DK2013175T3 - p38 Map-kinase-inhibitorer - Google Patents

p38 Map-kinase-inhibitorer Download PDF

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DK2013175T3
DK2013175T3 DK07732629.6T DK07732629T DK2013175T3 DK 2013175 T3 DK2013175 T3 DK 2013175T3 DK 07732629 T DK07732629 T DK 07732629T DK 2013175 T3 DK2013175 T3 DK 2013175T3
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alkyl
amino
phenyl
hydrogen
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DK2013175T5 (da
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David Charles Festus Moffat
Stéphane Pintat
Stephen Davies
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Chroma Therapeutics Ltd
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Claims (13)

1. Forbindelse med formlen (I):
(i) hvor: G er -CH= D er en eventuelt substitueret phenylring; R6 er hydrogen; P repræsenterer hydrogen og U repræsenterer et radikal med formlen (IA); eller U repræsenterer hydrogen og P repræsenterer et radikal med formlen (IA); -A-(CH2)z-X1-L1-Y-NH-CHRiR2 (IA) hvor A repræsenterer en eventuelt substitueret phenyl- eller cyclohexylring; z erO eller 1; Y er en binding, -C(=0)-, -S(=0)2-, -C(=0)NR3-, -C(=S)-NR3, -C(=NH)NR3 eller -S(=0) 2NR3-, hvor R3 er hydrogen eller eventuelt substitueret Ci-C6-alkyl; L1 er et divalent radikal med formlen -(Alk1)m(Q)n(Alk2)P-, hvor: m, n og p uafhængigt er 0 eller 1, Q er (i) et eventuelt substitueret divalent mono- eller bicyklisk carbocyklisk eller heterocyklisk radikal med 5-13 ringelementer, eller (ii), i tilfældet hvor både m og p er 0, et divalent radikal med formlen -X2-Q1- eller -Q1-X2-, hvor X2 er-O-, S- eller NRA_, hvor RA er hydrogen eller eventuelt substitueret Ci-C3-alkyl, og Q1 er en eventuelt substitueret divalent mono- eller bicyklisk carbocyklisk eller et heterocyklisk radikal med 5-13 ringelementer, Alk1 og Alk2 uafhængigt repræsenterer eventuelt substituerede divalente C3-C7- cycloalkylradikaler, eller eventuelt substitueret lige eller forgrenet, Ci-C6-al-kylen-, C2-C6-alkenylen- eller C2-C6-alkynylenrafikaler, der eventuelt kan indeholde eller ende i et ether- (-0-), thioether- (-S-) eller amino- (-NRA-) link, hvor RA er hydrogen eller eventuelt substitueret Ci-C3-alkyl; og X1 repræsenterer en binding; -C(=0); eller -S(=0)2-; -NR4C(=0)-, -C(=0)NR4-,-NR4C(=0)NR5-, -NR4S(=0)2-, eller -S(=0)2NR4- hvor R4 og Rs uafhængigt er hydrogen eller eventuelt substitueret Ci-C6-alkyl; Ri er en estergruppe, der kan hydrolyseres med ét eller flere intracellulære carboxylesteraseenzymer til en carboxylsyregruppe; R2 er sidekæden af en naturlig eller ikke-naturlig alphaaminosyre udvalgt fra: (i) Ci-Ce-alkyl, phenyl, 2,- 3-, eller 4-hydroxyphenyl, 2,- 3-, eller 4-methoxyphenyl, 2,-3-, eller 4-pyridylmethyl, benzyl, phenylethyl, 2-, 3-, eller 4-hydroxybenzyl, 2,- 3-, eller 4-benzyloxybenzyl, 2,- 3-, eller 4- Ci-Ce alkoxybenzyl, og benzyloxy(Ci-C6alkyl)-grupper; (ii) den karakteriserende gruppe af en naturlig α-aminosyre, hvori enhver funktionel gruppe