DK3149008T3 - Bestemte proteinkinaseinhibitorer - Google Patents

Bestemte proteinkinaseinhibitorer Download PDF

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DK3149008T3
DK3149008T3 DK15800531.4T DK15800531T DK3149008T3 DK 3149008 T3 DK3149008 T3 DK 3149008T3 DK 15800531 T DK15800531 T DK 15800531T DK 3149008 T3 DK3149008 T3 DK 3149008T3
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carboxamide
amino
pyridin
cyclopentyl
pyrimidine
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DK15800531.4T
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Weibo Wang
Tongshuang Li
Qiang Tian
Huajie Zhang
Haohan Tan
Xianlong Wang
Qihong Liu
Zhifu Li
Weipeng Zhang
Zhifang Chen
Lihua Jiang
Yanxin Liu
Li Linghu
Min Lin
Jing Sun
Xingdong Zhao
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Shanghai Fochon Pharmaceutical Co Ltd
Fochon Pharmaceuticals Ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Claims (15)

1. Forbindelse med formlen (I):
eller et farmaceutisk acceptabelt salt deraf, hvor: X er C eller N; YerCR11, O, S eller NR12; det 6-5-leddede sammensmeltede ringsystem A-B er valgt blandt:
Q er valgt blandt aryl og heteroaryl; R1 er valgt blandt: hydrogen, C1.10 alkyl, C2 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Ci-4 alkyr heterocyclyl, heterocyclyl-C1.4 alkyl, aryl, aryi-Ci-4 alkyl, heteroaryl og heteroaryl-Ci-4 alkyl, hvor alkyl, alkenyl, alkynyl, cycloalkyl og heterocyclyl hver især er ^substitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6a, og hvor aryl og heteroaryl hver især er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6b;
R2 er valgt blandt: hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 c.ycloalkyl-Ci-4alkyl, heterocyclyl, heterocyclyl-Ci-4 alkyl, aryl, aryl-Ci-4 alkyl, heteroaryl og heteroaryl-Ci-4 alkyl, hvor alkyl, alkenyl, alkynyl, cycloalkyl og heterocyclyl hver især er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6a, og hver aryl og heteroaryl er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6b; R3 og R4 uafhængigt er valgt blandt: hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl og C3-10 cycloalkyl; hvor alkyl, alkenyl, alkynyl og cycloalkyl hver især er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6a; eller R3 og R4 sammen med nitrogenatomerne, som de er bundet til, danner en 4-12-leddet ring indeholdende 0, 1, 2 eller 3 heteroatomer, som uafhængigt er valgt blandt oxygen, sulfur og nitrogen og valgfrit substitueret med 1 eller 2 R6a-grupper; med det forbehold, at når R3 og R4 begge er hydrogen, er R2 ikke aryl eller heteroaryl; hver R5 uafhængigt er valgt blandt: hydrogen, Cwo alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.10 cycloalkyl, -OR8, -NR7S(O)rR8, -NO2, -halogen, -S(O)rR7, -SR8, -S(O)2OR7, -OS(O)2R8, -S(O)rNR7R8, -NR7R8, -O(CR9R10)tNR7R8, -C(O)R7, -CO2R8, -CO2(CR9R10)tCONR7R8, -OC(O)R7 -CN, -C(O)NR7R8, -NR7C(O)R8, -OC(O)NR7R8, -NR7C(O)OR8, -NR7C(O)NR7R8, -CR7(N-OR8), -CHF2, -CF3, -OCHF2 og -OCF3; hvor Ci-ioalkyl, C2-10 alkenyl, C2-10 alkynyl og C3-10 cycloalkyl hver er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6a; hver