(WO201990158) Substituted pyrrolopyrimidine jak inhibitors and methods of making and using the same 机翻标题: 暂无翻译,请尝试点击翻译按钮。

源语言标题
(WO201990158) Substituted pyrrolopyrimidine jak inhibitors and methods of making and using the same
公开号/公开日
WO2019/090158WO2019/090158 / 2019-05-092019-08-01
申请号/申请日
WOUS2018/059071 / 2018-11-02
发明人
ANDERSON DAVID RANDOLPHHOCKERMAN SUSAN LANDISBLINN JAMES ROBERTJACOBSEN ERIC JON;
申请人
ACLARIS THERAPEUTICS;
主分类号
IPC分类号
C07D-239/95 C07D-471/04 C07D-487/04
摘要
(WO2019/090158) The present invention relates to new pyrrolopyridine compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of JAK1 and JAK3 kinase activity in a human or animal subject are also provided for the treatment diseases such as pruritus, alopecia, androgenetic alopecia, alopecia areata, vitiligo and psoriasis.
机翻摘要
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地址
代理人
(WO201990158) FRATTINI, Gregory D. ([US])
代理机构
;
优先权号
2017US-62581428 2018US-62670448
主权利要求
(WO201990158) CI. ,A I: What, is claimed is: 1. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (I.):   wherein:   Rj is selected from -CO2R.5, -Ci-C5alkyl-C02R5, ~C. C6-cycloalkyl-C02R5, - NHCO2R5, -N(CrC5aikyl)~C02Rs, ~0-C02R5, or -Cj-Csalkyl-O-COaRs;   R2is selected from H, -Ci-C4alkyl, -CrCeeyeioalkyl, or -CrC2alkyl VC6cycloalkyl, wherein ihe alkyl or eycloalkyi groups are optionally substituted with one or more groups selected from halogen, -OH, or -O-Cj-Csalky ; ii is 0, 1 or 2;   Ring A is substituted at one or more carbons with one, two, or three R.3 substiiuents wherein each R.3 group is independently selected from H, halogen, -Ch-C^aikyl, - Cs-Qcycloalkyl, -OH, or -O-Ci-C-salkyl wherein each alkyl or eycloalkyi group is optionally substituted with one or more groups selected from: halogen, -OH, ~C\~ Csa!kylalkoxy, or -O-CrCsalkyl;   Two R3 groups on the same or different carbon atoms of the ring A may be optionally- joined to form a spiroeyelic or bieyclie ring system with ring A;   R4 is selected from -C(0>R6, -CH2¾, -C(0)-CH=CH2, -C(0)-C(CH2OCH3)=CH2, - C(0)-CH=€HC¾, -C(0)-CH= HCH2R7R,¾-C(0)»C5»C5alkyl, or -C(0)-C3-  CfjCycloalkyl, wherein the alkyl or eycloalkyi groups may be optionally substituted with one or more groups selected from -OI-L halogen, alkyne, or -CN; R5 is selected from -Ci-Cjalkyl, or -Cj-Qcyeioaikyl wherein the alkyi or cycloalkyi groups may be optionally substituted by one or more groups selected from halogen, -OH, or -0~Cr~C5alkyl;   Re is selected from -Ct-Csa!kyl, -C^-Cicycloalk l, -Ci -Csalkyl-Ca-Cecycloalkyl, -  NR7R.S, -O-aryl, -O-beteroaryl, aryl, or beteroaryl wherein tire alkyi, cycloalkyi, aryl or heteroaryl groups can be optionally substituted by one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-Ct-Cjalkyl, or -O- C.rCyCycloalkyl;   R7and R§ are independently selected from II, -C1-C5 alkyi, -CpCs alkoxy, or -C3-C5 cycloalkyi wherein the alkyi groups may be optionally substituted by one or more groups selected from halogen, -OH, or -C ; and   R7and Rg may he optionally joined to form a ring to form a heteroc cle such as piperidine, pyrrolidine, or with another heteroatorn to form a ring such as ntorpholine,   A compound of Claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof wherein:   Ri is -CO2R5,   A compound of Claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Ri is -Ci-C5-aIkyi-C02Rs.   A compound of Claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Ri is ~C; C()-cycloalk i-C02R5. 