methylpropanamid(Forbindelse 9); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N,N-dimethylacetamid (Forbindelse 10); N-(l-carbamoylcyclopropyl)-3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 12); 3- (5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamid (Forbindelse 13); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-hydroxyacetamid (Forbindelse 14); 3- (3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N-methylpropanamid (Forbindelse 15); 2-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 16); 1- (3-(l,l-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 17); 5-((2-fluor-4-iodophenyl)amino)-l-(3-(4-hydroxypiperidine-l-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 18); N-cyclopropyl-3-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3.4.6.7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)propanamid (Forbindelse 19); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)-2-methylpropanamid (Forbindelse 20); 5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-l-(3-(4-methylpiperazine-l-carbonyl) phenyl)pyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 21); 5-((2-fluor-4-iodophenyl)amino)-l-(3-(3-hydroxypyrrolidine-l-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 22); 5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-l-(3-(piperazin-l-carbonyl)phenyl)pyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 23); 1- (3-(azetidine-l-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 24); N-cyclopropyl-2-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl- 2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 25); 2- (3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)acetamid (Forbindelse 26); 3- cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-l-(3-(pyrrolidin-l-carbonyl)phenyl)pyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 27); 2-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-methylpropanamid (Forbindelse 28); 2-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N,N-dimethylacetamid (Forbindelse 29); 2-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamid (Forbindelse 31); 2- (3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-hydroxyacetamid (Forbindelse 32); 3- cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-l-(3-(2-(3-hydroxyazetidin-l-yl)-2-oxo ethyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 33); 3-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)propanamid (Forbindelse 34); 2- (3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 35); 3- (3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N-methylpropanamid (Forbindelse 36); N-cyclopropyl-3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 37); 3-cyclopropyl-l-(3-(l,l"dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 38) ; 3-cyclopropyl-1-(3-( l,l-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluor-4-iodo phenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 39) ; N-cyclopropyl-3-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl- 2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)propanamid (Forbindelse 40); N-cyclopropyl-2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 41); 2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)acetamid (Forbindelse 42); 2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-methylpropanamid (Forbindelse 43); 2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N,N-dimethylacetamid (Forbindelse 44); 2,2-difluor-2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)acetamid (Forbindelse 45); 1- (3-(2-(azetidin-l-yl)-2-oxoethyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 46); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-hydroxyacetamid (Forbindelse 47); 5-((2-fluor-4-iodophenyl)amino)-l-(3-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl) phenyl)-3,6,8-trimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 48); 3- (5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)-N-(oxetan-3-yl)benzamid (Forbindelse 49); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamid (Forbindelse 50); 3- (5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)-N-(tetrahydrofuran-3-yl)benzamid (Forbindelse 51); 3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamid (Forbindelse 52); 3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)-N-(l-(hydroxymethyl)cyclopropyl) benzamid (Forbindelse 53); N-cyclopropyl-3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo- 3.4.6.7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 54); N-cyclopropyl-3-(5-((2-fluor-4-iodophenyl)amino)-3-(2-hydroxyethyl)-6,8-dimethyl- 2.4.7- trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 55); 1- (3-(azetidine-l-carbonyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 56); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 57); N-cyclopropyl-2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)acetamid (Forbindelse 58); N-cyclopropyl-2-(3-(3-ethyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)acetamid (Forbindelse 59); 2- (3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)-N-methylacetamid (Forbindelse 60); 3- (3-(3-ethyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)propanamid (Forbindelse 61); N-cyclopropyl-3-(3-ethyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 62); 5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-l-(3-(morpholin-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 63); l-(3-(l,l"dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 65); 1- (3-(l,l"dioxidothiomorpholine-4-carbonyl)phenyl)-3 -ethyl-5-((2-fluor-4- iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidin-2,4,7(lH,3H,6H)-trion (Forbindelse 66); 2- (3-(3-ethyl-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-N,N-dimethylacetamid (Forbindelse 67); 3- (3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)propanamid (Forbindelse 68); N-cyclopropyl-3-(5-((2-fluor-4-iodophenyl)amino)-3-isopropyl-6,8-dimethyl-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 69); 2-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-3-(oxetan-3-yl)-2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenoxy)acetamid (Forbindelse 71); N-cyclopropyl-3-(3-(difluoromethyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl- 2,4,7-trioxo-3,4/6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 72); N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)benzamid (Forbindelse 73); 2-(l-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-l,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)eddikesyre (Forbindelse 74); (R) -2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-hydroxyacetamid (Forbindelse 75); (S) -2-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)-2-hydroxyacetamid (Forbindelse 76); l-(3-(5-((2-fluor-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido [4,3-d]pyrimidin-l(2H)-yl)phenyl)cyclopropanecarboxamid (Forbindelse 77); l-(3-(3-cyclopropyl-5-((2-fluor-4-iodophenyl) amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)cyclopropan carboxamid (Forbindelse 78); og l-(3-(5-((2-fluor-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)cyclopropanecarboxamid (Forbindelse 79).
  10. 10. Farmaceutisk sammensætning omfattende en forbindelse eller et farmaceutisk acceptabelt salt ifølge et hvilket som helst af kravene 1-9 og én eller flere farmaceutisk acceptabelt bærestoffer, fortyndingsmidler eller excipienser.
  11. 11. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt, ifølge et hvilket som helst af krav 1-9, til anvendelse ved at inhibere MEK-enzymer, hvor forbindelsen foreligger i en mængde tilstrækkelig til at inhibere enzymet.
  12. 12. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt, ifølge et hvilket som helst af krav 1-9, til anvendelse i behandling af en MEK-medieret lidelse hos et individ, som lider af lidelsen, hvor forbindelsen foreligger i en virkningsfuld mængde.
  13. 13. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt ifølge et hvilket som helst af krav 1-9, til anvendelse i behandlingen eller forebyggelsen af en proliferativ sygdom eller en inflammatorisk sygdom hos et individ med behov derfor, hvor forbindelsen foreligger i en virkningsfuld mængde.
  14. 14. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt, ifølge et hvilket som helst af krav 1-9, til anvendelse i at nedbryde, at inhibere væksten af eller at dræbe cancerceller, hvor forbindelsen foreligger i en virkningsfuld mængde.
  15. 15. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt, ifølge et hvilket som helst af krav 1-9, til anvendelse ved at inhibere tumorstørrelsesforøgelse, at reducere størrelsen af en tumor, at reducere tumorproliferation eller at forebygge tumorproliferation hos et individ med behov derfor, hvor forbindelsen foreligger i en virkningsfuld mængde.
  16. 16. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt, til anvendelse ifølge krav 13, hvor den proliferative sygdom er cancer, psoriasis, restenose, autoimmun sygdom eller aterosklerose.
  17. 17. Forbindelse ifølge formel (I), dens tautomere form, dens stereoisomer eller dets farmaceutisk acceptable salt, til anvendelse ifølge krav 16, hvor canceren er småcellet eller ikke-småcellet lungekræft.
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