R6a uafhængigt er valgt blandt: -C1-10 alkyl, -C2-10alkenyl, -C2-10 alkynyl, -C3-10 cycloalkyl, -OR8, -NR7S(O)rR8, -NO2, -halogen, -S(O)rR7, -SR8, -S(O)2OR7, -OS(O)2R®, -S(O)rNR7R8, -NR7R8, -(CR9R10)tOR8, -(CR9R10)tNR7R8 -(CR9R10)tSR8, -(CR9R10)tS(O);R8, -(CR9R10)tCO2R8, -(CR9R10)tCONR7R8, -(CR9Rw)tNR7CO2R8, -(CR9R10)tOCONR7R8, -(CR9R10)tNR7CONR7R8 -(CR9R10)tNR7SO2NR7R8 -O(CR9R10)tNR7R8 -C(O)R7 -C(O)(CR9R10)tOR8 -C(O)(CR9R10)tNR7R8 -C(O)(CR9R10)tSR8 -C(O)(CR9R10)tS(O)rR8 -CO2R8, -CO2(CRsR10)tCONR7R8, -OC(O)R7, -CN, -C(O)NR7R8, -NR7C(O)R8, -OC(O)NR7R8, -NR7C(O)OR8, -NR7C(O)NR7R8, -CR7(N-OR8), -CHF2, -CF3, OCHFs og -OCF3; hver R6b uafhængigt er valgt blandt: R6a, ary I, aryl-Ci-4 alkyl, heteroaryl og heteroaryl-Ci-4 alkyl; hverR7 og hver R8 uafhængigt er valgt blandt: hydrogen, C1..10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, cycloalkyl-Ci-4alkyl, heterocyclyl, heterocyclyl-Ci-4 alkyl, aryl, aryl-Ci-4 alkyl, heteroaryl og heteroaryl-C1..4 alkyl; hvor alkyl, alkenyl, alkynyl, cycloalkyl og heterocyclyl hver er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6a, og aryl og heteroaryl hver især er usubstitueret eller substitueret med mindst en substituent, såsom en, to, tre eller fire substituenter, uafhængigt valgt blandt R6b; eller R7 og R8 sammen med atomet/atomerne, til hvilke de er bundet, danner en heterocyklisk ring med 4 til 12 led indeholdende 0, 1, eller 2 yderligere heteroatomer uafhængigt valgt blandt oxygen, suifur og nitrogen og valgfrit substitueret med 1 eller 2 R6b-grupper; hver R9 og hver RiQ uafhængigt er valgt blandt: hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, cycloalkyl-C-M alkyl, heterocyclyl, heterocyclyl-Ci.4 alkyl, aryl, aryl-Ci-4 alkyi, heteroaryl og heteroaryl-Ci-4 alkyl; eller R9 og R10 sammen med carbonatomet/carbonatomerne, til hvilke de er bundet, danner en ring på 3 til 7 led indeholdende 0, 1, eller 2 heteroatomer uafhængigt valgt blandt oxygen, sulfur og nitrogen og valgfrit substitueret med 1 eller 2 R6a-groups; R11 er valgt blandt: hydrogen, C1-10 alkyl, C3-10 cycloalkyl, Cs-iocycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aryl-Ci-4 alkyl, heteroaryl· heteroaryl-Ci-4 alkyl, -OR7, -NR7S(O)rR8, -S(O)rR7, -SR7, -S(O)2OR7, -OS(O)2R7, -S(O)rNR7R8, -NR7R8, -O(CR9R10)tNR7R8 -C(O)R7, -CO2R3, -CO2(CR9R10)tCONR7R8, -OC(O)R7, -CN, -C(O)NR7R8, -NR7C(O)R8, -OC(O)NR7R8, -NR7C(O)OR8, -NR7C(O)NR7R8, -CHF2, -CF3, -OCHF2 og -OCF3; R12 er valgt blandt: hydrogen, C1-10 alkyl, C3-10 cycloalkyi, Cs-iocycloalkyl-C1..4 aikyl, heterocyclyl, heterocyclyl-Ci-4 alkyl, aryl, aryl-Ci..4 alkyl, heteroaryl, heteroaryl-Ci-4 alkyl, -S(O)rR7 -C(O)R7, -CO2R7, -CO2(CR9R10)tCONR7R8 og -C(O)NR7R8; m uafhængigt er valgt blandt 0, 1, 2 og 3; hver r uafhængigt er valgt blandt 1 og 2; hver t uafhængigt er valgt blandt 1,2 og 3.
2, Forbindelse ifølge krav 1 eller farmaceutisk acceptabelt salt deraf, hvor det 6-5-leddede sammensmeltede ringsystem A-B er og
hvor hver R12 og hver R11 uafhængigt er valgt blandt hydrogen og C1-10 aikyl, for eksempel hvor hver R12 og hver R11 uafhængigt er valgt blandt hydrogen og methyl.