kan beskyttes; (iii) grupper -[Alk]nRe, hvor Alk er en (Ci-C6)alkyl- eller (C2-C6)alkenylgruppe, eventuelt afbrudt af ét eller flere -O-, eller -S- atomer eller -N(R7)- grupper [hvor R7 er et hydrogenatom eller en (Ci-C6)alkylgruppe], n er 0 eller 1, og R6 er en eventuelt substitueret cycloalkyl- eller cycloalkenylgruppe; (iv) en benzylgruppe substitueret i phenylringen af en gruppe med formlen -OCH2COR15, hvor R15 er hydroxyl, amino, (Ci-C6)alkoxy, phenyl(Ci-C6)al-koxy, (Ci-C6)alkylamino, di((Ci-C6)alkyl)amino, phenyl(Ci-C6)alkylamino, resten af et aminosyre- eller halid-, ester- eller amidderivat deraf, hvor resten er bundet via en amidbinding, hvilken aminosyre er udvalgt fra glycin, a- eller β-alanin, valin, leucin, isoleucin, phenylalanin, tyrosin, tryptophan, serin, threonin, cystein, methi-onin, asparagin, glutamin, lysin, histidin, arginin, glutaminsyre og asparaginsyre; (v) en heterocyklisk (Ci-C6)alkylgruppe, der enten er usubstitueret eller mono- eller disubstitueret i den heterocykliske ring med halo, nitro, carboxy, (C1-C6)alkoxy, cyano, (Ci-C6)alkanoyl, trifluormethyl (C1-C6)alkyl, hydroxy, formyl, amino, (Ci-C6)alkylamino, di-(Ci-C6)alkylamino, mercapto, (Ci-C6)alkylthio, hydroxy^ i-C6)a I kyl, mercapto(Ci-C6)alkyl eller (Ci-C6)alkylphenylmethyl; og (vi) en gruppe -CraRbRc, hvori: hver af Ra, Rb og Rc uafhængigt er hydrogen, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(CiC6)alkyl, (C3-C8)cycloalkyl; eller Rc er hydrogen og Ra og Rb uafhængigt er phenyl eller heteroaryl, såsom pyridyl; eller Rc er hydrogen, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(Ci-C6)alkyl, eller (C3-C8)cycloalkyl, og Ra og Rb sammen med carbonatom, hvortil de er bundet, danner et 3- til 8-leddet cycloalkyl eller en 5- til 6-leddet heterocyklisk ring; eller Ra, Rb og Rc sammen med carbonatom, hvortil de er bundet, danner en tri-cyklisk ring (for eksempel adamantyl); eller Ra og Rb hver uafhængigt er (Ci-Ce)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(Ci-C6)alkyl, eller en gruppe som defineret for Rc nedenfor, der ikke er hydrogen, eller Ra og Rb sammen med carbonatom, hvortil de er bundet, danner en cycloalkyl- eller heterocyklisk ring, og Rc er hydrogen, -OH, -SH, halogen, -CN,-C02H, (Ci-C4)perfluoroalkyl, -CH2OH -C02(Ci-C6)alkyl, -0(Ci-C6)alkyl,-0(C2-Ce)alkenyl, -S(Ci-C6)alkyl, -SO(Ci-C6)alkyl, -S02(Ci-Ce) alkyl, -S(C2-C6)alkenyl, -SO(C2-C6)alkenyl, -S02(C2-C6)alkenyl eller en gruppe -Q2-W, hvor Q2 repræsenterer en binding eller -O-, -S-, -SO- eller -SO2- og W repræsenterer en phenyl-, phenylalkyl-, (C3-C8)cycloalkyl-, (C3-C8)cycloalkylalkyl-, (C4-C8)cycloalkenyl-, (C4-C8)cycloalkenylalkyl-, heteroaryl- eller heteroarylalkylgruppe, hvilken gruppe W eventuelt kan være substitueret med én eller flere substituenter, der er uafhængigt udvalgt fra, hydroxyl, halogen, -CN, -CO2H -C02(Ci-C6)alkyl, -CONH2, -CONH(Ci-C6)alkyl, -CONH(Ci-C6alkyl)2, -CHO, -CH2OH (Ci-C4)perfluoralkyl, -0(Ci-C6)alkyl, -S(Ci-C6)alkyl, -SO(Ci-C6)alkyl, -S02(Ci-C6)alkyl, -NO2, -NH2,-NH(Ci-C6)alkyl, -N((Ci-C6)alkyl)2, -NHCO(Ci-C6)alkyl, (Ci-C6)alkyl, (C2-C6)alke-nyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, phenyl eller benzyl; og medmindre andet er nærmere angivet i den kontekst, hvori den forekommer, betyder termen "substitueret", når den anvendes til en hvilken som helst del heri, substitueret med op til fire forenelige substituenter, der hver er uafhængigt udvalgt fra (Ci-C6)alkyl, (Ci-C6)alkoxy, hydroxy, hydroxy(Ci-C6)alkyl, mercapto, mercapto(Ci-C6)alkyl, (Ci-C6)alkylthio, phenyl, halo indbefattende fluor, brom og chlor, trifluormethyl, trifluormethoxy, nitro, nitril (-CN), oxo, -COOH, -COORA, -CORA, -S02Ra, -CONH2, -S02NH2,-C0NHRA, -S02NHRa, -CONRaRb, -S02NRaRb, -NH2i -NHRa, -NRaRb, -OCONH2, -OCONHRA, -oconrarb, -NHCORA, -NHCOORA, -NRbCOORa, -NHS020Ra,-NRbS020H, -NRbS020Ra, -NHCONH2, -NRaCONH2,-NHCONHRb,-NRaCONHRb,-NHCONRaRb, eller - NRACONRARB, hvor RA og RB uafhængigt er en (Ci-C6)alkyl, (C3-Ce) cycloalkyl, phenyl eller monocyklisk heteroaryl med 5 eller 6 ringatomer.
2. Forbindelse ifølge krav 1, hvor P er hydrogen og U er et radikal med formlen (IA) som defineret i krav 1.
3. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor A er eventuelt substitueret 1,4-phenylen.
4. Forbindelse ifølge krav 1, hvilken forbindelse har formlen (IIA), (IIB) og (IIC):
{li Ά) (t!8) (HC) hvor R11 = F, R12 = H, R13 = H og R14 = H; eller R11 = F, R12 = F, R13 = H og R14 = H; eller R11 = F, R12 = H, R13 = F og R14 = F; eller R11 = F, R12 = F, R13 = F og R14 - F; eller R11 = F, R12 = F, R13 = F og R14 = H og hvor z, X1, L1, Y, R1 og R2 er som defineret i krav 1.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 1, hvor radikalet -Y-L1-X1-[CH2]z-, er -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2O-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -C(=0)-CH2-, -C(=0)-CH20-, -C(=0)-NH-CH2-, eller -C(=0)-NH-CH20-.
6. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor Ri er en estergruppe med formlen -(C=0)0Ri4, hvor Ru er ReRgRioC-, hvor (i) Rs er hydrogen eller eventuelt substitueret (Ci-C3)alkyl-(Z1)a-[(Ci-C3)al-kyl]b- eller (C2-C3)alkenyl-(Z1)a-[(Ci-C3)alkyl]b-, hvor a og b uafhængigt er 0 eller 1 og Zi er -O-, -S-, eller -NRn-, hvor Ru er hydrogen eller (Ci-C3)alkyl; og R9 og R10 uafhængigt er hydrogen eller (Ci-C3)alkyl-; (ii) Re er hydrogen eller eventuelt substitueret Ri2Ri3N-(Ci-C3)alkyl-, hvor R12 er hydrogen eller (Ci-Cs)alkyl og R13 er hydrogen eller (Ci-C3)alkyl; eller R12 og R13 sammen med det nitrogen, hvortil de er bundet, danner en eventuelt substitueret monocyklisk hetero-cyklisk ring af 5- eller 6- ringatomer eller et bicyklisk heterocyklisk ringsystem af 8 til 10 ringatomer, og R9 og R10 uafhængigt er hydrogen eller (Ci-Cs)alkyl-; eller (iii) Re og R9 taget sammen med det carbon, hvortil de er bundet, danner en eventuelt substitueret monocyklisk carbocyklisk ring af fra 3 til 7 ringatomer eller et bicyklisk carbocyklisk ringsystem af 8 til 10 ringatomer, og R10 er hydrogen.