5. A compound of Claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Ri is -NHCO2R5,   A compound of Claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Rj is -N(CrCsalkyl}-C02R5 .   A compound of Claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Ri is -G-CO2R5..  A compound of Claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Ri is -Ci-C5alkyl-0-C02R5,   A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (II):   wherein: tic is selected from -CO2R50, -Ci-Cs-aikyl-CO¾Rso, -C3-C6-cycloalk.yl-CQ2R.50, -NHCO2R50, -N(CrC5aikyI)-C02R5o, --O-CC^Rso, or -Ci-C3alkyi-0-C02Rso;   I20 is selected from H, -Cs-Csc cloalk l, or ~Ct-C2alkyl-C3-Cscycioalkyl wherein the alkyl or eycloalkyl groups are optionally substituted with one or more groups selected from halogen, ~OH, or -O-CrCsalkyl; n is 0 or 1 ; Ring Ϊ is substituted at one or more carbons with one, two, or three R3<) substituents wherein each 1¾; group is independently selected from H, halogen, -Ci-C aikyl, - CVQcycioalkyl, -OH, -0-Cj-C3alkyI, -NR70C(O)-CH=CH?.5  -NR7oC(0)-C(CH2OCH3)=CH2}~NR7oC(0)-CH=CHCH3, or -NR70C(O)-  CH=CHCH2RgoR o wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from: halogen, -OH, -CV Csalkyla!koxy, or -O-C Chalky! ;   Two R30 groups on the same carbon atom or two or three !½ groups on different carbon atoms of ring Ϊ may be optionally joined to form a spiroeyclic, bicyclic, or tricyclic ring system with ring I such as adamantyl;   R40 is selected from H, -OH, ~C(OVR¾), -OR^, -O-C(O)-R60, -NR7o~C(0)-R6o, -C C alkyi-C(0)-R6o, -SO2-R60,~SO2-MRS0R90, -Ci-Qalkyl-SQrRio, or -Cf-C4alkyl-   R50 is selected from -Cj-Csalkyl, or -Oj-Cjcycloalkyl wherein the alkyl or cycloalkyl groups may he optionally substituted by one or more groups selected from halogen. -OH, or -Q-Ci -Chalky!;   Rgij is selected from -Cj-Csalky!, -C^-C^cycloalkyi or -C i-Csaiky i-Cs-Cscycloalkyl wherein the alkyl or cycloalkyl groups can be optionally substituted by one or more groups selected from halogen. -CN, alkyne, -OH, or -O-Ci-Csafkyl;   R.70 is selected from H, -Ci-Csalkyl or -C¾~C7,5cycloalkyl;   ¾o and R90 are independently selected from H, -CpCsalkyl, -Cs-Csaikoxy, -C3-  Ctjcycloalkyi wherein the alkyl groups may be optionally substituted by one or more groups selected from halogen, -OH, or -CN; and   Rgo and 0 may be optionally joined to form a ring to form a heterocycle such as piperidine, pyrrolidine, or with another heteroatom to form a ring such as morpholine; wherein the compound of Formula (II) is not   -220-   ethyl 4-(((1 tI?I2s,3S,5s,7s)~5-hydroxyadamantan-2-yi)arr!ino)-1 H~pyrralo[2,3-&Jpyrldine-5-carboxylate,   ethyl 4-(cyciohexyiamino)~1 H-pyrra!o[2,3-&]pyridine-5-carboxyiate,   ethyl 4-(cyciopsntyiamino)-1 H-pyrroio[2,3-i)]pyrid!ne-5-cafboxyiate.   ethyi 4-{cyclohepty!amino}-1 H»pyrro [2,3-¾pyridine-5-carboxylate,   ethyi 4-{({1 S,2R)-2~meihy!eyclohexy!)amina)-1 H'-pyrrala[2,3-£s]pyhdine-5-carbaxylaie,   -221-   ethy! 4-{((1R2S)"2-methyteyc!ohexyl}amino)-1H"pyrrc [2,3-0]pyrldkie-5"Carboxy!aie:  ethyi 4-{(3-rnethyicyciohexyl)am!no}-1 H-pyrrolo[2,3-0]pyridine-5-carboxyiaie,   eihy! 4-{{4-meihy!cyclGhexyl)amino)-1 H-pyrroio[2,3-&]pyridine-5-carboxyiate,   ethyl 4-{{2,2~dimethylcyclohexyS)8mino)-1 H-pyrrolo[2I3~fe]py idir!e~S-Garboxytete, or.   ethyl 4-{{(1 S,2 ¾-2-ethy!cyciohexyl)amino)-1 H-pyrrolo[2.3-6jpyridine-5-carboxy!ate. 10. A compound of Claim. 