3. Forbindelse ifølge et hvilket som helst af kravene 1 til 2 eller et farmaceutisk acceptabelt salt deraf, hvor Q er valgt blandt heteroaryl; for eksempel hvor Q er valgt blandt pyridyl, pyridazinyl og 5,6,7,8-tetrahydro-1,6-
naphthyridinyl; hvorfor eksempel Q er valgt blandt pyridin-2-yl, pyridazin-3-yl og 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3 eller et farmaceutisk acceptabelt salt deraf, hvor R1 er valgt blandt hydrogen, C1-10 alkyl, heterocyclyl og heterocyclyl-Ci .4 alkyl, hvor heterocyclyl er usubstitueret eller substitueret med mindst en substituent uafhængigt valgt blandt R63, hvor hver R63 uafhængigt er valgt blandt C1-10 alkyl, -NR7R8, -(CR9R10)tOR8, -OR8, -C(O)R7, -(CR9R10)tS(O)rR8; hvor R7, R8, R9, R10, t og r er som beskrevet i krav 1.
5. Forbindelse ifølge krav 4 eller et farmaceutisk acceptabelt salt deraf, hvor Q er valgt blandt pyridin-2-yl, pyridazin-3-yl og R’ er valgt blandt heterocyclyl og heterocyclyl-Ci .4 alkyl-grupper bestående af de følgende grupper:
hver heterocyclyl er usubstitueret eller substitueret med mindst en, såsom 1, 2, 3 eller 4 substituenter uafhængigt valgt blandt R6a, hvor hver R6a uafhængigt er valgt blandt Cmo alkyl, -NR7R8, -(CR9R10)tOR8, -OR8, -C(O)R7, -C(O)NR7R8, -(CR9R10)tS(O)rR8; hvor R7, R8, R9, R10, t og r er som beskrevet i krav 1.
6. Forbindelse ifølge et hvilket som helst af kravene 4 til 5 eller et farmaceutisk acceptabelt salt deraf, hvor R6a uafhængigt er valgt blandt hydrogen, methyl, ethyl, hydroxyl, hydroxymethyl, hydroxyethyl, hydroxyacetyl,
methoxy methyl, methoxyethyl· acetyl, hydroxyacetyl, (methylsulfonyl)ethyl, amino, carbamoyl, methylamino og dimethylamino.
7-ΓΛΑ^ορΘη1γΙ-2-((5-(6-6^Ρ3:6<Ιί3Ζ3Ρ^οΙο[3.1.1 ]heptan-3-yi)pyridin-2-yl)amino)-A/;A/-dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7-cyclopentyl-2-((5-((7R8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyndin-2-yl)amino)-/V7/V-d!methylthieno[3,2-d]pyrim!d!n-6-carboxamid, 7-cyclopentyl-2-((5-((7S,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-y!)pyridin-2-yl)amino)-A/,/V-dimethylth!eno[3,2-djpydmidin-6-carboxamid, 7-cydopentyl-2-((5-((7/:?,8aS)-7-hydroxyhexahydropyrroloi1,2-a]pyrazin-2(1H)-yi)pyndin-2-y!)amino)-/V,/V-dimethytthieno[3,2-d]pynmidin-6-carboxarnid, 2-((5-(3,6-ά!3Ζ3Ρ^οΙο[3.2.0]ήθρί3Γν·3-^^^!η-2^Ι^!ηο)-7^οίορθΓ^Ι-/ν,Λ/-dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7-cydopentyl-/V,A/-dimethyl-2-((5-(6-methyl-3,6-diazabicydo[3.2.0]heptan-3-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, 7-cydopentyl-2-((5-(6-ethyi-3,6-diazabicydo[3.2.0]hepian-3-yl)pyridin-2- yl)amino)-/V7/V-dimethylthieno[3,2-c(]pyrimidin-6-carboxamid, 7-cyclopentyl-/V,/V-dimethyl-2-((6-(piperazin-1-yl)pyridazin-3-y!)amino)thieno[3,2- d] pyrimidin-6-carboxamid, 7-cyclopenty!-/V,/V-dimethyl-2-((6-(4-me1:hylpiperazin-1-yl)pyridazin-3- yl)ainino)thieno[3,2-cf|pyrimidin-6-carboxamid, 2-((6-(4-acetyipipΘrazin-1-yl)pyπdaz!n-3-yl)amίno)-7-cyciopentyl·/VJ^/~ dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7-cyclopentyl-2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-3-yi)amino)-/V,/V- dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7-cydopentyl-/V,/V-dimethyl-2-((6-(4-(2-(methylsulfonyl)©thyl)piperaziii-1-yl)pyndazin~3-yl)amho)thieno[3!2-(^pyrimidin-6“Carboxarnid! 