7. Forbindelse ifølge krav 6, hvor R14 er methyl, ethyl, n- eller iso-propyl, η-, sec- eller tert-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- eller 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl eller methoxyethyl.
8. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor R2 er phenyl, benzyl, iso-butyl, cyclohexyl eller tbutoxymethyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor Ri er en estergruppe med formlen -(C=0)0Ri4, hvor R14 er cyclopentyl, og R2 er phenyl, benzyl, iso-butyl, cyclohexyl eller t-butoxymethyl.
10. Forbindelse ifølge krav 1, der er udvalgt fra gruppen bestående af Cyclopentyl (S)-(3-{4-[6-Amino-5-(2,4-difluorbenzoyl)-2-oxo-2/-/-pyridin-1- yl]-3,5-difluorphenoxy}propylamino)phenylacetat Cyclopentyl (S)-2-(3-{4-[6-Amino-5-(2,4-difluorbenzoyl)-2-oxo-2/-/-pyridin-1-yl]-3,5-difluorphenoxy}propylamino)-4-methylpentanoat Eksempel 42 Cyclopentyl (2F?)-[(3-{4-[6-amino-5-(2,4-difluorbenzoyl)-2-oxo-pyridin-1(2H)-yl]-3,5-difluorphenoxy}propyl)amino](phenyl)acetat
2-Morpholin-4-ylethyl /V-(3-{4-[6-amino-5-(2,4-difluorbenzoyl)-2-oxopyridin-1-(2/-/)-yl]-3,5-difluorphenoxy}propyl)-L-leucinat 2-(Dimethylamino)ethyl /V-(3-{4-[6-amino-5-(214-difluorbenzoyl)-2-oxopyri-din-1 -(2/-/)-yl]-3,5-difluorphenoxy}propyl)-L-leucinat Cyclopentyl /V-[2-(4-{6-amino-5-[(4-fluorphenyl)carbonyl]-2-oxopyridin-1(2/-/)-yl}phenyl)ethyl]-L-leucinat Cyclopentyl /V-(5-{4-[6-amino-5-(2,4-difluorbenzoyl)-2-oxopyridin-1(2/-0-yl]-3,5-difluorphenoxy}pentyl)-L-leucinat Cyclopentyl /V-[3-(4-{6-amino-5-[(4-fluorphenyl)carbonyl]-2-oxopyridin-1(2H)-yl}phenyl)propyl]-L-leucinat Cyclopentyl (2S)-4-amino-2-[(3-{4-[6-amino-5-(2,4-difluorbenzoyl)-2-ox-opyridin-1(2/-/-yl]-3,5-difluorphenoxy}propyl)amino]butanoat Cyclopentyl /V-(5-{4-[6-amino-5-(4-fluorbenzoyl)-2-oxopyridin-1(2/-/)-yl]-3,5-difluorphenoxy}pentyl)-L-leucinat Cyclopentyl A/-[2-(4-{6-amino-5-[(2,4-difluorphenyl)carbonyl]-2-oxopyridin-1(2/-/)-yl}phenyl)ethyl]-L-leucinat tert-Butyl A/-[2-(4-{6-amino-5-[(2,4-difluorphenyl)carbonyl]-2-oxopyridin-1(2/-/)-yl}phenyl)ethyl]-L-leucinat Cyclopentyl (2S)-{[2-(4-{6-amino-5-[(4-fluorphenyl)carbonyl]-2-oxopyridin-1(2/-/)-yl}phenyl)ethyl]amino}(phenyl)ethanoat Cyclopentyl /V-[2-(4-{6-amino-5-[(4-methylphenyl)carbonyl]-2-oxopyridin-1(2/-/)-yl}phenyl)ethyl]-L-leucinat Cyclopentyl A/-[2-(4-{6-amino-5-[(4-chlorphenyl)carbonyl]-2-oxopyridin-1(2/-/)-yl}phenyl)ethyl]-L-leucinat.