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   RJ O is -CO^Rio-   R.20is selected from H, -Ci-C4aikyl,   wherein the alkyl or cycloalkyl groups are optionally substituted with one or more groups selected from halogen, -OH, or -O-Ci-Csaikyi;   1 1. A compound, of Claim 9, or a pharmaceutically acceptable salt, hydra te or solvate thereof, wherein:   R;o k -Ct-C5-alkyl-C02R.5G.   12,. A compound of Claim 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Ri is -C3-C6-cycIoalk l-C02l s.   13, A compound of Claim 9, or a pharmaceutical ly acceptable salt, hydrate or solvate thereof, wherein:   R io is ~NHCO- f½>, 4, A compound of Claim 9, or a pharmaceutically acceptable salt, hydraie or solvate thereof wherein: io is -N(C;-C5alkyl) C02R5o. A compound of Claim 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Rio is -Q-CO2R50.   A compound of Claim 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:   Rso is -Ci-C3alkyi~0-e02R.5o.   A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof of Formula (Hi):  wherein:   Riooo is selected from -CO2R5000, -Ci -Cjalkyl-COsRsooo, ^ C cycloalk !-COaRsooo, -NHC02R50oo, -N(Ci-Cs alkyl)-C02R50oo, -0-C02RSooo, or -C3-C5alkyl-0-   R2.000 is selected from H, ~Cj-C4aikyl5-Cj-Cseyeloa kyl, or   C6cycloaikyl5wherein the alky I or cycloalkyl groups are optionally substituted with one or more groups selected from halogen, -OH, or -O-Ci-Csalkyl; n is 0, 1 or 2;   Ring Q is substituted at one or more carbons with one, two, or tirree ¾ substituents wherein each R30 0 group is independently selected from H, halogen, -C-.-i^alkyl, -C^-Cecycloalkyl. -OH, or -O-Ct-Csalkyl wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from: halogen, -OH. - CpCsalkylalkoxy, or -O-Cj-Cjalkyl; Two !½■(¾groups on the same or different carbon atoms of the ring Q may be optionally joined to form a spirocyciic or bkyelie ring system with ring Q;   R4000 is selected from -C(0)-R6ooo, -CHTRSOOO, -C(0)-CH=€H2, -C(0)- C((."H2Oi:f Ci -C(0)-C>- Csalkyl, or -C(0)~CVC6eyc]oa!kyl5wherein the alky] or cycloalkyl groups may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or ~CN: 500 hs selected .from H, -Ci-Cjalkyl. and -Cs-Qcyeloalkyl wherein the a!kyi or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, -OH, -C3-C5 cycloalkyl, or -O-Cj-Csalkyl; 6000 is selected from -Cj-Cjalkyl, -Cs-Gscycloalkyl, -CrCsalkyl-Ca-CbCycl alkyl, - R7ooijRsooo» -O-aryi, -Q-heieroaryl, aryl, or heteroaryi wherein the alkyl, cycloalkyl, aryl or heteroaryi groups can be optionally substituted by one or more groups selected from halogen, -CN, alkyne, -OH, trifluorornethy!, -0-Ci~C5alkyl, or -0-C¾-QeyeloaIkyl;   R7000 and Rgooo are independently selected from H, -Ci-Cs alkyl, -Ci-C*alkoxy, or - C3-C5 cycloalkyl where the alkyl groups may be optionally substituted by one or more groups selected from halogen, -OH, -CN, or -C3-C5 cycloalkyl;   R7000a*d Rgooo ma be optionally joined to form a ring to form a heterocycle such as piperidine, pyrrolidine, or with another heteroatom to fomi a ring such as morphoiine. 18. A compound, or a phamiaceuiically acceptable salt, hydrate or solvate thereof, of Formula {IV): wherein:   Rioooo is selected from -CO2R.50000, -CJ -Cs-alkyl-COa scooo, -Cj-Q-cycloalkyl-  CGa- , - CO?x,. -NiC :··< alky!)-C02RSOooo, -O-CO2R50000, or -C  Csalkyl-O-C hRjoooo;   R20000 is selected from H, -Ct-C-jalkyl, -C rCftCycloalkyl. or --Cv-Cjalkyi-CV Cscycioalkyi wherein the aikyl or cycloaikyl groups are optionally substituted with one or more groups selected from halogen, -OH, or -O-C.