7-cyclopentyl-A/,A/-dimethyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yljaminoithienofS^-^pyrimidin-e-carboxamid, 7-ογοΙορθηϊγΙ-Λ/,ΛΜϊηθ^Ι-2-((6-Π8^Ι-5,6,7,8-ίθ1Γ3Γ^Γθ-1,6-η3ρΐΊίΐΊγ^ΐη-2- yl)amino)thieno[3,2-a]pyrimidin-6-carboxam!d, 7-cycίopentyl·2-((5-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-/V,Λ/-dimethylthieno[3,2-cT|pyrimidin-6-carboxamid, 7-cydoper!tyl-2-((5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-/V,/V-d!methylthieno[3,2-d]pyrimidin-6-carboxam!d, 7-cycloperityl-/\/,A/-dimethyl-2-((5-(4-(2-(methylsulfonyi)ethyl)piperazin-1-yi)pyridin-2"yl)amino)thieno[3,2-d]pynmidin-6-carboxamidi T-cyclopentyl^^CS^-ethylpiperazin-l-yQpyndin^-ybaminoj-A/./V- dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7-cyciopentyl-2-((5-((3S!5/:?)”3,5"diniethylp!perazin"1"yl)pynd!n-2"yl)amino)-/V,/V- dimethylthieno[3,2-d]pyrimidin-6-carboxamid 7-cyclopentyl-A/,/V-dimethyl-2-((5-((3S,5R)-3!4,5-trin':ethylpiperazin-1-yl)pyridin-2- yl )amino)thieno[3:2-c/]pyrimidin-6-carboxamid 7-cyclopentyl-2-((5-((3S,5F?)-4-ethyl-3I5-dimethylpiperazin-1-yl)pyridin-2- ylJaminoj-fy/V-dimethylthienoiS^-c^yrimidin-e-carboxamid 7- cyciopentyl"/VΛ/-dimethyl·2-((5-(1”methyl·2,4-d!Oxo1,3,8-triazaspiro[4.5]decan- 8- yi)pyridin-2-yl)amino)thieno[3,2-<^pyrimidin-6-carboxamid 2-((5-(4-caΓbamoyl·4~(methylamino)piperidiΠ"1 -yl)pyridin-2-yl)amino)-7- cyclopentyl -A/,A/-dimethylthieno[3,2-d]pyrimidin-6-carboxamid azetidin-1-yl(7-cyclopentyl-2-((5-(piperazin-1-yl)pyndin-2-yl)amino)th!eno[3,2-d]pyrimidin-6-yl)methanon, (7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6- yI)( 3-methoxyazetidin-1 -yljmethanon, (7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6- yI)( 3-hydroxyazetidin-1 -yljmethanon, (7-cyclopentyl-2-((5-(piperazin-1-yljpyridin-2-yl)aminojthieno[3,2-d]pyrimidin-6- yl)( piperidin-1-yljmethanon, (7-cyclopentyl-2-((5-(piperazin-1-yi)pyridin-2-yljaminojthieno[3,2-d]pyrimidin-6-ylj( 4-methylpiperazin-1-yl)methanon, (7-cyclopentyl-2-((5-(piperazin-1-yljpyndin-2-yl)aminojthieno[3,2-d]pynmidin-6-ylj( piperazin-1-yljmethanon, 7-cyclopentyl-A/-cyclopropyl-2-((5-(piperazin-1-yijpyridin-2-yljamino)thieno[3,2- d]pyrimidin-6-carboxamid, (7-cyciopentyl-2-((5-(piperazin-1-yl)pyridin-2-yljaminojthieno[3,2-djpyrimidin-6-ylj(pyrroiidin-1 -yljmethanon, 7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d|pyrimidin-6- carboxamid, 7-ογοΙορΘη1γ!-/ν-ΓΠθ^Ι-2-((5-(ρίρβΓ3ζϊη-1-γΙ)ργ^ίη-2-ν'θ3Γηίπο)1ΐΊ!Θηο[3,2- d/pyrim id i n-6-carboxam id, 7-ογοΙορβηίγΙ-/ν-θ^γί-2-((5-(ρίρβΓ3ζίη-1-γΙ)ργπά!η-2^Ι)3Γηίηο)ίΝθηο[3,2- d]py ri m id i n-6-carboxam i d, (7-cyc!opentyl-2-((5-(piperazin-1-yljpyridin-2-yl)aminojthieno[3,2-d]pyTimidin-6- ylj(morpholino)methanon, azetidin-1-yl(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2- yljaminojthienof 3,2-d]pyrimidin-6-yl)methanon, (7-cyclopenty!