11. Forbindelse ifølge et hvilket som helst af de foregående krav, hvilken forbindelse er i form af et farmaceutisk acceptabelt salt.
12. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af de foregående krav, sammen med en farmaceutisk acceptabel bærer.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 10 til behandling af autoimmun eller inflammatorisk sygdom.
DK07732629.6T 2006-05-04 2007-05-01 p38 Map-kinase-inhibitorer DK2013175T5 (da)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0608855A GB0608855D0 (en) 2006-05-04 2006-05-04 Inhibitors of MAP kinase enzymes
GB0613914A GB0613914D0 (en) 2006-07-13 2006-07-13 Inhibitors of p38 map kinase
PCT/GB2007/001596 WO2007129040A1 (en) 2006-05-04 2007-05-01 p38 MAP KINASE INHIBITORS

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DK2013175T3 true DK2013175T3 (da) 2017-02-20
DK2013175T5 DK2013175T5 (da) 2020-12-21

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US (1) US8044211B2 (da)
EP (1) EP2013175B9 (da)
JP (1) JP5340918B2 (da)
KR (1) KR101429780B1 (da)
CN (1) CN102942520B (da)
AU (1) AU2007246869B2 (da)
BR (1) BRPI0711310B8 (da)
CA (1) CA2650970C (da)
CY (1) CY1118518T1 (da)
DK (1) DK2013175T5 (da)
ES (1) ES2605727T3 (da)
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JP5555186B2 (ja) * 2008-02-29 2014-07-23 クロマ セラピューティクス リミテッド ｐ３８ＭＡＰキナーゼ阻害剤
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AR073711A1 (es) 2008-10-01 2010-11-24 Astrazeneca Ab Derivados de isoquinolina
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GB201211310D0 (en) 2012-06-26 2012-08-08 Chroma Therapeutics Ltd CSF-1R kinase inhibitors
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GB201306901D0 (en) * 2013-04-16 2013-05-29 Chroma Therapeutics Ltd Combination
CN106459042B (zh) 2014-04-02 2019-06-28 英特穆恩公司 抗纤维化吡啶酮类
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KR101429780B1 (ko) 2014-08-18
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AU2007246869A1 (en) 2007-11-15
ES2605727T3 (es) 2017-03-16
PT2013175T (pt) 2017-02-14
CN102942520B (zh) 2015-03-04
WO2007129040A1 (en) 2007-11-15
JP5340918B2 (ja) 2013-11-13
CY1118518T1 (el) 2017-07-12
EP2013175B1 (en) 2016-11-09
HUE033281T2 (en) 2017-11-28
JP2009535385A (ja) 2009-10-01
BRPI0711310B8 (pt) 2021-05-25
BRPI0711310A2 (pt) 2011-12-06
AU2007246869B2 (en) 2012-10-18
EP2013175A1 (en) 2009-01-14
NZ573348A (en) 2012-01-12
CN102942520A (zh) 2013-02-27
CA2650970C (en) 2014-09-16
US8044211B2 (en) 2011-10-25
DK2013175T5 (da) 2020-12-21
CA2650970A1 (en) 2007-11-15
BRPI0711310B1 (pt) 2020-12-15
KR20090014187A (ko) 2009-02-06
US20090099185A1 (en) 2009-04-16

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