-Csalkyl; n is 0 or 1 ;   Ring S is substituted at one or more carbons with one, two, or three R3.3 substituents wherein each R30000 group is independently selected from H, halogen, -C|- C4alkyi, -CrQcycloaikyi, -00, -0-Ci-C5alkyl, ~NR700QQC(O)~eH-CB2 ;~NR7(H)ooC(0)-C(Ce?.OCH3)=€e?., -NR7OOQOC(0>CH-CHCH3, or ~NR70oo C(OV wherein each: alkyl or cycloaikyl group is optionally substituted with one or more groups selected from; halogen, -CN, -OH, -C\- Cjalkylaikoxy, or -O-Ci-Csalkyl;   Two R30000 groups on the same carbon atom or two or three 30 groups on different carbon atoms of ring S may be optionally joined to form a spirocyclic, bieyclie, or tricyclic ring system with ring S such as adamaniyl;   R40000 is selected from H, -OH, ~C(0)-R6oooo>-OReoooo, -0-C(0)-R6 io >¾ -NR-amr  C(0)-R6oooo, "CrC4aikyhC(0)-R6oooo, -SOTRAOOOO, -S02-NRgoooo¾oooo, ~d~C4alkyi-S02-R6oo5or -C \ -C4alkyl-S02NRsoooo 0ooo;   -226- R50000 is selected from H, -Ci-Csalkyl, and -Q-CecycloaJkyl wherein the alkyi or eycioalky! groups may be optionally substituted by one or more groups selected from halogen, ~OH, ··(': ¾··(..'·; cycloalkyl, or -O-CrCsalkyl;   Rfioooo is selected from -d-QalkyL -Cg- jcyeioalkyl or -Ci-Csaikyl-C3-G¾cycloaIkyl wherein the alkyl or cycloalkyl groups can be optionally substituted by one or more groups selected from halogen, -CN, alkyne, -Oi l, or -O-Ci-CsaJkyl;   R70000 is selected from II, -Cj-Csalky! or -Cs-Qcyeloalkyl;   Rgoooo and R90 0 are independently selected from H, -Ci-Csalkyl, -Cf -Csalkoxy, or - (¾-i¾cycloalkyl wherein the alkyl groups may be optionally substituted by one or more groups selected! from halogen, -OH, or -CN; and   R«oooo an R 0000 may be optionally joined to form a ring to form a heterocycle such as piperidine. pyrrolidine, or with another heteroatom to form a ring such as morpholine; wherein the compound of Formula (TV) is not   ethyl ^(((IR^s.SS.SsJsJ-S-hydrox adamantan^-y aminoJ-l W-pyrro!oi2,3-63pyridine-5-carboxylate,   ethyl 4-(cyclohexy!amino)-1 H-pyrroloi2.3- d]pyridine-5-carboxylaie.  -227-   ethyl 4-(cyciopentylarninQ)-1 H-pyrrQ!o[2,3-i)]pyridirie-5-carboxyiate.   ethyi 4-(cyciohepty!amlno)-1 H-pyrroio[2l3-i ]pyridir!e-5-cafboxy!atsl  ethyl 4-(((1 S R)-2-methylcyclohexyi}amino)--1 H^yrro!o[2,3~&]pyridine-5-carboxy!ate!  ethyl 4-{({1 Rl2S)-2-methyicyclohexyl)afYiino)-1H-pyrroio[2,3-i?]pyridine-5-carboxy!ate,   ethyl 4-({3-rnethyicyc!ohexyi)amino)-1 H--pyrro!o[2)3--&3pyi'iciin&-5--carboxyiat8,   ethyl 4-((4-methy!cyciohex i)amino)-1 H-pyrroio^^-bJpyridine-S-carboxyiate,   ethyl 4-{{2,2~dimethyicyciohexyi)amino}-1 H~pyrroSo[2I3-i3]pyridjne~5-Garboxylate, or.    ethyl 4-(((1 S^ftl^-etb ic ohex amincH H-pyrroioi2,3-D]pyriciine-5-carboxyiste.   The compound of Claim 1, wherein the compound Is selected from the group consisting   ethyi -(((3 RAR)~ I -(2-cyanoacety!)-4~methylpiperidii3"3- yl)(meEhyl)aEnino)-l//-pyTroio[2,3-i>]pyridine-5-carboxyIateJ  metby! 4-(( 3R,4R}- I -(2-cyani(sace!y])-4"Enethy!piperii3iii-3- yi)(j¾etbyi)antino)- i if-pyjTo1o[2,3-£?3pyrtdine-5'Ca!-bo.¾yiate,   ~230~ methyl 4-(roetliyi{(3A!,4 R)-4 -methyl- 1 -(pyrrolidine- 1 - c rbonyi)p!pgridin"3-yl)amino)"i -pyn-o [2,3-i]pyTidine-5-- carhoxvlate.   ethyl 4~(i!ieihyl((3/<i.4R)-4-methyI-i -(pyrrolidine-, carbonyl)piperidin-3-y])ariiiiio)-! -pyrro!o[23-6ip}Tidine-5- carboxylaie.   isopropy! 4-(methyl((3 ?,4.R)-4-metby!- 1 -(pyrrolidine- i - carbonyi)piperidi5i-3-yI}ainii5o)-l i~py!Toio2I3-?]pyrsdi!ie-5- carboxyiate,   isopropy! 