-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yljamino)thieno[3,2- d]pyrimidin-6-yl)(3-methoxyazetidin-1-yljmethanon, (7-cyclopentyl-2-((5-(4-methylpiperazin-1-yljpyridin-2-yljamino)thieno[3,2-d]pyrimidin-6-ylj(piperidin-1 -yljmethanon, (7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yljaminojthieno[3,2- d]pyhmidin-6-ylj(4-methylpiperazin-1-yljmethanon, 7-cyclopentyl-W-cyclopropyl-2-((5-(4-methylpiperazin-1-yljpyridin-2- yl)amino)thieno[3,2-c^pyrimidin-6-carboxamid, (7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-yl)(pyrrolidin-1-yi)methanon: 7-cyclopentyl-A/-methyi-2-((5-(4-methylpiperazin-1-yi)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, (7-cyciopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-yl)(morpholino)methanon, /V,/V-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(piperazin-1-yl)pyridin-2-yQaminojthienoiS^-djpyrimidin-e-carboxamid, A/,/V-dimethyi-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(4-methylpiperazin-1-yl)pyrid!n-2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, A/,/V-dimethyl-7-((1r,4r)-4-methyicyclohexyl)-2-((5,6,7,8-tetrahydro-1,6-naphthyridm -2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, Λ'Λ/-ό^©^Ι-2~((6-^©^Ρ5!6 T’S-tetrahydro-l.e-naphthyridin^-yQaminoj-T-^lr^r )-4-methylcyclohexyi)thieno[3,2-d]pyrimidin-6-carboxamid, 2-((6-acetyl"5,6i7,8-tetrahydro-1;6-naphthyridin-2-yl)amino)-/V7/V-dimethyl-7-((1r,4r) -4-methylcyclohexyl)thieno[3:2-d]pyrimidm-6-carboxamid, 2~((6-(2-hydroxyacetyl)-5,6,7:8-tetrahydro-1!6-naphthyridin-2-yl)amino)-/V./V-· dimethyi-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidin-6-carboxamid, <V/V-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2"((6-(piperazin~1-yl)pyridazin-3-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, /'VJ/V-dimethyl-7”((1r,4r)--4-methylcyclohexyl)-2-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)amino)thieno[3,2-d]pyrirnidin-6-carboxamid, 2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-/V,/V-dimethyl-7-((1r!4r)-4-methylcyclohexyl)thieno[3,2-<^pyrimidin-6-carboxamid, 2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-3-yl)amino)-/V7/V-dimethyl-7-((1 r, 4r)-4-methylcyclohexyl)thieno[3:2-d]pyrimidin-6-carboxamid, eller et farmaceutisk acceptabelt salt deraf.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6 eller et farmaceutisk acceptabelt salt deraf, hvor R2 er valgt blandt C3-10 cycloalkyi, hvor cycloalkyi er usubstitueret eller substitueret med mindst en substituent uafhængigt valgt blandt R6a, RSa er som beskrevet i krav 1; for eksempel hvor R2 er valgt blandt cyclopentyl og cyclohexyl, hvor cyclohexyl er usubstitueret eller substitueret med methyl.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7 eller et farmaceutisk acceptabelt salt deraf, hvor R3 og R4 uafhængigt er valgt blandt hydrogen, C1-10 alkyl og cyclopropyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 7 eller et farmaceutisk acceptabelt salt deraf, hvor R3 og R4 sammen med nitrogenatomerne, som de er bundet til, danner azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl og morpholino, hvor den dannede ring er usubstitueret eller substitueret med methyl, hydroxyl og methoxy.
10 Forbindelse ifølge et hvilket som helst af kravene 1 til 9 eller et farmaceutisk acceptabelt salt deraf, hvor R5 uafhængigt er valgt blandt hydrogen, C1-10 alkyl og -C(O)R7, hvor R7 er valgt blandt methyl og hydroxymethyl.