4-(((3R,4R)~ 1 -((S)-3-fluoropyrrolidine- 1 -carbonyi)-4- riiethylpiperidin-3-yl){methyi)amino)-l/-/-pyiToSo[2,3-5pyTidi!"i£   5-carboxyS te,   ethyl 4-(((3/?,4/¾- 1 -((S)-3-i1uoropytroljdjirie--l--ca!rt )riyl>-4-   ethyl 4 ((3i?,4?>{-((R)-3-{luoTOpy!ToHd)i5e-i-carboKyl)-4- methy{piperidin-3-y1Xmethyl)arcjno l/f-pyrro3o[2,3-6]pyridine- 5-carboxylate,   -231-   ¾ H 2-rnethoxyethyi 4-(((35tS)- 1 -b iyryM-raethylpiperidin-S y])amino)-l/-pyrrolo[2,3-i']p> idi!ie-5-carboxy]aie,  O  'i-meihoxyethyl 4 ((3 {(4f)-4-ine!hyI- 1 -(3- meibylbuta;ioyl)piperidin"3"y!)amirio)"i/iv--;p5';i o!o[2,3-- i>]pyridine-5~carboxylaie.  2-meihoxyeihyl 4-(((35,4S)-4-methyl-l-propylpiperid{n-3- yl)amirAi!)-] /-pTrolo[2,3~i)]pyTiclme"5-carboxylate.   -methoxyethyi 4-(((3S,4S)-l-eihyi-4-methylpiperidin-3- yl)amino)-l/-/-pyrro]o[2,3-6]pyridine-5-carboxyIaie, methyl 4-(((3 R,6S)~ 1 -acryloyl-6-methy 3piperidin-3 -yijan ino)- t//-p trolo[2,3-&]pyrtdine-5-carboxy!ate>  ethyl 4~(({3i?,6S)~ i -acryloyi~6~!Tiethylpiperidin-3~y:)amkio)~ ί / - p> Toio[2,3-i!]pyTidine-5-c£irboxyiate,   isopropyl 4-(((3i¾65)-l-acfyloyi-6-me0iylpiperidin-3-yi)amino)- i /-pyrrolo[2,3-6]pyridir!e-5-carboxyiate.   methyl (/¾-4-((l-aci7loylpiperidiTi-3-yi)anii3io)-] /:/-pyrrolo 2,3- έ> jpyrkime -5 -carboxylate,   ethyl ( H~((1 -acryloy]piperidin-3-yi)attiino)- 1 i ~pyrroIo[233- 6jpyridine-5-carboxylate,   isopropyi (/f)-4- ( 1 -acr loyipiperidL -3-yl)amino)- 1 /- pyrrekf[2sj-&!pyridirie-5-c;srboxy5ate¾  2-methoxyethyl (/?)-4-{( ί -acryloy tpiperidin-3 -yt)amino)- 1 H- pyrrolo[2,3-ii]pyridine-5-carboxylate,   -234-   -235-   ~236~   -237- ethyl 4-(( 1 -aer toy 3~6-msthy ipiperidin-3 ~y l)arnino)- 1 H- pyrroloi2,3-&3pyridine-5-carboxylaie,  ethyl 4-(([-acry'loy!-6-ineihylpiperidii!-3-yl)(iiieihy])airiii5.cs)- 1 /-/- pyrro;o[2,3-¾]pyridme-5-carboxylaie,   ethyl 4-(( 1 -acryioy{piperidin-3-yl)amino>li/-pyrrolo[2>3- ¾]p>Tidine-5-cas'boxylaie,   methyl 4-({l-acr>'loyl-6-methy!piperidin"3~yl)a!nirio)-l//" pyrrolo[2,3-fe3pyriiiine-5-carboxylate,   snethyl 4-((l~acryloyl-6-iiie!hylpipenciiiJ-3-yi)(rt!eihy])aimino)- l W-pyrrolo[2,3-¾3pyrjdine-5-carboxylate,   isopropyl 4-(( ί -atryloyi-6-methyipiperidin-3-y Qamino)- 1 /- pyrri o[2s3--ft]pyridine--5--earbGxy].ate,   isopropyl 4-((l~acryloyl-6-meihylpiperidin"3"y!)(meibyl)!iffiirfo)"   1 -pyrrolo [2 ,3 ~£]pyridme-5 -carboxylate,   -238- -   -239- ethyl 4-({(3RAK)~ 1 2-cyanopKspatKtyl)-4'raetbylpiperidin-j   yl)amino)-l -pyiToloi2,3-&3py«dine»5-cat¾oxyiate, ii-   propyl (/ )~4-({ I -(2-cyanoacetyi)piperidin-3-yl)amino)-i 7- pyfTolo[2,3-&]pyridiae-5-ca!toxyiat8,   2-raethoxyethy] (i?)- -((l -(2-cysrf5 acetyl)pjperidm-3-yi)axoiRo)- i /-pynOlo[2,3-¾]pyTidiiie~5-carboxylaie, - 3- 3- - 0 H °"propyl 4-(((3 ?,6S)-l-(2-cyanoacet !)-6-rnethyipiperidin-3-  XT o yl)amino)- 1 /-pyrroio[2,3-6]pyridine-5-carboxy!ate.   -242- -   -   -243- The compound of Claim 9, wherein the compound is selected from the group consisting of:   methyl 4 (4 2-c anoacetoxy)-2-methylcyciohexyl)(jrieth l)atnino) l//-pyrrolo[2s3-¾]pyridiae-5-carboxyiate,   ethyl 4-(((ljR,3jR 3-hydroxycyc!opentyl)(me1¾y{)amino 1 H- pyrrolo[2,3-&]pyridine-5-(;arbiixylates  ethyl 4-(((li?,3i?)-3-(2-cyanoacetoxy)cyciope!3tyi)(!iiethyl)amino)- l -pyrro3o[2,3-i>Jp>Tidine-5-carb0xylaie,   ethyl 4-((( 1 S,3S)-3-(2-cyanoacetoxy)cyclopentyl)(meihyl)airimo)-  I /7-pyrro io [2 , 3 - ¾] pyr idine - 5 -c arboxy late   ethyl 4-(((15,3,S 3-hydroxycycIopentylXmethyi)amino)-l //- pytToio[2,3-&3pyri<iine-5-cafboxylate,   -246- /-/- 1 H- iiio)- nio>   -247-   -248-   -249- -   -250- .3- - - - -   -252- compound of Claim 17, wherein the compound is selected from the group consisting , The compound of Claim 18, wherein the compound is selected from the group consisting   ethyl 4-((3-(2-cyaiu!etby!)cyclohes.y])aminc)-l//-pyrrolo[2,3-  6Jp>ridine-5-carboxyiates ~(m Ethyl 4-((3-(2-cya!ioethyi)cyc]ohexyl)amino)" pyfroio[253-*]p ridine-5-car oxyiate,   (rac)-(irans)-Eihyl 4-((3-(2-cyanoethyI)cyc3ohexyl)amino)-l //- pyrroio[2,3-6jpyridine-5-carboxyiate,  (cis) Ethy! 4~((3-(2-cyaTioethyf)cycio exyl)amino}- 1 /-pyrrolo[2,   ¾]pyridine-5-carboxylate, enanriorner ! ,   Cra isomer s!ngls ananticmer lohexyf)anii!io)-1 W-pyrrolo[2,3- laie, enantiomer 2,   Cis isomer, single e artttonw   (trans) Ethyl 4-((3-{2-cyanoeihy!)cyclohexy3)amHio)-li¾- pyrrolo[2,3-iii]pyrid!Ee-5-carboxyfaie enaniiomer 1,  Trans isomer, single enantiomer exyl)amino)- enaniiomer 2 hexyl)amino)-i/i- xy!ate, ahex> )amino)~ 1 H- xylats, no)-l -pyrrolo[2^- id.   -255-   Cis-enarsiiamer 1  -   ••256- isopropyl 4-((( i S,35 3-(2-cyattoethyi)cyclohexyl)amino   pysTolo[2,3-*]pyr!dine-5-carboxylaie,   isopropyl 4-({(li?,3i?)-3~(2-cyaEioethyl)cyclohexyi)amino)-L¥- pyrroio[2,3-djpyridine~5-carbox;ylaie.   cyclopropy! 4-(f( 15,3 )-3-(2-cyaooeihyf)cyc iobexy l)amino)- 1 H~ pynxs!o 2 ~¾pyxidme-5~earboxylate,   cyclopropy! 4~(((lii3/i}-3"(2~cyanoethyi)cyciohexyi)amino}-l - pyrro!o[2,3-i?]pyrtdiije-5-carl)oxy!aie5  0   if; cyciopropyimethyi ~(((15,,3¾-3~(2-C3¾noeihyi}cyciohexyl)amiiic)- l/ ^yrroio[2,3-fc]pyridiiie-5-carboxy]ate.   cyciopropyimethyi 4-(((l f,3 ?)-3-(2-cyarioethyI)cyclohexyi)amino - i//-pyrro o[2,3-0]pyridine-5-carboxylaie, or   cyciopropyimethyi 4-((( 1 i?,Zv,3S,5f,7.v)-5-hydroxyadaojaf!tan-2- yl)ammo)-l/' -pyrrolo[2,3-fe]pyridine-5-carboxylate.   -257- 23, A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim I , a pharmaceutically acceptable salt thereof a derivative thereof, or a combination thereof; and a pharmaceutically acceptable carrier. 24. A method of treating a JAKl - and/or JAK3 -mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effecti ve amount of a compound of Claim 1 , a derivative thereof, or a combination thereof. 25. The method of Claim 24, further comprising administering another therapeutic agent.   26, The method of Claim 24, wherein said JAKl - and/or J AK3 -mediated disease is selected from the group consisting of an autoimmune disorders or responses, broad activation of the immune responses, bacterial infection, viral infection, inflammation, a chronic and/or acute inflammatory disorder or condition, and/or auto-inflammatory disorder, fibrotie disorders, metabolic disorders, a neoplasm, cardiovascular disorders, cerebrovascular disorders, a skin disorder, pruritus, a hair loss disorder, a cancer or malignancy, autoimmune connective tissue disease, an autoimmune condition; Still's disease, adult- onset Still's disease, Thl 7-assoeia.ted inflammation, polychondritis (e.g. relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dennatomyositis; myasthenia gravis; Arthritis (e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease-associated arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondyiitis/spondyloarthritis/spondyloarthropathy (ankylosing spondylitis), gout, scleroderma (systemic scleroderma, juvenile scleroderma), Reiter's syndrome/reactive arthritis, lyme disease, lupus/ systemic lupus erythematosus (SLE) (lupus