11. Forbindelse valgt blandt 7-cyclopentyl-/V,/V-dimethyl-2-(5-piperazin-1 -yl)pyridin-2-ylamino)thieno[3,2-c(]pyrimidin-6-carboxamid, 7-cyclopentyl-/V;/V-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)thieno[3 ,2-d]pyrimidin-6-carboxamid, 7-cyclopentyl-/V,/V-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-pyrrolo[3,2-d]pyrimidin-6-carboxamid, 7-cyclopentyl-/V,/V-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-5H- pyrroio[3,2-djpynmidin-6-carboxamid, 7-cyclopentyl-/V,A/-dimethyl-2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrroto[2,1 ,ή[1,2,4]triazin-6-carboxamid, 7-cyclopentyl-/V,A/-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2- yi)amino)pyrrolo[2,1-f][1,2,4]triazin-6-ærboxamid, 7-cyclopentyi-/V,A/-dimethyl-2-((5-(piperazin-1-y!)pyridin-2-yi)amino)furo[3,2-d]pyrimidin-6-carboxamid, 7-cyclopentyl-/V,/V-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yljaminojfurop^-dlpynmidin-e-carboxamid, 7^εΙορβ^^,Λ/,5-ίΓ^θ^Ε2-(5-(ρϊρβΓ3ζίπ-1^Ι)ργ^ίη-2-γΐ3Γηίηο)-5Η-pyrroio[3, 2-cflpyrimidin-6-carboxamid, 7-cyclopentyl-A/,A/,5-tnmethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-y!amino)-5H-pyrrolo[3,2-d]pyrimidin-6-ærboxamid, (S)-7-cyc!opentyl-/V,/V-dimethyl-2-((5-(3-oxotetrahydro-3H-oxazolo[3,4”a]pyrazin-7( 1 H)-y1 )pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, (R)-7-cyclopentyi-A/,A/-dimethyl-2-((5-(3-oxotetrahydro-3H-oxazoio[3;4"a]pyrazin~ 7( 1h')-yi)pyridin~2-yl)amino)th!eno[3,2-d]pyrimidin-6-carboxamid, (R) -7-cyclopentyl-/V,A/-dimethyl-2-((5-(morpholin-2-yl)pyridin-2-yl)amino)thieno[3,2-d]pynmidin-6-carboxamid, 2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-A/,A/-dimethylthienof 3,2-d]pyrimidin-6-carboxamid, 7-ογοΙορΘ^^,/ν^™ΘίΗγΙ-2-((5~(4-(™Θ^γΐ3ηίηο)ρίρθ^ίπ-1-γί^ί^!η-2- yl)amino)thieno[3,2-c/]pyrimidin-6-carboxamid, 7-cyciopentyl·2-((5-(4-(dimethylamίno)piperidίn-1-yl)pyήd!Π-2yl)amίno)"/V,Λ/- dimethylthieno[3,2-d]pyrimidin-6-carboxamid, (S) -7-cyciopentyi~2-((5"(3"(methoxymethyl)piperazin-1-yl)pyridin-2-yl)am!no)-A/.,/V-dimethylthieno[3,2-d]pyrimidin-6-carboxamid, (S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-methylpiperazin-1-yi)pyridin-2-yl)amino)-A/,A/-dimethylthieno[3,2-d]pynmidin-6-carboxamid, (S)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)pyridin-2-yl)amino )-/V,/V-dimethylthieno[3,2-cf|pynmidin-6-carboxamid, (S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-1-yl)pyridin-2-yi)amino)-A/,/V-dimethylthieno[3,2-<y]pyrimidin-6--carboxam!d, (S)-7-cyclopenty’-2-((5-(3-(hydroxymethyl)-4-methyipiperazin-1-yl)pyrid!n-2-yl)amino)-A/,/V-dimethylthieno[3,2-djpyrimidin-6"Carboxamid, (S)7-cyclopΘntyl·-2-((5"(4-ethyl·3”(hydΓOxymethyi)piperaz!n-1-yΠpyπdίn-2-yljaminoj-A/./V-dimethylthienotS^-dlpyrimidin-e-carboxamid, (R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-1-yl)pyndin-2-yl)amino)- A/,/V-dimethylthieno[3,2-cf]pyrimidin-6-carboxamid, (RJ-T-cyciopentyi^-iCS-CS-imethoxymethyQ^-methylpiperazin-l-yQpyridin^-yl)amino)-/V../V-dimethylthieno[3,2-d]pynmidin-6-carboxamid! (R)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)piperazin-1-y!)pyrid!n-2- yl)amino)-A/,/V-d:methylthieno[3,2-d]pyrimidin-6-carboxamid, (R)-7-cyclopentyi-2-((5-(3-(hydroxymethyl)piperazin-1-y!)pyridin-2-yi)amino)-A/-/V- dimethylthieno[3,2-d]pyrimidin-6-carboxamid, (R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)"4-methylpiperazin-1-yl)pyridin-2-yl)amino)-/V;/V-d!methyithieno[3,2-d]pyrimidin-6-carboxamid, (R)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)p!peraz!n-1-yi)pyridin-2- yl)amino )-/V,/V-dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7-cyclopentyl-/V,/V-dimethyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid, 7-cyciopenty!-A/;/V-dimethyi-2-((5-(1-meihyipipendin-4-yl)pyndin-2- yl)amino)thieno [3:2-cnpynmidin-6-carboxamid, 2-((5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)amino)-7-cyclopentyl- N,N -dimethylthieno[3,2-d]pyrimidin-6-carboxamid, T-cyclopentykA/,/ν^ί™θίήγΕ2-( (5-(pi perazi n-4-ylmethy I )pyridin-2~ yl)amino)thieno[3,2-^pyrimidin-6-carboxamid, 7-cyclopentyl-/V;/V-dimethyl-2-((5-((4-methylpiperazin-1-yl)rnethyl)pyridin-2-yl)amino)thieno[3,2-c/]pynmidin-6-carboxamid, 7-cycioρentyl·2-((5-((4-ethylpiperazin-1-yl)methyi)pyridin-2-yl)amino)-Λ/Λ·-dimethy1thieno[3,2-d]pyrimidin-6-carboxamid, 2-((5-((1 S, 4S)-2,5-diazabicyclo[2.2.1]heptan-2-yi)pyridin-2-yl)amino)-7- cyclopentyl-/V,/V-dimethylthieno[3,2-c/]pyrimidin-6-carboxamid, 7-cyclopentyl-fiV,A/-dimethyl-2-((5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)thieno[3,2-d]pyr!midin-6-carboxamid, (R) -7-cydopenty1-2-((5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yi)pyridin-2-yl)amiao)-A/,/V-dimethylthieno[3,2-d]pynmid!n-6-carboxamid, (S) -7-cydopentyl-2-((5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yi)pyridin-2- y1)amino)-A/,/V-dimethyithieno[3,2-c/]pyrimidin-6-carboxamid, 2-((5-((1 R4R)-2,5-diazabicydo[2.2 1 ]heptan-2-yl)pyndin-2-yi)amirio)-7-cycϊop©ntyl·Λ/,Λ/-dimethylthieno[3,2-djpyπmid!n-6-carboxamidl 2-((5-(3,6-diazabicydo[3.1.1 ]heptan-3-yl)pyridin-2-yl)ammo)-7-cydopentyl-/V,/V-dimethylthieno[3,2-d]pyrimidin-6-carboxamid, 7^οΙορθΓ^!-Λι(/ν"ΰ^θ^Ι-2-((5-(6-ΠΊβίΐΊνΊ-3,6-άϊ3Ζ3Ρ^θΙο[3.1.1 ]heptan-3- yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-carboxamid,
12. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller et farmaceutisk acceptabelt salt deraf og msndst en farmaceutisk acceptabel bærer.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller et farmaceutisk acceptabelt salt deraf eller en farmaceutisk sammensætning deraf ifølge krav 12 til anvendelse ved behandling af maligne hyperproliferative lidelser.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller et farmaceutisk acceptabelt salt deraf eller en farmaceutisk sammensætning deraf ifølge krav 12 og valgfrit i kombination med et andet terapeutisk stof til anvendelse ved behandling, modvirkning eller forebyggelse af maligne hyperproliferative lidelser, som reagerer på inhibering af cyclin-afhængig kinase 4/6.
15. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller et farmaceutisk acceptabelt salt deraf eller en farmaceutisk sammensætning deraf ifølge krav 12 og valgfrit i kombination med et andet terapeutisk stof til anvendelse ved behandling af en celleproliferativ lidelse.
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