erythematosus, pediatric systemic lupus erythematosus, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy, carditis, myocarditis, angiogenesis disorders, myelodysplastic syndrome, atherosclerosis, restenosis (restenosis of an atherosclerotic coronary artery), acute coronary syndrome, myocardial infarction, cardiac-allograft   -258- vasculopat y, transplant arteriopathy; vasculitis (large vessel vasculitis, small vessel vasculitis, giant-cell arteritis, polyarteritis nodosa, vasculitis syndromes including: Takayasu's arteritis, Wegener's granulomatosis, Beehcet's Disease), stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI); gastrointestinal disorders, enterocolitis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, enteritis syndrome/spastic colon, celiac disease; acute and chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (for example, primary biliary cirrhosis or cirrhosis due to fatty liver disease (for example, alcoholic and nonalcoholic steatosis); esophagitis, gastritis, gastric and. duodenal ulcers, peritonitis: Nephropathy, immunologically mediated glomerdonephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathies, diabetic kidney disease/diabetic nephropathy, renal fibrosis, renal ischemic/reperrusion injury, HIV associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulonephritis, chronic kidney disease, (for example, diabetic nephropathy), hypertension induced, nephropathy, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; pulmonary inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury: Meniere's disease; ocular disorders including, (e.g.), ocular inflammation, uveitis, dry eye/keratoconj uncti vi lis sicca, scleritis, episcleritis, keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy (diabetic retinopathy, immune mediated retinopathy, macular degeneration, wet macular degeneration, dry (age related) macular degeneration); Mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (BBS), systemic mast cell disease (SMCD), myelodysplastic syndrome, idiopathic thrombocytic pupura; bone resorption diseases; Neurodegenerative disorders, neurological/ neuromuscular disorders (e.g.), multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guiliain-Barret syndrome, meningitis, encephalitis, traumatic brain injury; nervous system damage, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke/neuronai ischemia, spinal cord Injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disease; pain (acute pain, chronic pain, neuropathic pain, or fibromyalgia) paresthetica, nerve irritation, peripheral neuropathy; pruritus/itch (atopic pruritus, xerotic pruritus, pruritus associated with psoriasis/psoriatie itch/psoriasis-associated itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary-associated itch, renal associated itch/renal itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichen simplex chronicus associated pruritus, iyniphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dernvatitis-associated itch, atopic itch/atopic puritis. bullous itch, brachioradial pruritus) neurogenic itch, neuropathic itch, notalgia paresthetica, pruritic popular eruption of Hi V, psychogenic itch, swimmer's itch, pruritus or uremic itch, urticarial itch: dermatologic disorders (e.g.), dermatologie drug reactions/drug eruptions, xerosis/dry skin, skin rash, skin sensitization, skin irritation, sunburn, shaving, body louse, head lice/pediculosis, pubic lice, cutaneous larva migrans, scabies, parasitic infection, insect infestation, urticaria! hives, popular uritcaria, insect- bites, insect stings, dandruff, foreign objects or devices on skin, fungal infection, herpes, varicell&'ehicken pox, eosinophilic folliculitis, dermatosis of pregnancy /pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses, histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis, psoriasis/psoriasis vulgaris, lichen planus, lichen scierosus, acne (acne vulgaris, comedonai acne, inflammatory acne, nodu!o-cystic acne, scarring acne, acne keloidalis nuchae), atopies (allergic contact sensitization, allergic dermatitis) dermatitis (atopic dermatitis/eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis (Sweet's syndrome), chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE Syndrome), hidrademtis suppurativa, hives, pyoderma gangrenosum, alopecia (eyebrow alopecia, intranasal hair alopecia, scarring alopecia (central centrifugal   -260- cicatricial alopecia), nonscarriiig alopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU), ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata)), androgenetic/androgenic alopecia (AGA)/maie and female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis (hereditary hypotrichosis simplex), lichen planopilaris (frontal fibrosing alopecia), punctate palmoplanar keratoderma, erythema elevatinum diutinum (EED), neutrophilic eccrine hidradenitis, palisading neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, vitiligo including segmental viiiligo (umsegxnentai vitiligo, bisegmental vitiligo, multi segmental vitiligo) non-segmenta! vitiligo (acral, facial, or acrofacial vitiligo, eenirofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginal inflammatory vitiligo, quadriehfome"vitiligo, blue vitiligo, oebner phenomenon, vulgaris vitiligo, generalized vitiligo, universal vitiligo), mixed vitiligo/nonsegmental associated with segmental vitiligo, focal vitiligo, solitary mucosal vitiligo or vitiligo with or without leukotrieia (involvement of body hair); bullous diseases, irnrmmohullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), gestational pemphigoid, xeroderma pigmentosum; disorders of fibrosis and scarring: fibroids, hepatic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low grade scarring such as, scleroderma, increased fibrosis, keloids, post-surgical scars; wound healing, surgical scarring, radiation induced fibrosis (for example, head and neck, gastrointestinal or pulmonary), CNS scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (for example, endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjorgren's syndrome, sarcoidosis, familial Mediterranean fever, Cryopyrin associated periodic syndrome (Muckie-Weils syndrome, familial cold auto-mflammatory syndrome/familial cold uticaria TNF receptor associated periodic syndrome, neonatal-onset multisystem inflammatory disease), hyperoxia induced inflammations, reperfusion injury, postsurgical trauma, tissue injury, elevated temperature syndrome; diabetes (Type 1 diabetes, Type 11 diabetes)/ diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, Addison's   -261- disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid-·· resistance, glucose intolerance, metabolic syndrome, thyroid illness, hypophysitis; systemic immune senescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome, auioimmune thrombocytopenia, sympathetic ophthalmia; secondary hematologic(...)
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